Skip to main content

Advertisement

SpringerLink
Log in

The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease

  • Review Paper
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Mitochondrial malfunction appears to be intimately associated with age and age-related complex disorders but the precise pathological relevance of such malfunction remains unclear. Mitochondrial, and more specifically bioenergetic, malfunction is commonly encountered in cancer, degenerative disorders and aging. The identification of a mitochondrial–nuclear retrograde signaling pathway in yeast has facilitated the study of the corresponding retrograde signaling mechanisms induced in response to mitochondrial malfunction in mammals including human. Mitochondrial–nuclear crosstalk is critical for the maintenance of cellular homeostasis, and some mitochondrial DNA mutations may perturb crosstalk signaling. However, ascertaining whether mitochondrial malfunction is a cause or a consequence of disease development will be key to determining whether or not impaired crosstalk signaling is of direct pathological and hence therapeutic relevance. Here, we review what is known about the nuclear adaptive compensatory mechanisms induced in response to mitochondrial malfunction. We discuss the role of mitochondrial DNA variants in modulating the penetrance of human inherited disease caused by mutations in the nuclear genome and explore the underlying mechanisms by which they influence the retrograde response. We conclude that mitochondrial DNA variants have the potential to induce molecular signals through the mitochondrial–nuclear crosstalk mechanism, thereby promoting nuclear compensation in response to mitochondrial malfunction. The implications for the development of genetic or pharmaceutical interventions for the treatment of mitochondrial malfunction in complex disease are also explored.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Achilli A, Rengo C, Magri C, Battaglia V, Olivieri A, Scozzari R, Cruciani F, Zeviani M, Briem E, Carelli V, Moral P, Dugoujon JM, Roostalu U, Loogvali EL, Kivisild T, Bandelt HJ, Richards M, Villems R, Santachiara-Benerecetti AS, Semino O, Torroni A (2004) The molecular dissection of mtDNA haplogroup H confirms that the Franco-Cantabrian glacial refuge was a major source for the European gene pool. Am J Hum Genet 75:910–918

    CAS  PubMed Central  PubMed  Google Scholar 

  • Acin-Perez R, Salazar E, Brosel S, Yang H, Schon EA, Manfredi G (2009) Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects. EMBO Mol Med 1:392–406

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H, Birch-Machin MA, von Zglinicki T, Saretzki G (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 121:1046–1053

    CAS  PubMed  Google Scholar 

  • Arning L, Haghikia A, Taherzadeh-Fard E, Saft C, Andrich J, Pula B, Hoxtermann S, Wieczorek S, Akkad DA, Perrech M, Gold R, Epplen JT, Chan A (2010) Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease. J Mol Med (Berl) 88:431–436

    CAS  Google Scholar 

  • Arnold RS, Sun CQ, Richards JC, Grigoriev G, Coleman IM, Nelson PS, Hsieh CL, Lee JK, Xu Z, Rogatko A, Osunkoya AO, Zayzafoon M, Chung L, Petros JA (2009) Mitochondrial DNA mutation stimulates prostate cancer growth in bone stromal environment. Prostate 69:1–11

    CAS  PubMed Central  PubMed  Google Scholar 

  • Arnold RS, Sun Q, Sun CQ, Richards JC, O’Hearn S, Osunkoya AO, Wallace DC, Petros JA (2013) An inherited heteroplasmic mutation in mitochondrial gene COI in a patient with prostate cancer alters reactive oxygen, reactive nitrogen and proliferation. Biomed Res Int 2013. doi:10.1155/2013/239257

  • Bae JW, Kim DB, Choi JY, Park HJ, Lee JD, Hur DG, Bae SH, da Jung J, Lee SH, Kim UK, Lee KY (2012) Molecular and clinical characterization of the variable phenotype in Korean families with hearing loss associated with the mitochondrial A1555G mutation. PLoS One 7:e42463

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ (2007) Mitochondrial genetic background modifies breast cancer risk. Cancer Res 67:4687–4694

    CAS  PubMed  Google Scholar 

  • Ballard JW, Melvin RG (2011) Early life benefits and later life costs of a two amino acid deletion in Drosophila simulans. Evolution 65:1400–1412

    CAS  PubMed  Google Scholar 

  • Ballard JW, Melvin RG, Lazarou M, Clissold FJ, Simpson SJ (2010) Cost of a naturally occurring two-amino acid deletion in cytochrome c oxidase subunit 7A in Drosophila simulans. Am Nat 176:E98–E108

    PubMed  Google Scholar 

  • Bannwarth S, Procaccio V, Lebre AS, Jardel C, Chaussenot A, Hoarau C, Maoulida H, Charrier N, Gai X, Xie HM, Ferre M, Fragaki K, Hardy G, Mousson de Camaret B, Marlin S, Dhaenens CM, Slama A, Rocher C, Paul Bonnefont J, Rotig A, Aoutil N, Gilleron M, Desquiret-Dumas V, Reynier P, Ceresuela J, Jonard L, Devos A, Espil-Taris C, Martinez D, Gaignard P, Le Quan Sang KH, Amati-Bonneau P, Falk MJ, Florentz C, Chabrol B, Durand-Zaleski I, Paquis-Flucklinger V (2013) Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet 50:704–714

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bar F, Bochmann W, Widok A, von Medem K, Pagel R, Hirose M, Yu X, Kalies K, Konig P, Bohm R, Herdegen T, Reinicke AT, Buning J, Lehnert H, Fellermann K, Ibrahim S, Sina C (2013) Mitochondrial gene polymorphisms that protect mice from colitis. Gastroenterology 145:1055–1063

    PubMed  Google Scholar 

  • Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367:795–804

    CAS  PubMed Central  PubMed  Google Scholar 

  • Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL, Shulman GI (2007) Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56:1376–1381

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bellizzi D, D’Aquila P, Giordano M, Montesanto A, Passarino G (2012) Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics 4:17–27

    CAS  PubMed  Google Scholar 

  • Bi R, Zhang AM, Jia X, Zhang Q, Yao YG (2012) Complete mitochondrial DNA genome sequence variation of Chinese families with mutation m.3635G>A and Leber hereditary optic neuropathy. Mol Vis 18:3087–3094

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bodzioch M, Lapicka-Bodzioch K, Zapala B, Kamysz W, Kiec-Wilk B, Dembinska-Kiec A (2009) Evidence for potential functionality of nuclearly-encoded humanin isoforms. Genomics 94:247–256

    CAS  PubMed  Google Scholar 

  • Bonaiti B, Olsson M, Hellman U, Suhr O, Bonaiti-Pellie C, Plante-Bordeneuve V (2010) TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance? Eur J Hum Genet 18:948–952

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bonnen PE, Yarham JW, Besse A, Wu P, Faqeih EA, Al-Asmari AM, Saleh MA, Eyaid W, Hadeel A, He L, Smith F, Yau S, Simcox EM, Miwa S, Donti T, Abu-Amero KK, Wong LJ, Craigen WJ, Graham BH, Scott KL, McFarland R, Taylor RW (2013) Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. Am J Hum Genet 93:471–481

    CAS  PubMed Central  PubMed  Google Scholar 

  • Braidy N, Gai WP, Xu YH, Sachdev P, Guillemin GJ, Jiang XM, Ballard JW, Horan MP, Fang ZM, Chong BH, Chan DK (2013a) Uptake and mitochondrial dysfunction of alpha-synuclein in human astrocytes, cortical neurons and fibroblasts. Transl Neurodegener 2:20

    PubMed Central  PubMed  Google Scholar 

  • Braidy N, Gai WP, Xu YH, Sachdev P, Guillemin GJ, Jiang XM, Ballard JW, Horan MP, Fang ZM, Chong BH, Chan DK (2013b) Alpha-synuclein transmission and mitochondrial toxicity in primary human foetal enteric neurons in vitro. Neurotox Res (in press)

  • Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951–957

    CAS  PubMed Central  PubMed  Google Scholar 

  • Burgess DJ (2013) Disease genetics: double danger from mitochondrial mutations. Nat Rev Genet 14:678–679

    Google Scholar 

  • Burgstaller JP, Schinogl P, Dinnyes A, Muller M, Steinborn R (2007) Mitochondrial DNA heteroplasmy in ovine fetuses and sheep cloned by somatic cell nuclear transfer. BMC Dev Biol 7:141

    PubMed Central  PubMed  Google Scholar 

  • Butow RA, Docherty R, Parikh VS (1988) A path from mitochondria to the yeast nucleus. Philos Trans R Soc Lond B Biol Sci 319:127–133

    CAS  PubMed  Google Scholar 

  • Cannon MV, Dunn DA, Irwin MH, Brooks AI, Bartol FF, Trounce IA, Pinkert CA (2011) Xenomitochondrial mice: investigation into mitochondrial compensatory mechanisms. Mitochondrion 11:33–39

    CAS  PubMed Central  PubMed  Google Scholar 

  • Celotto AM, Chiu WK, Van Voorhies W, Palladino MJ (2011) Modes of metabolic compensation during mitochondrial disease using the Drosophila model of ATP6 dysfunction. PLoS One 6:e25823

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chae S, Ahn BY, Byun K, Cho YM, Yu MH, Lee B, Hwang D, Park KS (2013) A systems approach for decoding mitochondrial retrograde signaling pathways. Sci Signal 6:rs4

    PubMed  Google Scholar 

  • Chang CJ, Yin PH, Yang DM, Wang CH, Hung WY, Chi CW, Wei YH, Lee HC (2009) Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell Mol Life Sci 66:1755–1765

    CAS  PubMed  Google Scholar 

  • Chen EI (2012) Mitochondrial dysfunction and cancer metastasis. J Bioenerg Biomembr 44:619–622

    CAS  PubMed  Google Scholar 

  • Chen LY, Zhang Y, Zhang Q, Li H, Luo Z, Fang H, Kim SH, Qin L, Yotnda P, Xu J, Tu BP, Bai Y, Songyang Z (2012) Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell 47:839–850

    CAS  PubMed Central  PubMed  Google Scholar 

  • Choi SJ, Kim SH, Kang HY, Lee J, Bhak JH, Sohn I, Jung SH, Choi YS, Kim HK, Han J, Huh N, Lee G, Kim BC, Kim J (2011) Mutational hotspots in the mitochondrial genome of lung cancer. Biochem Biophys Res Commun 407:23–27

    CAS  PubMed  Google Scholar 

  • Civitarese AE, Ukropcova B, Carling S, Hulver M, DeFronzo RA, Mandarino L, Ravussin E, Smith SR (2006) Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 4:75–87

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clay Montier LL, Deng JJ, Bai Y (2009) Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics 36:125–131

    PubMed  Google Scholar 

  • Collerton J, Ashok D, Martin-Ruiz C, Pyle A, Hudson G, Yadegarfar M, Davies K, Jagger C, von Zglinicki T, Kirkwood TB, Chinnery PF (2013) Frailty and mortality are not influenced by mitochondrial DNA haplotypes in the very old. Neurobiol Aging 34(2889):e1–e4

    PubMed  Google Scholar 

  • Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760–764

    CAS  PubMed  Google Scholar 

  • Copeland WC (2008) Inherited mitochondrial diseases of DNA replication. Annu Rev Med 59:131–146

    CAS  PubMed Central  PubMed  Google Scholar 

  • Coskun P, Wyrembak J, Schriner SE, Chen HW, Marciniack C, Laferla F, Wallace DC (2012) A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta 1820:553–564

    CAS  PubMed Central  PubMed  Google Scholar 

  • Courtenay MD, Gilbert JR, Jiang L, Cummings AC, Gallins PJ, Caywood L, Reinhart-Mercer L, Fuzzell D, Knebusch C, Laux R, McCauley JL, Jackson CE, Pericak-Vance MA, Haines JL, Scott WK (2012) Mitochondrial haplogroup X is associated with successful aging in the Amish. Hum Genet 131:201–208

    PubMed  Google Scholar 

  • Cronin-Furman EN, Borland MK, Bergquist KE, Bennett JP Jr, Trimmer PA (2013) Mitochondrial quality, dynamics and functional capacity in Parkinson’s disease cybrid cell lines selected for Lewy body expression. Mol Neurodegener 8:6

    CAS  PubMed Central  PubMed  Google Scholar 

  • Crovetto F, Lattuada D, Rossi G, Mangano S, Somigliana E, Bolis G, Fedele L (2013) A role for mitochondria in gestational diabetes mellitus? Gynecol Endocrinol 29:259–262

    CAS  PubMed  Google Scholar 

  • Cui H, Huang P, Wang Z, Zhang Y, Zhang Z, Xu W, Wang X, Han Y, Guo X (2013) Association of decreased mitochondrial DNA content with the progression of colorectal cancer. BMC Cancer 13:110

    CAS  PubMed Central  PubMed  Google Scholar 

  • D’Aurelio M, Vives-Bauza C, Davidson MM, Manfredi G (2010) Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cells. Hum Mol Genet 19:374–386

    PubMed Central  PubMed  Google Scholar 

  • Dai Y, Kiselak T, Clark J, Clore E, Zheng K, Cheng A, Kujoth GC, Prolla TA, Maratos-Flier E, Simon DK (2013) Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice. Mitochondrion 13:282–291

    CAS  PubMed  Google Scholar 

  • Damiano M, Diguet E, Malgorn C, D’Aurelio M, Galvan L, Petit F, Benhaim L, Guillermier M, Houitte D, Dufour N, Hantraye P, Canals JM, Alberch J, Delzescaux T, Deglon N, Beal MF, Brouillet E (2013) A role of mitochondrial complex II defects in genetic models of Huntington’s disease expressing N-terminal fragments of mutant huntingtin. Hum Mol Genet 22:3869–3882

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dato S, Crocco P, D’Aquila P, de Rango F, Bellizzi D, Rose G, Passarino G (2013) Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity. Int J Mol Sci 14:16443–16472

    CAS  PubMed Central  PubMed  Google Scholar 

  • de Moura MB, dos Santos LS, Van Houten B (2010) Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 51:391–405

    PubMed  Google Scholar 

  • De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N (2003) Lamin A truncation in Hutchinson-Gilford progeria. Science 300:2055

    PubMed  Google Scholar 

  • De Smet C, Lurquin C, Lethe B, Martelange V, Boon T (1999) DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol 19:7327–7335

    PubMed Central  PubMed  Google Scholar 

  • Dhillon VS, Fenech M (2013) Mutations that affect mitochondrial functions and their association with neurodegenerative diseases. Mutat Res. doi:10.1016/j.mrrev.2013.09.001

  • Dickinson A, Yeung KY, Donoghue J, Baker MJ, Kelly RD, McKenzie M, Johns TG, St John JC (2013) The regulation of mitochondrial DNA copy number in glioblastoma cells. Cell Death Differ 20:1644–1653

    Google Scholar 

  • DiMauro S, Schon EA, Carelli V, Hirano M (2013) The clinical maze of mitochondrial neurology. Nat Rev Neurol 9:429–444

    CAS  PubMed  Google Scholar 

  • Ding Y, Xia B, Yu J, Leng J, Huang J (2013) Mitochondrial DNA mutations and essential hypertension. Int J Mol Med 32:768–774

    CAS  PubMed  Google Scholar 

  • Dubec SJ, Aurora R, Zassenhaus HP (2008) Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release. Rejuvenation Res 11:611–619

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dunn DA, Cannon MV, Irwin MH, Pinkert CA (2012) Animal models of human mitochondrial DNA mutations. Biochim Biophys Acta 1820:601–607

    CAS  PubMed Central  PubMed  Google Scholar 

  • Duno M, Wibrand F, Baggesen K, Rosenberg T, Kjaer N, Frederiksen AL (2013) A novel mitochondrial mutation m.8989G>C associated with neuropathy, ataxia, retinitis pigmentosa—the NARP syndrome. Gene 515:372–375

    CAS  PubMed  Google Scholar 

  • Dupuis L (2013) Mitochondrial quality control in neurodegenerative diseases. Biochimie. doi:10.1016/j.biochi.2013.07.033

  • Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144:79–91

    CAS  PubMed Central  PubMed  Google Scholar 

  • Echaniz-Laguna A, Chassagne M, Ceresuela J, Rouvet I, Padet S, Acquaviva C, Nataf S, Vinzio S, Bozon D, de Mousson Camaret B (2012) Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy. J Med Genet 49:146–150

    CAS  PubMed  Google Scholar 

  • Ehrlich M (2009) DNA hypomethylation in cancer cells. Epigenomics 1:239–259

    CAS  PubMed Central  PubMed  Google Scholar 

  • Eid T (2013) A one-two punch for aging and brain malformations. Sci Transl Med 5:206ec166

    Google Scholar 

  • El-Hattab AW, Scaglia F (2013) Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics 10:186–198

    CAS  PubMed  Google Scholar 

  • Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF (2008) Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83:254–260

    CAS  PubMed Central  PubMed  Google Scholar 

  • Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298

    CAS  PubMed  Google Scholar 

  • Feldhaus P, Fraga DB, Ghedim FV, De Luca RD, Bruna TD, Heluany M, Matos MP, Ferreira GK, Jeremias IC, Heluany C, Streck EL, Zugno AI (2011) Evaluation of respiratory chain activity in lymphocytes of patients with Alzheimer disease. Metab Brain Dis 26:229–236

    CAS  PubMed  Google Scholar 

  • Fernandez-Caggiano M, Barallobre-Barreiro J, Rego-Perez I, Crespo-Leiro MG, Paniagua MJ, Grille Z, Blanco FJ, Domenech N (2012) Mitochondrial haplogroups H and J: risk and protective factors for ischemic cardiomyopathy. PLoS One 7:e44128

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fernandez-Caggiano M, Barallobre-Barreiro J, Rego-Perez I, Crespo-Leiro MG, Paniagua MJ, Grille Z, Blanco FJ, Domenech N (2013) Mitochondrial DNA haplogroup H as a risk factor for idiopathic dilated cardiomyopathy in Spanish population. Mitochondrion 13:263–268

    CAS  PubMed  Google Scholar 

  • Fernandez-Moreno M, Tamayo M, Soto-Hermida A, Mosquera A, Oreiro N, Fernandez-Lopez C, Fernandez JL, Rego-Perez I, Blanco FJ (2011) mtDNA haplogroup J modulates telomere length and nitric oxide production. BMC Musculoskelet Disord 12:283

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fernandez-Vizarra E, Enriquez JA, Perez-Martos A, Montoya J, Fernandez-Silva P (2011) Tissue-specific differences in mitochondrial activity and biogenesis. Mitochondrion 11:207–213

    CAS  PubMed  Google Scholar 

  • Fetterman JL, Zelickson BR, Johnson LW, Moellering DR, Westbrook DG, Pompilius M, Sammy MJ, Johnson M, Dunham-Snary KJ, Cao X, Bradley WE, Zhang J, Wei CC, Chacko B, Schurr TG, Kesterson RA, Dell’italia LJ, Darley-Usmar VM, Welch DR, Ballinger SW (2013) Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochem J 455:157–167

    CAS  PubMed  Google Scholar 

  • Finsterer J, Ahting U (2013) Mitochondrial depletion syndromes in children and adults. Can J Neurol Sci 40:635–644

    PubMed  Google Scholar 

  • Formentini L, Sanchez-Arago M, Sanchez-Cenizo L, Cuezva JM (2012) The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell 45:731–742

    CAS  PubMed  Google Scholar 

  • Gill T, Levine AD (2013) Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction. J Biol Chem 288:26246–26255

    CAS  PubMed  Google Scholar 

  • Gomez-Duran A, Pacheu-Grau D, Martinez-Romero I, Lopez-Gallardo E, Lopez-Perez MJ, Montoya J, Ruiz-Pesini E (2012) Oxidative phosphorylation differences between mitochondrial DNA haplogroups modify the risk of Leber’s hereditary optic neuropathy. Biochim Biophys Acta 1822:1216–1222

    CAS  PubMed  Google Scholar 

  • Gouspillou G, Bourdel-Marchasson I, Rouland R, Calmettes G, Biran M, Deschodt-Arsac V, Miraux S, Thiaudiere E, Padois P, Detaille D, Franconi JM, Babot M, Trezeguet V, Arsac L, Diolez P (2013) Mitochondrial energetics is impaired in vivo in aged skeletal muscle. Aging Cell. doi:1111/acel.12147

  • Gu X, Yao Y, Wu G, Lv T, Luo L, Song Y (2013) The plasma mitochondrial DNA is an independent predictor for post-traumatic systemic inflammatory response syndrome. PLoS One 8:e72834

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guardado-Estrada M, Medina-Martinez I, Juarez-Torres E, Roman-Bassaure E, Macias L, Alfaro A, Alcantara-Vazquez A, Alonso P, Gomez G, Cruz-Talonia F, Serna L, Munoz-Cortez S, Borges-Ibanez M, Espinosa A, Kofman S, Berumen J (2012) The Amerindian mtDNA haplogroup B2 enhances the risk of HPV for cervical cancer: de-regulation of mitochondrial genes may be involved. J Hum Genet 57:269–276

    CAS  PubMed  Google Scholar 

  • Guarente L (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guha M, Avadhani NG (2013) Mitochondrial Retrograde Signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion 13:577–591

    CAS  PubMed  Google Scholar 

  • Guha M, Tang W, Sondheimer N, Avadhani NG (2010) Role of calcineurin, hnRNPA2 and Akt in mitochondrial respiratory stress-mediated transcription activation of nuclear gene targets. Biochim Biophys Acta 1797:1055–1065

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423:456–461

    CAS  PubMed  Google Scholar 

  • Guo Z, Yang H, Wang C, Liu S (2012) Mitochondrial DNA haplogroup M is associated with late onset of hepatocellular carcinoma. Exp Ther Med 3:499–502

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guo W, Zheng B, Cai Z, Xu L, Guo D, Cao L, Wang Y (2013) The polymorphic AluYb8 insertion in the MUTYH gene is associated with reduced type 1 protein expression and reduced mitochondrial DNA content. PLoS One 8:e70718

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gupta S, De S, Srivastava V, Hussain M, Kumari J, Muniyappa K, Sengupta S (2013) RECQL4 and p53 potentiate the activity of polymerase gamma and maintain the integrity of the human mitochondrial genome. Carcinogenesis (in press)

  • Gutierrez Cortes N, Pertuiset C, Dumon E, Borlin M, Hebert-Chatelain E, Pierron D, Feldmann D, Jonard L, Marlin S, Letellier T, Rocher C (2012) Novel mitochondrial DNA mutations responsible for maternally inherited nonsyndromic hearing loss. Hum Mutat 33:681–689

    CAS  PubMed  Google Scholar 

  • Haendeler J, Drose S, Buchner N, Jakob S, Altschmied J, Goy C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 29:929–935

    CAS  PubMed  Google Scholar 

  • Hagen CM, Aidt FH, Hedley PL, Jensen MK, Havndrup O, Kanters JK, Moolman-Smook JC, Larsen SO, Bundgaard H, Christiansen M (2013) Mitochondrial haplogroups modify the risk of developing hypertrophic cardiomyopathy in a Danish population. PLoS One 8:e71904

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hannah-Shmouni F, Sirrs S, Mezei MM, Waters PJ, Mattman A (2013) Increased prevalence of hypertension in young adults with high heteroplasmy levels of the MELAS m.3243A>G mutation. JIMD Rep (in press)

  • Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I (2001) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci USA 98:6336–6341

    CAS  PubMed Central  PubMed  Google Scholar 

  • He SL, Tan WH, Zhang ZT, Zhang F, Qu CJ, Lei YX, Zhu YH, Yu HJ, Xiang YZ, Guo X (2013) Mitochondrial-related gene expression profiles suggest an important role of PGC-1alpha in the compensatory mechanism of endemic dilated cardiomyopathy. Exp Cell Res 319:2604–2616

    CAS  PubMed  Google Scholar 

  • Helbling D, Buchaklian A, Wang J, Wong LJ, Dimmock D (2013) Reduced mitochondrial DNA content and heterozygous nuclear gene mutations in patients with acute liver failure. J Pediatr Gastroenterol Nutr 57:438–443

    CAS  PubMed  Google Scholar 

  • Hiona A, Sanz A, Kujoth GC, Pamplona R, Seo AY, Hofer T, Someya S, Miyakawa T, Nakayama C, Samhan-Arias AK, Servais S, Barger JL, Portero-Otin M, Tanokura M, Prolla TA, Leeuwenburgh C (2010) Mitochondrial DNA mutations induce mitochondrial dysfunction, apoptosis and sarcopenia in skeletal muscle of mitochondrial DNA mutator mice. PLoS One 5:e11468

    PubMed Central  PubMed  Google Scholar 

  • Horan MP, Gemmell NJ, Wolff JN (2013a) From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression. Eur J Hum Genet 21:1335–1337

    Google Scholar 

  • Horan MP, Rumbley JN, Melvin RG, Le Couteur DG, Ballard JW (2013b) Quaternary protein modeling to predict the function of DNA variation found in human mitochondrial cytochrome c oxidase. J Hum Genet 58:127–134

    CAS  PubMed  Google Scholar 

  • Horvath R, Holinski-Feder E, Neeve VC, Pyle A, Griffin H, Ashok D, Foley C, Hudson G, Rautenstrauss B, Nurnberg G, Nurnberg P, Kortler J, Neitzel B, Bassmann I, Rahman T, Keavney B, Loughlin J, Hambleton S, Schoser B, Lochmuller H, Santibanez-Koref M, Chinnery PF (2012) A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy. Mov Disord 27:789–793

    CAS  PubMed  Google Scholar 

  • Hosgood HD 3rd, Liu CS, Rothman N, Weinstein SJ, Bonner MR, Shen M, Lim U, Virtamo J, Cheng WL, Albanes D, Lan Q (2010) Mitochondrial DNA copy number and lung cancer risk in a prospective cohort study. Carcinogenesis 31:847–849

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hu J, Hwang SS, Liesa M, Gan B, Sahin E, Jaskelioff M, Ding Z, Ying H, Boutin AT, Zhang H, Johnson S, Ivanova E, Kost-Alimova M, Protopopov A, Wang YA, Shirihai OS, Chin L, DePinho RA (2012) Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell 148:651–663

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hung WY, Wu CW, Yin PH, Chang CJ, Li AF, Chi CW, Wei YH, Lee HC (2010) Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim Biophys Acta 1800:264–270

    CAS  PubMed  Google Scholar 

  • Hwang S, Kwak SH, Bhak J, Kang HS, Lee YR, Koo BK, Park KS, Lee HK, Cho YM (2011) Gene expression pattern in transmitochondrial cytoplasmic hybrid cells harboring type 2 diabetes-associated mitochondrial DNA haplogroups. PLoS One 6:e22116

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P (2003) Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci USA 100:13042–13047

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664

    CAS  PubMed  Google Scholar 

  • Jin YN, Yu YV, Gundemir S, Jo C, Cui M, Tieu K, Johnson GV (2013) Impaired mitochondrial dynamics and Nrf2 signaling contribute to compromised responses to oxidative stress in striatal cells expressing full-length mutant huntingtin. PLoS One 8:e57932

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070

    CAS  PubMed  Google Scholar 

  • Jones MM, Manwaring N, Wang JJ, Rochtchina E, Mitchell P, Sue CM (2007) Mitochondrial DNA haplogroups and age-related maculopathy. Arch Ophthalmol 125:1235–1240

    PubMed  Google Scholar 

  • Jones AW, Yao Z, Vicencio JM, Karkucinska-Wieckowska A, Szabadkai G (2012) PGC-1 family coactivators and cell fate: roles in cancer, neurodegeneration, cardiovascular disease and retrograde mitochondria-nucleus signalling. Mitochondrion 12:86–99

    CAS  PubMed  Google Scholar 

  • Joseph AM, Adhihetty PJ, Wawrzyniak NR, Wohlgemuth SE, Picca A, Kujoth GC, Prolla TA, Leeuwenburgh C (2013) Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS One 8:e69327

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jung HJ, Kim Y, Chang J, Kang SW, Kim JH, Kwon HJ (2013) Mitochondrial UQCRB regulates VEGFR2 signaling in endothelial cells. J Mol Med (Berl) 91:1117–1128

    CAS  Google Scholar 

  • Kabekkodu SP, Bhat S, Mascarenhas R, Mallya S, Bhat M, Pandey D, Kushtagi P, Thangaraj K, Gopinath PM, Satyamoorthy K (2013) Mitochondrial DNA variation analysis in cervical cancer. Mitochondrion. doi:10.1016/j.mito.2013.07.001

  • Kaipparettu BA, Ma Y, Park JH, Lee TL, Zhang Y, Yotnda P, Creighton CJ, Chan WY, Wong LJ (2013) Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways. PLoS One 8:e61747

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kao LP, Ovchinnikov D, Wolvetang E (2012) The effect of ethidium bromide and chloramphenicol on mitochondrial biogenesis in primary human fibroblasts. Toxicol Appl Pharmacol 261:42–49

    CAS  PubMed  Google Scholar 

  • Kelley DE, He J, Menshikova EV, Ritov VB (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51:2944–2950

    CAS  PubMed  Google Scholar 

  • Kelly RD, Mahmud A, McKenzie M, Trounce IA, St John JC (2012a) Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A. Nucleic Acids Res 40:10124–10138

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kelly RD, Rodda AE, Dickinson A, Mahmud A, Nefzger CM, Lee W, Forsythe JS, Polo JM, Trounce IA, McKenzie M, Nisbet DR, St John JC (2012b) Mitochondrial DNA haplotypes define gene expression patterns in pluripotent and differentiating embryonic stem cells. Stem Cells 31:703–716

    Google Scholar 

  • Kennedy SR, Salk JJ, Schmitt MW, Loeb LA (2013) Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 9:e1003794

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kenney MC, Chwa M, Atilano SR, Pavlis JM, Falatoonzadeh P, Ramirez C, Malik D, Hsu T, Woo G, Soe K, Nesburn AB, Boyer DS, Kuppermann BD, Jazwinski SM, Miceli MV, Wallace DC, Udar N (2013a) Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration. PLoS One 8:e54339

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kenney MC, Hertzog D, Chak G, Atilano SR, Khatibi N, Soe K, Nobe A, Yang E, Chwa M, Zhu F, Memarzadeh M, King J, Langberg J, Small K, Nesburn AB, Boyer DS, Udar N (2013b) Mitochondrial DNA haplogroups confer differences in risk for age-related macular degeneration: a case control study. BMC Med Genet 14:4

    CAS  PubMed Central  PubMed  Google Scholar 

  • Keogh M, Chinnery PF (2013) Hereditary mtDNA heteroplasmy: a baseline for aging? Cell Metab 18:463–464

    CAS  PubMed  Google Scholar 

  • Khan NA, Govindaraj P, Jyothi V, Meena AK, Thangaraj K (2013a) Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy. Mol Vis 19:1282–1289

    CAS  PubMed Central  PubMed  Google Scholar 

  • Khan NA, Govindaraj P, Soumittra N, Srilekha S, Ambika S, Vanniarajan A, Meena AK, Uppin MS, Sundaram C, Taly AB, Bindu PS, Gayathri N, Thangaraj K (2013b) Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India. Invest Ophthalmol Vis Sci 54:3999–4005

    CAS  PubMed  Google Scholar 

  • Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim do H, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS (2013) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19:83–92

    CAS  PubMed  Google Scholar 

  • King H, Aubert RE, Herman WH (1998) Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21:1414–1431

    CAS  PubMed  Google Scholar 

  • Klaunig JE, Kamendulis LM (2004) The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44:239–267

    CAS  PubMed  Google Scholar 

  • Koczor CA, Torres RA, Fields EJ, Boyd A, He S, Patel N, Lee EK, Samarel AM, Lewis W (2013) Thymidine kinase and mtDNA depletion in human cardiomyopathy: epigenetic and translational evidence for energy starvation. Physiol Genomics 45:590–596

    CAS  PubMed  Google Scholar 

  • Kohlhaas M, Maack C (2013) Calcium release microdomains and mitochondria. Cardiovasc Res 98:259–268

    CAS  PubMed  Google Scholar 

  • Kornblum C, Nicholls TJ, Haack TB, Scholer S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk M, Kunz WS, Prokisch H (2013) Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet 45:214–219

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA (2005) Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309:481–484

    CAS  PubMed  Google Scholar 

  • Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK (2008) Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 68:1777–1785

    CAS  PubMed  Google Scholar 

  • Kumar M, Tanwar M, Faiq MA, Pani J, Shamsi MB, Dada T, Dada R (2013) Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients. Mol Vis 19:220–230

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kumarasamy S, Gopalakrishnan K, Abdul-Majeed S, Partow-Navid R, Farms P, Joe B (2013) Construction of two novel reciprocal conplastic rat strains and characterization of cardiac mitochondria. Am J Physiol Heart Circ Physiol 304:H22–H32

    CAS  PubMed Central  PubMed  Google Scholar 

  • Laberge RM, Adler D, DeMaria M, Mechtouf N, Teachenor R, Cardin GB, Desprez PY, Campisi J, Rodier F (2013) Mitochondrial DNA damage induces apoptosis in senescent cells. Cell Death Dis 4:e727

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lan Q, Lim U, Liu CS, Weinstein SJ, Chanock S, Bonner MR, Virtamo J, Albanes D, Rothman N (2008) A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood 112:4247–4249

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lando D, Gorman JJ, Whitelaw ML, Peet DJ (2003) Oxygen-dependent regulation of hypoxia-inducible factors by prolyl and asparaginyl hydroxylation. Eur J Biochem 270:781–790

    CAS  PubMed  Google Scholar 

  • Larsson NG (2010) Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem 79:683–706

    CAS  PubMed  Google Scholar 

  • Lee HC, Chang CM, Chi CW (2010) Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 9(Suppl 1):S47–S58

    CAS  PubMed  Google Scholar 

  • Lee HS, Ma H, Juanes RC, Tachibana M, Sparman M, Woodward J, Ramsey C, Xu J, Kang EJ, Amato P, Mair G, Steinborn R, Mitalipov S (2012) Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Rep 1:506–515

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee C, Yen K, Cohen P (2013) Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab 24:222–228

    CAS  PubMed  Google Scholar 

  • Lerner C, Bitto A, Pulliam D, Nacarelli T, Konigsberg M, Van Remmen H, Torres C, Sell C (2013) Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. Aging Cell 12:966–977

    Google Scholar 

  • Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lin TK, Lin HY, Chen SD, Chuang YC, Chuang JH, Wang PW, Huang ST, Tiao MM, Chen JB, Liou CW (2012) The creation of cybrids harboring mitochondrial haplogroups in the Taiwanese population of ethnic Chinese background: an extensive in vitro tool for the study of mitochondrial genomic variations. Oxid Med Cell Longev 2012:824275

    PubMed Central  PubMed  Google Scholar 

  • Ling X, Wen L, Zhou Y (2012) Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance. Int J Med Sci 9:545–554

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Z, Butow RA (2006) Mitochondrial retrograde signaling. Annu Rev Genet 40:159–185

    CAS  PubMed  Google Scholar 

  • Liu T, Liu PY, Marshall GM (2009) The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res 69:1702–1705

    CAS  PubMed  Google Scholar 

  • Lloyd RE, McGeehan JE (2013) Structural analysis of mitochondrial mutations reveals a role for bigenomic protein interactions in human disease. PLoS One 8:e69003

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lopez-Gallardo E, Solano A, Herrero-Martin MD, Martinez-Romero I, Castano-Perez MD, Andreu AL, Herrera A, Lopez-Perez MJ, Ruiz-Pesini E, Montoya J (2009) NARP syndrome in a patient harbouring an insertion in the MT-ATP6 gene that results in a truncated protein. J Med Genet 46:64–67

    CAS  PubMed  Google Scholar 

  • Lopez-Lluch G, Irusta PM, Navas P, de Cabo R (2008) Mitochondrial biogenesis and healthy aging. Exp Gerontol 43:813–819

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lynch SM, Weinstein SJ, Virtamo J, Lan Q, Liu CS, Cheng WL, Rothman N, Albanes D, Stolzenberg-Solomon RZ (2011) Mitochondrial DNA copy number and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention study. Cancer Prev Res (Phila) 4:1912–1919

    CAS  Google Scholar 

  • Maechler P (2013) Mitochondrial function and insulin secretion. Mol Cell Endocrinol 379:12–18

    CAS  PubMed  Google Scholar 

  • Martinez-Reyes I, Sanchez-Arago M, Cuezva JM (2012) AMPK and GCN2-ATF4 signal the repression of mitochondria in colon cancer cells. Biochem J 444:249–259

    CAS  PubMed  Google Scholar 

  • Marzetti E, Calvani R, Cesari M, Buford TW, Lorenzi M, Behnke BJ, Leeuwenburgh C (2013) Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials. Int J Biochem Cell Biol 45:2288–2301

    CAS  PubMed  Google Scholar 

  • Maybury BD (2013) Mitochondrial DNA damage is uncommon in cancer but can promote aggressive behaviour. Anticancer Res 33:3543–3552

    CAS  PubMed  Google Scholar 

  • McLean AJ, Le Couteur DG (2004) Aging biology and geriatric clinical pharmacology. Pharmacol Rev 56:163–184

    CAS  PubMed  Google Scholar 

  • Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood AM, Haugen E, Bracken CP, Rackham O, Stamatoyannopoulos JA, Filipovska A, Mattick JS (2011) The human mitochondrial transcriptome. Cell 146:645–658

    CAS  PubMed Central  PubMed  Google Scholar 

  • Minocherhomji S, Tollefsbol TO, Singh KK (2012) Mitochondrial regulation of epigenetics and its role in human diseases. Epigenetics 7:326–334

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mito T, Kikkawa Y, Shimizu A, Hashizume O, Katada S, Imanishi H, Ota A, Kato Y, Nakada K, Hayashi J (2013) Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development. PLoS One 8:e55789

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mondal R, Ghosh SK, Choudhury JH, Seram A, Sinha K, Hussain M, Laskar RS, Rabha B, Dey P, Ganguli S, Nathchoudhury M, Talukdar FR, Chaudhuri B, Dhar B (2013) Mitochondrial DNA copy number and risk of oral cancer: a report from Northeast India. PLoS One 8:e57771

    CAS  PubMed Central  PubMed  Google Scholar 

  • Monnot S, Samuels DC, Hesters L, Frydman N, Gigarel N, Burlet P, Kerbrat V, Lamazou F, Frydman R, Benachi A, Feingold J, Rotig A, Munnich A, Bonnefont JP, Steffann J (2013) Mutation dependance of the mitochondrial DNA copy number in the first stages of human embryogenesis. Hum Mol Genet 22:1867–1872

    CAS  PubMed  Google Scholar 

  • Moreno-Loshuertos R, Ferrin G, Acin-Perez R, Gallardo ME, Viscomi C, Perez-Martos A, Zeviani M, Fernandez-Silva P, Enriquez JA (2011) Evolution meets disease: penetrance and functional epistasis of mitochondrial tRNA mutations. PLoS Genet 7:e1001379

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller EE, Brunner SM, Mayr JA, Stanger O, Sperl W, Kofler B (2012a) Functional differences between mitochondrial haplogroup T and haplogroup H in HEK293 cybrid cells. PLoS One 7:e52367

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mueller EE, Schaier E, Brunner SM, Eder W, Mayr JA, Egger SF, Nischler C, Oberkofler H, Reitsamer HA, Patsch W, Sperl W, Kofler B (2012b) Mitochondrial haplogroups and control region polymorphisms in age-related macular degeneration: a case-control study. PLoS One 7:e30874

    CAS  PubMed Central  PubMed  Google Scholar 

  • Muller-Hocker J, Horvath R, Schafer S, Hessel H, Muller-Felber W, Kuhr J, Copeland WC, Seibel P (2011) Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase gamma (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study. J Cell Mol Med 15:445–456

    CAS  PubMed  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murphy MP (2013) Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab 18:145–146

    CAS  PubMed  Google Scholar 

  • Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, Hwang D, Barzilai N, Cohen P (2009) Humanin: a novel central regulator of peripheral insulin action. PLoS One 4:e6334

    PubMed Central  PubMed  Google Scholar 

  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389

    CAS  PubMed  Google Scholar 

  • Nardelli C, Labruna G, Liguori R, Mazzaccara C, Ferrigno M, Capobianco V, Pezzuti M, Castaldo G, Farinaro E, Contaldo F, Buono P, Sacchetti L, Pasanisi F (2013) Haplogroup T is an obesity risk factor: mitochondrial DNA haplotyping in a morbid obese population from southern Italy. Biomed Res Int 2013:631082

    PubMed Central  PubMed  Google Scholar 

  • Neeve VC, Samuels DC, Bindoff LA, van den Bosch B, Van Goethem G, Smeets H, Lombes A, Jardel C, Hirano M, Dimauro S, De Vries M, Smeitink J, Smits BW, de Coo IF, Saft C, Klopstock T, Keiling BC, Czermin B, Abicht A, Lochmuller H, Hudson G, Gorman GG, Turnbull DM, Taylor RW, Holinski-Feder E, Chinnery PF, Horvath R (2012) What is influencing the phenotype of the common homozygous polymerase-gamma mutation p.Ala467Thr? Brain 135:3614–3626

    PubMed Central  PubMed  Google Scholar 

  • Ngo JK, Pomatto LC, Davies KJ (2013) Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging. Redox Biol 1:258–264

    CAS  PubMed Central  PubMed  Google Scholar 

  • Niikura T, Tajima H, Kita Y (2006) Neuronal cell death in Alzheimer’s disease and a neuroprotective factor, humanin. Curr Neuropharmacol 4:139–147

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nishimoto I, Matsuoka M, niikura T (2004) Unravelling the role of humanin. Trends Mol Med 10:102–105

    CAS  PubMed  Google Scholar 

  • O’Hagan HM, Wang W, Sen S, Destefano Shields C, Lee SS, Zhang YW, Clements EG, Cai Y, Van Neste L, Easwaran H, Casero RA, Sears CL, Baylin SB (2011) Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 20:606–619

    PubMed Central  PubMed  Google Scholar 

  • Osellame LD, Duchen MR (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9:1633–1635

    Google Scholar 

  • Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pallardo FV, Lloret A, Lebel M, d’Ischia M, Cogger VC, Le Couteur DG, Gadaleta MN, Castello G, Pagano G (2010) Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down syndrome, Fanconi anaemia and Werner syndrome. Biogerontology 11:401–419

    CAS  PubMed  Google Scholar 

  • Palmieri L, Alberio S, Pisano I, Lodi T, Meznaric-Petrusa M, Zidar J, Santoro A, Scarcia P, Fontanesi F, Lamantea E, Ferrero I, Zeviani M (2005) Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy. Hum Mol Genet 14:3079–3088

    CAS  PubMed  Google Scholar 

  • Parikh VS, Morgan MM, Scott R, Clements LS, Butow RA (1987) The mitochondrial genotype can influence nuclear gene expression in yeast. Science 235:576–580

    CAS  PubMed  Google Scholar 

  • Park TY, Kim SH, Shin YC, Lee NH, Lee RK, Shim JH, Glimcher LH, Mook-Jung I, Cheong E, Kim WK, Honda F, Morio T, Lim JS, Lee SK (2013) Amelioration of neurodegenerative diseases by cell death-induced cytoplasmic delivery of humanin. J Control Release 166:307–315

    CAS  PubMed  Google Scholar 

  • Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35:7505–7513

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pello R, Martin MA, Carelli V, Nijtmans LG, Achilli A, Pala M, Torroni A, Gomez-Duran A, Ruiz-Pesini E, Martinuzzi A, Smeitink JA, Arenas J, Ugalde C (2008) Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet 17:4001–4011

    CAS  PubMed  Google Scholar 

  • Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, Koomen J, Chen J, Lane WS, Seto E (2011) SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol 31:4720–4734

    CAS  PubMed Central  PubMed  Google Scholar 

  • Peng YZ, Wang YW, Ning D, Guo YM (2013) Changes of haematic parameters, redox status and mitochondrial complex activity in the heart and liver of broilers fed with different density diets under low ambient temperature. Avian Pathol 42:327–334

    CAS  PubMed  Google Scholar 

  • Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671

    CAS  PubMed Central  PubMed  Google Scholar 

  • Petersen KF, Dufour S, Shulman GI (2005) Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med 2:e233

    PubMed Central  PubMed  Google Scholar 

  • Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, Mudanohwo EE, Hargreaves I, Heales S, Land J, Holton JL, Houlden H, Blake J, Champion M, Flinter F, Robb SA, Page R, Rose M, Palace J, Crowe C, Longman C, Lunn MP, Rahman S, Reilly MM, Hanna MG (2012a) Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology 79:1145–1154

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pitceathly RD, Smith C, Fratter C, Alston CL, He L, Craig K, Blakely EL, Evans JC, Taylor J, Shabbir Z, Deschauer M, Pohl U, Roberts ME, Jackson MC, Halfpenny CA, Turnpenny PD, Lunt PW, Hanna MG, Schaefer AM, McFarland R, Horvath R, Chinnery PF, Turnbull DM, Poulton J, Taylor RW, Gorman GS (2012b) Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain 135:3392–3403

    PubMed Central  PubMed  Google Scholar 

  • Purdue MP, Hofmann JN, Colt JS, Hoxha M, Ruterbusch JJ, Davis FG, Rothman N, Wacholder S, Schwartz KL, Baccarelli A, Chow WH (2012) A case-control study of peripheral blood mitochondrial DNA copy number and risk of renal cell carcinoma. PLoS One 7:e43149

    CAS  PubMed Central  PubMed  Google Scholar 

  • Qu F, Liu X, Zhou F, Yang H, Bao G, He X, Xing J (2011) Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: a case-control analysis. Cancer 117:3148–3155

    CAS  PubMed  Google Scholar 

  • Rackham O, Shearwood AM, Mercer TR, Davies SM, Mattick JS, Filipovska A (2011) Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins. RNA 17:2085–2093

    CAS  PubMed Central  PubMed  Google Scholar 

  • Raimundo N, Song L, Shutt TE, McKay SE, Cotney J, Guan MX, Gilliland TC, Hohuan D, Santos-Sacchi J, Shadel GS (2012) Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148:716–726

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ramos A, Santos C, Mateiu L, Gonzalez MdM, Alvarez L et al (2013) Frequency and pattern of heteroplasmy in the complete human mitochondrial genome. PLoS One 8:e74636

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rand DM, Haney RA, Fry AJ (2004) Cytonuclear coevolution: the genomics of cooperation. Trends Ecol Evol 19:645–653

    PubMed  Google Scholar 

  • Rauch TA, Zhong X, Wu X, Wang M, Kernstine KH, Wang Z, Riggs AD, Pfeifer GP (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci USA 105:252–257

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ridge PG, Maxwell TJ, Corcoran CD, Norton MC, Tschanz JT, O’Brien E, Kerber RA, Cawthon RM, Munger RG, Kauwe JS (2012) Mitochondrial genomic analysis of late onset Alzheimer’s disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging. PLoS One 7:e45134

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ridge PG, Koop A, Maxwell TJ, Bailey MH, Swerdlow RH, Kauwe JS, Honea RA, Alzheimer’s Disease Neuroimaging Initiative (2013) Mitochondrial haplotypes associated with biomarkers for Alzheimer’s disease. PLoS One 8:e74158

    CAS  PubMed Central  PubMed  Google Scholar 

  • Rivera-Torres J, Acin-Perez R, Cabezas-Sanchez P, Osorio FG, Gonzalez-Gomez C, Megias D, Camara C, Lopez-Otin C, Enriquez JA, Luque-Garcia JL, Andres V (2013) Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labelling with amino acids in cell culture. J Proteomics 91C:466–477

    Google Scholar 

  • Ro S, Ma HY, Park C, Ortogero N, Song R, Hennig GW, Zheng H, Lin YM, Moro L, Hsieh JT, Yan W (2013) The mitochondrial genome encodes abundant small noncoding RNAs. Cell Res 23:759–774

    CAS  PubMed  Google Scholar 

  • Rodell A, Rasmussen LJ, Bergersen LH, Singh KK, Gjedde A (2013) Natural selection of mitochondria during somatic lifetime promotes healthy aging. Front Neuroenergetics 5:7

    PubMed Central  PubMed  Google Scholar 

  • Rose G, Passarino G, Scornaienchi V, Romeo G, Dato S, Bellizzi D, Mari V, Feraco E, Maletta R, Bruni A, Franceschi C, De Benedictis G (2007) The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring. BMC Genomics 8:293

    PubMed Central  PubMed  Google Scholar 

  • Ross OA, McCormack R, Curran MD, Duguid RA, Barnett YA, Rea IM, Middleton D (2001) Mitochondrial DNA polymorphism: its role in longevity of the Irish population. Exp Gerontol 36:1161–1178

    CAS  PubMed  Google Scholar 

  • Ross JM, Stewart JB, Hagstrom E, Brene S, Mourier A, Coppotelli G, Freyer C, Lagouge M, Hoffer BJ, Olson L, Larsson NG (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501:412–415

    CAS  PubMed  Google Scholar 

  • Ruiz-Pesini E, Lott MT, Procaccio V, Poole JC, Brandon MC, Mishmar D, Yi C, Kreuziger J, Baldi P, Wallace DC (2007) An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res 35:D823–D828

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sahin E, Depinho RA (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464:520–528

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, Maser RS, Tonon G, Foerster F, Xiong R, Wang YA, Shukla SA, Jaskelioff M, Martin ES, Heffernan TP, Protopopov A, Ivanova E, Mahoney JE, Kost-Alimova M, Perry SR, Bronson R, Liao R, Mulligan R, Shirihai OS, Chin L, DePinho RA (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359–365

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanchez-Arago M, Chamorro M, Cuezva JM (2010) Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis 31:567–576

    CAS  PubMed  Google Scholar 

  • Sanchez-Cenizo L, Formentini L, Aldea M, Ortega AD, Garcia-Huerta P, Sanchez-Arago M, Cuezva JM (2010) Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem 285:25308–25313

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanjuan-Pla A, Cervera AM, Apostolova N, Garcia-Bou R, Victor VM, Murphy MP, McCreath KJ (2005) A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1alpha. FEBS Lett 579:2669–2674

    CAS  PubMed  Google Scholar 

  • Santoro A, Balbi V, Balducci E, Pirazzini C, Rosini F, Tavano F, Achilli A, Siviero P, Minicuci N, Bellavista E, Mishto M, Salvioli S, Marchegiani F, Cardelli M, Olivieri F, Nacmias B, Chiamenti AM, Benussi L, Ghidoni R, Rose G, Gabelli C, Binetti G, Sorbi S, Crepaldi G, Passarino G, Torroni A, Franceschi C (2010) Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer’s disease. PLoS One 5:e12037

    PubMed Central  PubMed  Google Scholar 

  • Schagdarsurengin U, Richter AM, Hornung J, Lange C, Steinmann K, Dammann RH (2010) Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences. Mol Cancer 9:264

    PubMed Central  PubMed  Google Scholar 

  • Scheibye-Knudsen M, Scheibye-Alsing K, Canugovi C, Croteau DL, Bohr VA (2013) A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging. Aging (Albany NY) 5:192–208

    CAS  Google Scholar 

  • Schroeder EA, Raimundo N, Shadel GS (2013) Epigenetic silencing mediates mitochondria stress-induced longevity. Cell Metab 17:954–964

    CAS  PubMed  Google Scholar 

  • Selvanayagam P, Rajaraman S (1996) Detection of mitochondrial genome depletion by a novel cDNA in renal cell carcinoma. Lab Invest 74:592–599

    CAS  PubMed  Google Scholar 

  • Shen J, Platek M, Mahasneh A, Ambrosone CB, Zhao H (2010) Mitochondrial copy number and risk of breast cancer: a pilot study. Mitochondrion 10:62–68

    CAS  PubMed  Google Scholar 

  • Shidara Y, Yamagata K, Kanamori T, Nakano K, Kwong JQ, Manfredi G, Oda H, Ohta S (2005) Positive contribution of pathogenic mutations in the mitochondrial genome to the promotion of cancer by prevention from apoptosis. Cancer Res 65:1655–1663

    CAS  PubMed  Google Scholar 

  • Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shimasaki Y, Pan N, Messina LM, Li C, Chen K, Liu L, Cooper MP, Vita JA, Keaney JF Jr (2013) Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics. Circ Res 113:891–901

    CAS  PubMed  Google Scholar 

  • Sikorska M, Sandhu JK, Simon DK, Pathiraja V, Sodja C, Li Y, Ribecco-Lutkiewicz M, Lanthier P, Borowy-Borowski H, Upton A, Raha S, Pulst SM, Tarnopolsky MA (2009) Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids. Muscle Nerve 40:381–394

    CAS  PubMed  Google Scholar 

  • Silva DF, Selfridge JE, Lu J, E L, Roy N, Hutfles L, Burns JM, Michaelis EK, Yan S, Cardoso SM, Swerdlow RH (2013) Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. Hum Mol Genet 22:3931–3946

    Google Scholar 

  • Singhapol C, Pal D, Czapiewski R, Porika M, Nelson G, Saretzki GC (2013) Mitochondrial telomerase protects cancer cells from nuclear DNA damage and apoptosis. PLoS One 8:e52989

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sitarz KS, Yu-Wai-Man P, Pyle A, Stewart JD, Rautenstrauss B, Seeman P, Reilly MM, Horvath R, Chinnery PF (2012) MFN2 mutations cause compensatory mitochondrial DNA proliferation. Brain 135: e219, 1–3

    Google Scholar 

  • Smiraglia DJ, Kulawiec M, Bistulfi GL, Gupta SG, Singh KK (2008) A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 7:1182–1190

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sobenin IA, Sazonova MA, Postnov AY, Bobryshev YV, Orekhov AN (2013) Changes of mitochondria in atherosclerosis: possible determinant in the pathogenesis of the disease. Atherosclerosis 227:283–288

    CAS  PubMed  Google Scholar 

  • Strauss KA, DuBiner L, Simon M, Zaragoza M, Sengupta PP, Li P, Narula N, Dreike S, Platt J, Procaccio V, Ortiz-Gonzalez XR, Puffenberger EG, Kelley RI, Morton DH, Narula J, Wallace DC (2013) Severity of cardiomyopathy associated with adenine nucleotide translocator-1 deficiency correlates with mtDNA haplogroup. Proc Natl Acad Sci USA 110:3453–3458

    CAS  PubMed Central  PubMed  Google Scholar 

  • Su YC, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 22:4545–4561

    CAS  PubMed  Google Scholar 

  • Sun C, Chen H, Guo W, Zhang K, Qi Q, Gu X, Zhu D, Wang Y (2010) A common mutation of the MYH gene is associated with increased DNA oxidation and age-related diseases. Free Radic Biol Med 48:430–436

    CAS  PubMed  Google Scholar 

  • Suzuki S, Takei M, Ehara T, Nishio S, Inaba H, Hashizume K (2009) Atypical early onset of diabetes, deafness and lung cancer in a male patient with mitochondrial mutations in peripheral mononuclear cells. BMJ Case Rep 2009. doi:10.1136/bcr.03.2009.1648

  • Synofzik M, Schicks J, Wilhelm C, Bornemann A, Schols L (2012) Charcot-Marie-Tooth hereditary neuropathy due to a mitochondrial ATP6 mutation. Eur J Neurol 19:e114–e116

    PubMed  Google Scholar 

  • Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O, Mitalipov S (2009) Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461:367–372

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tachibana M, Amato P, Sparman M, Woodward J, Sanchis DM, Ma H, Gutierrez NM, Tippner-Hedges R, Kang E, Lee HS, Ramsey C, Masterson K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer R, Mitalipov S (2013) Towards germline gene therapy of inherited mitochondrial diseases. Nature 493:627–631

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tajima H, Niikura T, Hashimoto Y, Ito Y, Kita Y, Terashita K, Yamazaki K, Koto A, Aiso S, Nishimoto I (2002) Evidence for in vivo production of humanin peptide, a neuroprotective factor against Alzheimer’s disease-related insults. Neurosci Lett 324:227–231

    CAS  PubMed  Google Scholar 

  • Takasugi M, Yagi S, Hirabayashi K, Shiota K (2010) DNA methylation status of nuclear-encoded mitochondrial genes underlies the tissue-dependent mitochondrial functions. BMC Genomics 11:481

    PubMed Central  PubMed  Google Scholar 

  • Takibuchi G, Imanishi H, Morimoto M, Ishikawa K, Nakada K, Toyama-Sorimachi N, Kikkawa Y, Takenaga K, Hayashi JI (2013) Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype. Mitochondrion 13:881–887

    CAS  PubMed  Google Scholar 

  • Tao R, Vassilopoulos A, Parisiadou L, Yan Y, Gius D (2013) Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid Redox Signal (in press)

  • Tarnopolsky M, Meaney B, Robinson B, Sheldon K, Boles RG (2013) Severe infantile Leigh syndrome associated with a rare mitochondrial ND6 mutation, m.14487T>C. Am J Med Genet A 161A:2020–2023

    PubMed  Google Scholar 

  • Teng L, Zheng J, Leng J, Ding Y (2012) Clinical and molecular characterization of a Han Chinese family with high penetrance of essential hypertension. Mitochondrial DNA 23:461–465

    CAS  PubMed  Google Scholar 

  • Thyagarajan B, Wang R, Barcelo H, Koh WP, Yuan JM (2012) Mitochondrial copy number is associated with colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 21:1574–1581

    CAS  PubMed Central  PubMed  Google Scholar 

  • Thyagarajan B, Wang R, Nelson H, Barcelo H, Koh WP, Yuan JM (2013) Mitochondrial DNA copy number is associated with breast cancer risk. PLoS One 8:e65968

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tiao MM, Liou CW, Huang LT, Wang PW, Lin TK, Chen JB, Chou YM, Huang YH, Lin HY, Chen CL, Chuang JH (2013) Associations of mitochondrial haplogroups b4 and e with biliary atresia and differential susceptibility to hydrophobic bile acid. PLoS Genet 9:e1003696

    CAS  PubMed Central  PubMed  Google Scholar 

  • Torroni A, Wallace DC (1994) Mitochondrial DNA variation in human populations and implications for detection of mitochondrial DNA mutations of pathological significance. J Bioenerg Biomembr 26:261–271

    CAS  PubMed  Google Scholar 

  • Torroni A, Huoponen K, Francalacci P, Petrozzi M, Morelli L, Scozzari R, Obinu D, Savontaus ML, Wallace DC (1996) Classification of European mtDNAs from an analysis of three European populations. Genetics 144:1835–1850

    CAS  PubMed Central  PubMed  Google Scholar 

  • Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (2006) Harvesting the fruit of the human mtDNA tree. Trends Genet 22:339–345

    CAS  PubMed  Google Scholar 

  • Tranah GJ (2011) Mitochondrial–nuclear epistasis: implications for human aging and longevity. Ageing Res Rev 10:238–252

    CAS  PubMed Central  PubMed  Google Scholar 

  • Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–423

    CAS  PubMed  Google Scholar 

  • Tseng LM, Yin PH, Chi CW, Hsu CY, Wu CW, Lee LM, Wei YH, Lee HC (2006) Mitochondrial DNA mutations and mitochondrial DNA depletion in breast cancer. Genes Chromosomes Cancer 45:629–638

    CAS  PubMed  Google Scholar 

  • Udar N, Atilano SR, Memarzadeh M, Boyer DS, Chwa M, Lu S, Maguen B, Langberg J, Coskun P, Wallace DC, Nesburn AB, Khatibi N, Hertzog D, Le K, Hwang D, Kenney MC (2009) Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 50:2966–2974

    PubMed  Google Scholar 

  • Ussakli CH, Ebaee A, Binkley J, Brentnall TA, Emond MJ, Rabinovitch PS, Risques RA (2013) Mitochondria and tumor progression in ulcerative colitis. J Natl Cancer Inst 105:1239–1248

    CAS  PubMed  Google Scholar 

  • Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, Hadzic N, Samyn M, Baker A, Rahman S, Stewart H, Morris AA, Seller A, Fratter C, Taylor RW, Poulton J (2013) Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. Eur J Hum Genet. doi:10.1038/ejhg.2013.112

  • Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA (2008) DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40:392–394

    CAS  PubMed  Google Scholar 

  • Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–94

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wallace DC (2008) Mitochondria as chi. Genetics 179:727–735

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wallace DC (2010) Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51:440–450

    CAS  PubMed  Google Scholar 

  • Wallace DC (2013) A mitochondrial bioenergetic etiology of disease. J Clin Invest 123:1405–1412

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol 5. doi:10.1101/cshperspect.a021220

  • Wang D, Su LY, Zhang AM, Li YY, Li XA, Chen LL, Long H, Yao YG (2012) Mitochondrial DNA copy number, but not haplogroup, confers a genetic susceptibility to leprosy in Han Chinese from Southwest China. PLoS One 7:e38848

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang B, Van Veldhoven PP, Brees C, Rubio N, Nordgren M, Apanasets O, Kunze M, Baes M, Agostinis P, Fransen M (2013a) Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells. Free Radic Biol Med 65C:882–894

    Google Scholar 

  • Wang CH, Wu SB, Wu YT, Wei YH (2013b) Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp Biol Med (Maywood) 238:450–460

    Google Scholar 

  • Wang X, Pickrell AM, Rossi SG, Pinto M, Dillon LM, Hida A, Rotundo RL, Moraes CT (2013c) Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool. Hum Mol Genet 22:3976–3986

    CAS  PubMed  Google Scholar 

  • Weng SW, Kuo HM, Chuang JH, Lin TK, Huang HL, Lin HY, Liou CW, Wang PW (2013) Study of insulin resistance in cybrid cells harboring diabetes-susceptible and diabetes-protective mitochondrial haplogroups. Mitochondrion 13:888–897

    CAS  PubMed  Google Scholar 

  • Widmer RJ, Flammer AJ, Herrmann J, Rodriguez-Porcel M, Wan J, Cohen P, Lerman LO, Lerman A (2013) Circulating humanin levels are associated with preserved coronary endothelial function. Am J Physiol Heart Circ Physiol 304:H393–H397

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wu CW, Yin PH, Hung WY, Li AF, Li SH, Chi CW, Wei YH, Lee HC (2005) Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer 44:19–28

    CAS  PubMed  Google Scholar 

  • Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH (2007) Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 67:10823–10830

    CAS  PubMed  Google Scholar 

  • Xia P, An HX, Dang CX, Radpour R, Kohler C, Fokas E, Engenhart-Cabillic R, Holzgreve W, Zhong XY (2009) Decreased mitochondrial DNA content in blood samples of patients with stage I breast cancer. BMC Cancer 9:454

    PubMed Central  PubMed  Google Scholar 

  • Xie CH, Naito A, Mizumachi T, Evans TT, Douglas MG, Cooney CA, Fan CY, Higuchi M (2007) Mitochondrial regulation of cancer associated nuclear DNA methylation. Biochem Biophys Res Commun 364:656–661

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, Amos CI, Shields PG, Benowitz NL, Gu J, de Andrade M, Swan GE, Wu X (2008) Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 100:1104–1112

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X (2013) Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis 34:2521–2524

    CAS  PubMed  Google Scholar 

  • Yamada T, Ivarsson N, Hernandez A, Fahlstrom A, Cheng AJ, Zhang SJ, Bruton JD, Ulfhake B, Westerblad H (2012) Impaired mitochondrial respiration and decreased fatigue resistance followed by severe muscle weakness in skeletal muscle of mitochondrial DNA mutator mice. J Physiol 590:6187–6197

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yan MH, Wang X, Zhu X (2013) Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 62:90–101

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell 31:449–461

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang JN, Seluanov A, Gorbunova V (2013) Mitochondrial inverted repeats strongly correlate with lifespan: mtDNA inversions and aging. PLoS One 8:e73318

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:14670–14675

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yao Z, Jones AW, Fassone E, Sweeney MG, Lebiedzinska M, Suski JM, Wieckowski MR, Tajeddine N, Hargreaves IP, Yasukawa T, Tufo G, Brenner C, Kroemer G, Rahman S, Szabadkai G (2012) PGC-1beta mediates adaptive chemoresistance associated with mitochondrial DNA mutations. Oncogene 32:2592–2600

    PubMed  Google Scholar 

  • Yin PH, Lee HC, Chau GY, Wu YT, Li SH, Lui WY, Wei YH, Liu TY, Chi CW (2004) Alteration of the copy number and deletion of mitochondrial DNA in human hepatocellular carcinoma. Br J Cancer 90:2390–2396

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yu E, Calvert PA, Mercer JR, Harrison J, Baker L, Figg NL, Kumar S, Wang JC, Hurst LA, Obaid DR, Logan A, West NE, Clarke MC, Vidal-Puig A, Murphy MP, Bennett MR (2013a) Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans. Circulation 128:702–712

    CAS  PubMed  Google Scholar 

  • Yu M, Wan Y, Zou Q (2013b) Reduced mitochondrial DNA copy number in Chinese patients with osteosarcoma. Transl Res 161:165–171

    CAS  PubMed  Google Scholar 

  • Zacharias DG, Kim SG, Massat AE, Bachar AR, Oh YK, Herrmann J, Rodriguez-Porcel M, Cohen P, Lerman LO, Lerman A (2012) Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans. PLoS One 7:e31065

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang F, Broughton RE (2013) Mitochondrial–nuclear interactions: compensatory evolution or variable functional constraint among vertebrate oxidative phosphorylation genes? Genome Biol Evol 5:1781–1791

    PubMed Central  PubMed  Google Scholar 

  • Zhang W, Li Z, Hao J, Zhang Z, Liu L, Mao N, Miao J, Zhang L (2012) S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice. Pharmacol Biochem Behav 100:361–369

    CAS  PubMed  Google Scholar 

  • Zheng S, Qian P, Li F, Qian G, Wang C, Wu G, Li Q, Chen Y, Li J, Li H, He B, Ji F (2012) Association of mitochondrial DNA variations with lung cancer risk in a Han Chinese population from southwestern China. PLoS One 7:e31322

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zheng H, Li S, Hsu P, Qu CK (2013) Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence. J Biol Chem 288:25727–25738

    CAS  PubMed  Google Scholar 

  • Zuo L, Motherwell MS (2013) The impact of reactive oxygen species and genetic mitochondrial mutations in Parkinson’s disease. Gene 532:18–23

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

    Martin P. Horan & David N. Cooper

Authors
  1. Martin P. Horan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David N. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin P. Horan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Horan, M.P., Cooper, D.N. The emergence of the mitochondrial genome as a partial regulator of nuclear function is providing new insights into the genetic mechanisms underlying age-related complex disease. Hum Genet 133, 435–458 (2014). https://doi.org/10.1007/s00439-013-1402-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-013-1402-4

Keywords

Search

Navigation