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Mitochondrial Manipulation as a Treatment for Aging

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The Future of Aging

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Abstract

The mitochondrial theory of aging states that the accumulation of damage to the mitochondrial genome is an important contributing factor to aging. In this review we analyze evidence in favor of this theory and consider the biochemical mechanisms that may be involved. The current state of the art in mitochondrial DNA transfection, cloning and in vivo manipulation is discussed as it relates to future therapeutic applications.

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References

  • Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MR (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 25:9176–9184

    PubMed  CAS  Google Scholar 

  • Allen JF (1993) Control of gene expression by redox potential and the requirement for chloroplast and mitochondrial genomes. J Theor Biol 165:609–631

    PubMed  CAS  Google Scholar 

  • Barrett TG (2001) Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes. Best Pract Res Clin Endocrinol Metab 15:325–343

    PubMed  CAS  Google Scholar 

  • Bayona-Bafaluy MP, Blits B, Battersby BJ, Shoubridge EA, Moraes CT (2005) Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease. Proc Natl Acad Sci USA 102:14392–14397

    Google Scholar 

  • Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

    PubMed  CAS  Google Scholar 

  • Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517

    PubMed  CAS  Google Scholar 

  • Bhat HK, Epelboym I (2004) Quantitative analysis of total mitochondrial DNA: competitive polymerase chain reaction versus real-time polymerase chain reaction. J Biochem Mol Toxicol 18:180–186

    PubMed  CAS  Google Scholar 

  • Birket MJ, Birch-Machin MA (2007) Ultraviolet radiation exposure accelerates the accumulation of the aging-dependent T414G mitochondrial DNA mutation in human skin. Aging Cell 6:557–564

    PubMed  CAS  Google Scholar 

  • Boddapati SV, Tongcharoensirikul P, Hanson RN, D’souza GG, Torchilin VP, Weissig V (2005) Mitochondriotropic liposomes. J Liposome Res 15:49–58

    PubMed  CAS  Google Scholar 

  • Bonnefoy N, Fox TD (2007) Directed alteration of Saccharomyces cerevisiae mitochondrial DNA by biolistic transformation and homologous recombination. Methods Mol Biol 372:153–166

    PubMed  CAS  Google Scholar 

  • Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Benit P, Forster V, Rustin P, Sahel JA, Corral-Debrinski M (2007) Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits. Rejuvenation Res 10:127–144

    PubMed  CAS  Google Scholar 

  • Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V, Baracca A, Tallini G, Martinuzzi A, Lenaz G, Rugolo M, Romeo G (2006) Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res 66:6087–6096

    PubMed  CAS  Google Scholar 

  • Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Durr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M (1997) Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet 6:1771–1780

    PubMed  CAS  Google Scholar 

  • Cassarino DS, Fall CP, Swerdlow RH, Smith TS, Halvorsen EM, Miller SW, Parks JP, Parker WD Jr, Bennett JP Jr (1997) Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson’s disease. Biochim Biophys Acta 1362:77–86

    PubMed  CAS  Google Scholar 

  • Cervin C, Liljestrom B, Tuomi T, Heikkinen S, Tapanainen JS, Groop L, Cilio CM (2004) Cosegregation of MIDD and MODY in a pedigree: functional and clinical consequences. Diabetes 53:1894–1899

    PubMed  CAS  Google Scholar 

  • Cetica P, Pintos L, Dalvit G, Beconi M (2002) Activity of key enzymes involved in glucose and triglyceride catabolism during bovine oocyte maturation in vitro. Reproduction 124:675–681

    PubMed  CAS  Google Scholar 

  • Chabi B, de Camaret BM, Chevrollier A, Boisgard S, Stepien G (2005) Random mtDNA deletions and functional consequence in aged human skeletal muscle. Biochem Biophys Res Commun 332:542–549

    PubMed  CAS  Google Scholar 

  • Chen Z, Lu W, Garcia-Prieto C, Huang P (2007) The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 39:267–274

    PubMed  CAS  Google Scholar 

  • Chinnery PF, Samuels DC, Elson J, Turnbull DM (2002) Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360:1323–1325

    PubMed  CAS  Google Scholar 

  • D’souza GG, Rammohan R, Cheng SM, Torchilin VP, Weissig V (2003) DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells. J Control Release 19;92:189–197

    Google Scholar 

  • Davidson MH, Yannicelli HD (2006) New concepts in dyslipidemia in the metabolic syndrome and diabetes. Metab Syndr Relat Disord 4:299–314

    PubMed  CAS  Google Scholar 

  • de Andrade PB, Rubi B, Frigerio F, van den Ouweland JM, Maassen JA, Maechler P (2006) Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function. Diabetologia 49:1816–1826

    PubMed  CAS  Google Scholar 

  • de Grey AD (1997) A proposed refinement of the mitochondrial free radical theory of aging. Bioessays 19:161–166

    PubMed  Google Scholar 

  • Debray FG, Lambert M, Chevalier I, Robitaille Y, Decarie JC, Shoubridge EA, Robinson BH, Mitchell GA (2007) Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics 119:722–733

    PubMed  Google Scholar 

  • Decanini A, Nordgaard CL, Feng X, Ferrington DA, Olsen TW (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607–615

    PubMed  CAS  Google Scholar 

  • Edland SD, Silverman JM, Peskind ER, Tsuang D, Wijsman E, Morris JC (1996) Increased risk of dementia in mothers of Alzheimer’s disease cases: evidence for maternal inheritance. Neurology 47:254–256

    PubMed  CAS  Google Scholar 

  • Fan W, Waymire KG, Narula N, Li P, Rocher C, Coskun PE, Vannan MA, Narula J, MacGregor GR, Wallace DC (2008) A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319:958–962

    PubMed  CAS  Google Scholar 

  • Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI (2008) Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett 266:6–11

    Google Scholar 

  • Fridlender B, Fry M, Bolden A, Weissbach A (1972) A new synthetic RNA-dependent DNA polymerase from human tissue culture cells (HeLa-fibroblast-synthetic oligonucleotides-template-purified enzymes). Proc Natl Acad Sci USA 69:452–455

    PubMed  CAS  Google Scholar 

  • Gingrich JR, Pelkey KA, Fam SR, Huang Y, Petralia RS, Wenthold RJ, Salter MW (2004) Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2. Proc Natl Acad Sci USA 101:6237–6242

    PubMed  CAS  Google Scholar 

  • Godinot C, de LE, Hervouet E, Simonnet H (2007) Actuality of Warburg’s views in our understanding of renal cancer metabolism. J Bioenerg Biomembr 39:235–241

    PubMed  CAS  Google Scholar 

  • Gokey NG, Cao Z, Pak JW, Lee D, McKiernan SH, McKenzie D, Weindruch R, Aiken JM (2004) Molecular analyses of mtDNA deletion mutations in microdissected skeletal muscle fibers from aged rhesus monkeys. Aging Cell 3:319–326

    PubMed  CAS  Google Scholar 

  • Grasso DG, Nero D, Law RH, Devenish RJ, Nagley P (1991) The C-terminal positively charged region of subunit 8 of yeast mitochondrial ATP synthase is required for efficient assembly of this subunit into the membrane F0 sector. Eur J Biochem 199:203–209

    PubMed  CAS  Google Scholar 

  • Greco M, Villani G, Mazzucchelli F, Bresolin N, Papa S, Attardi G (2003) Marked aging-related decline in efficiency of oxidative phosphorylation in human skin fibroblasts. FASEB J 17:1706–1708

    PubMed  CAS  Google Scholar 

  • Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint BG, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419

    PubMed  CAS  Google Scholar 

  • Hong WK, Han EH, Kim DG, Ahn JY, Park JS, Han BG (2007) Amyloid-beta-peptide reduces the expression level of mitochondrial cytochrome oxidase subunits. Neurochem Res 32:1483–1488

    PubMed  CAS  Google Scholar 

  • Indo HP, Davidson M, Yen HC, Suenaga S, Tomita K, Nishii T, Higuchi M, Koga Y, Ozawa T, Majima HJ (2007) Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7:106–118

    PubMed  CAS  Google Scholar 

  • Kato Y, Miura Y, Inagaki A, Itatsu T, Oiso Y (2002) Age of onset possibly associated with the degree of heteroplasmy in two male siblings with diabetes mellitus having an A to G transition at 3243 of mitochondrial DNA. Diabet Med 19:784–786

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Khan SM, Cassarino DS, Abramova NN, Keeney PM, Borland MK, Trimmer PA, Krebs CT, Bennett JC, Parks JK, Swerdlow RH, Parker WD Jr, Bennett JP Jr (2000) Alzheimer’s disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol 48:148–155

    PubMed  CAS  Google Scholar 

  • King MP, Attardi G (1989) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246:500–503

    PubMed  CAS  Google Scholar 

  • Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38:518–520

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Lai LP, Tsai CC, Su MJ, Lin JL, Chen YS, Tseng YZ, Huang SK (2003) Atrial fibrillation is associated with accumulation of aging-related common type mitochondrial DNA deletion mutation in human atrial tissue. Chest 123:539–544

    PubMed  CAS  Google Scholar 

  • Lazarou M, McKenzie M, Ohtake A, Thorburn DR, Ryan MT (2007) Analysis of the assembly profiles for mitochondrial- and nuclear-DNA-encoded subunits into complex I. Mol Cell Biol 27:4228–4237

    PubMed  CAS  Google Scholar 

  • Ledoux SP, Druzhyna NM, Hollensworth SB, Harrison JF, Wilson GL (2007) Mitochondrial DNA repair: a critical player in the response of cells of the CNS to genotoxic insults. Neuroscience 145:1249–1259

    PubMed  CAS  Google Scholar 

  • Lee HC, Hsu LS, Yin PH, Lee LM, Chi CW (2007a) Heteroplasmic mutation of mitochondrial DNA D-loop and 4977-bp deletion in human cancer cells during mitochondrial DNA depletion. Mitochondrion 7:157–163

    PubMed  CAS  Google Scholar 

  • Lee HC, Wei YH (2007) Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med (Maywood ) 232:592–606

    CAS  Google Scholar 

  • Lee M, Choi JS, Choi MJ, Pak YK, Rhee BD, Ko KS (2007b) DNA delivery to the mitochondria sites using mitochondrial leader peptide conjugated polyethylenimine. J Drug Target 15:115–122

    PubMed  CAS  Google Scholar 

  • Lenaz G, Baracca A, Carelli V, D’Aurelio M, Sgarbi G, Solaini G (2004) Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta 1658:89–94

    PubMed  CAS  Google Scholar 

  • Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145

    PubMed  CAS  Google Scholar 

  • Liu CY, Lee CF, Hong CH, Wei YH (2004) Mitochondrial DNA mutation and depletion increase the susceptibility of human cells to apoptosis. Ann NY Acad Sci 1011:133–45.:133–145

    PubMed  CAS  Google Scholar 

  • Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 35:7497–7504

    PubMed  CAS  Google Scholar 

  • Maassen JA, ‘T Hart LM, Ouwens DM (2007) Lessons that can be learned from patients with diabetogenic mutations in mitochondrial DNA: implications for common type 2 diabetes. Curr Opin Clin Nutr Metab Care 10:693–697

    PubMed  CAS  Google Scholar 

  • Mark RJ, Hensley K, Butterfield DA, Mattson MP (1995) Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J Neurosci 15:6239–6249

    PubMed  CAS  Google Scholar 

  • Menzies RA, Gold PH (1971) The turnover of mitochondria in a variety of tissues of young adult and aged rats. J Biol Chem 246:2425–2429

    PubMed  CAS  Google Scholar 

  • Mori M, Yamagata T, Goto T, Saito S, Momoi MY (2004) Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev 26:453–458

    PubMed  Google Scholar 

  • Mott JL, Zhang D, Farrar PL, Chang SW, Zassenhaus HP (1999) Low frequencies of mitochondrial DNA mutations cause cardiac disease in the mouse. Ann NY Acad Sci 893:353–357

    PubMed  CAS  Google Scholar 

  • Mott JL, Zhang D, Stevens M, Chang S, Denniger G, Zassenhaus HP (2001) Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations. Mutat Res 474:35–45

    PubMed  CAS  Google Scholar 

  • Murphy R, Turnbull DM, Walker M, Hattersley AT (2008) Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 25:383–399

    Google Scholar 

  • Naviaux RK, Nyhan WL, Barshop BA, Poulton J, Markusic D, Karpinski NC, Haas RH (1999) Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol 45:54–58

    PubMed  CAS  Google Scholar 

  • Nicolson GL (2007) Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem 100:1352–1369

    PubMed  CAS  Google Scholar 

  • Niu X, Trifunovic A, Larsson NG, Canlon B (2007) Somatic mtDNA mutations cause progressive hearing loss in the mouse. Exp Cell Res 313:3924–3934

    PubMed  CAS  Google Scholar 

  • Oguro H, Iwama A (2007) Life and death in hematopoietic stem cells. Curr Opin Immunol 19:503–509

    PubMed  CAS  Google Scholar 

  • Oliveira-Sales EB, Dugaich AP, Carillo BA, Abreu NP, Boim MA, Martins PJ, D’Almeida V, Dolnikoff MS, Bergamaschi CT, Campos RR (2008) Oxidative stress contributes to renovascular hypertension. Am J Hypertens 21:98–104

    PubMed  CAS  Google Scholar 

  • Pak JW, Aiken JM (2004) Low levels of mtDNA deletion mutations in ETS normal fibers from aged rats. Ann NY Acad Sci 1019:289–293

    PubMed  CAS  Google Scholar 

  • Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 26:719–723

    PubMed  Google Scholar 

  • Parker WD Jr, Filley CM, Parks JK (1990) Cytochrome oxidase deficiency in Alzheimer’s disease. Neurology 40:1302–1303

    PubMed  Google Scholar 

  • Perna NT, Kocher TD (1996) Mitochondrial DNA: molecular fossils in the nucleus. Curr Biol 6:128–129

    PubMed  CAS  Google Scholar 

  • Pineau B, Mathieu C, Gerard-Hirne C, De Paepe R, Chetrit P (2005) Targeting the NAD7 subunit to mitochondria restores a functional complex I and a wild type phenotype in the Nicotiana sylvestris CMSII mutant lacking nad7. J Biol Chem 280:25994–26001

    Google Scholar 

  • Prithivirajsingh S, Story MD, Bergh SA, Geara FB, Ang KK, Ismail SM, Stevens CW, Buchholz TA, Brock WA (2004) Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation. FEBS Lett 571:227–232

    PubMed  CAS  Google Scholar 

  • Przybylowski M, Bartido S, Borquez-Ojeda O, Sadelain M, Riviere I (2007) Production of clinical-grade plasmid DNA for human Phase I clinical trials and large animal clinical studies. Vaccine 25:5013–5024

    PubMed  CAS  Google Scholar 

  • Puddu P, Puddu GM, Cravero E, De PS, Muscari A (2007) The putative role of mitochondrial dysfunction in hypertension. Clin Exp Hypertens 29:427–434

    PubMed  CAS  Google Scholar 

  • Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T (2003) Mitochondrial threshold effects. Biochem J 370:751–762

    PubMed  CAS  Google Scholar 

  • Sayre LM, Moreira PI, Smith MA, Perry G (2005) Metal ions and oxidative protein modification in neurological disease. Ann Ist Super Sanita 41:143–164

    PubMed  CAS  Google Scholar 

  • Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF (2004) The epidemiology of mitochondrial disorders–past, present and future. Biochim Biophys Acta 1659:115–120

    PubMed  CAS  Google Scholar 

  • Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 7:97–109

    PubMed  CAS  Google Scholar 

  • Schmiedel J, Jackson S, Schafer J, Reichmann H (2003) Mitochondrial cytopathies. J Neurol 250:267–277

    PubMed  CAS  Google Scholar 

  • Schoeler S, Szibor R, Gellerich FN, Wartmann T, Mawrin C, Dietzmann K, Kirches E (2005) Mitochondrial DNA deletions sensitize cells to apoptosis at low heteroplasmy levels. Biochem Biophys Res Commun 332:43–49

    PubMed  CAS  Google Scholar 

  • Simon DK, Lin MT, Zheng L, Liu GJ, Ahn CH, Kim LM, Mauck WM, Twu F, Beal MF, Johns DR (2004) Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease. Neurobiol Aging 25:71–81

    PubMed  CAS  Google Scholar 

  • Smigrodzki RM, Khan SM (2005) Mitochondrial microheteroplasmy and a theory of aging and age-related disease. Rejuvenation Res 8:172–198

    PubMed  CAS  Google Scholar 

  • Smith DG, Cappai R, Barnham KJ (2007) The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochim Biophys Acta 1768:1976–1990

    PubMed  CAS  Google Scholar 

  • Song S, Pursell ZF, Copeland WC, Longley MJ, Kunkel TA, Mathews CK (2005) DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci USA 102:4990–4995

    PubMed  CAS  Google Scholar 

  • Srivastava S, Moraes CT (2001) Manipulating mitochondrial DNA heteroplasmy by a mitochondrially targeted restriction endonuclease. Hum Mol Genet 10:3093–3099

    PubMed  CAS  Google Scholar 

  • Stuart JA, Brown MF (2006) Mitochondrial DNA maintenance and bioenergetics. Biochim Biophys Acta 1757:79–89

    PubMed  CAS  Google Scholar 

  • Sun F, Cui J, Gavras H, Schwartz F (2003) A novel class of tests for the detection of mitochondrial DNA-mutation involvement in diseases. Am J Hum Genet 72:1515–1526

    PubMed  CAS  Google Scholar 

  • Suzuki S, Oka Y, Kadowaki T, Kanatsuka A, Kuzuya T, Kobayashi M, Sanke T, Seino Y, Nanjo K (2003) Clinical features of diabetes mellitus with the mitochondrial DNA 3243 (A-G) mutation in Japanese: maternal inheritance and mitochondria-related complications. Diabetes Res Clin Pract 59:207–217

    PubMed  CAS  Google Scholar 

  • Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63:8–20

    PubMed  CAS  Google Scholar 

  • Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr, Davis RE, Parker WD Jr (1997) Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 49:918–925

    PubMed  CAS  Google Scholar 

  • Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, Trillat AC, Stern DM, Arancio O, Yan SS (2005) ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 19:597–598

    PubMed  CAS  Google Scholar 

  • Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M, Maruyama W, Naoi M, Ibi T, Sahashi K, Shamoto M, Fuku N, Kurata M, Yamada Y, Nishizawa K, Akao Y, Ohishi N, Miyabayashi S, Umemoto H, Muramatsu T, Furukawa K, Kikuchi A, Nakano I, Ozawa K, Yagi K (2002) Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J Biomed Sci 9:534–541

    PubMed  CAS  Google Scholar 

  • Tawata M, Hayashi JI, Isobe K, Ohkubo E, Ohtaka M, Chen J, Aida K, Onaya T (2000) A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes. Diabetes 49:1269–1272

    PubMed  CAS  Google Scholar 

  • Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 102:17993–17998

    PubMed  CAS  Google Scholar 

  • Trifunovic A, Larsson NG (2008) Mitochondrial dysfunction as a cause of ageing. J Intern Med 263:167–178

    PubMed  CAS  Google Scholar 

  • Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly Y, 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

    PubMed  CAS  Google Scholar 

  • Trounce IA, Pinkert CA (2007) Cybrid models of mtDNA disease and transmission, from cells to mice. Curr Top Dev Biol 77:157–183

    PubMed  CAS  Google Scholar 

  • Turner C, Killoran C, Thomas NS, Rosenberg M, Chuzhanova NA, Johnston J, Kemel Y, Cooper DN, Biesecker LG (2003) Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet 112:303–309

    PubMed  Google Scholar 

  • Van GG, Martin JJ, Van BC (2002) Progressive external ophthalmoplegia and multiple mitochondrial DNA deletions. Acta Neurol Belg 102:39–42

    Google Scholar 

  • Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39: 540–543

    PubMed  CAS  Google Scholar 

  • Vestweber D, Schatz G (1989) DNA-protein conjugates can enter mitochondria via the protein import pathway. Nature 338:170–172

    PubMed  CAS  Google Scholar 

  • Vidal-Puig AJ, Grujic D, Zhang CY, Hagen T, Boss O, Ido Y, Szczepanik A, Wade J, Mootha V, Cortright R, Muoio DM, Lowell BB (2000) Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem 275:16258–16266

    PubMed  CAS  Google Scholar 

  • Yang Q, Kim SK, Sun F, Cui J, Larson MG, Vasan RS, Levy D, Schwartz F (2007) Maternal influence on blood pressure suggests involvement of mitochondrial DNA in the pathogenesis of hypertension: the Framingham Heart Study. J Hypertens 25:2067–2073

    PubMed  CAS  Google Scholar 

  • Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR (2004) Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: An in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA 101:16525–16530

    PubMed  CAS  Google Scholar 

  • Yoon YG, Koob MD (2003) Efficient cloning and engineering of entire mitochondrial genomes in Escherichia coli and transfer into transcriptionally active mitochondria. Nucleic Acids Res 31:1407–1415

    PubMed  CAS  Google Scholar 

  • Zhang D, Mott JL, Chang SW, Stevens M, Mikolajczak P, Zassenhaus HP (2005) Mitochondrial DNA mutations activate programmed cell survival in the mouse heart. Am J Physiol Heart Circ Physiol 288:H2476–H2483

    PubMed  CAS  Google Scholar 

  • Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G (2003) Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci USA 100:1116–1121

    PubMed  CAS  Google Scholar 

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  1. Gencia, Inc., Charlottesville, VA, USA

    Rafal Smigrodzki & Francisco R. Portell

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  1. Rafal Smigrodzki
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  2. Francisco R. Portell
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Correspondence to Rafal Smigrodzki .

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  1. Intervene Biomedical, LLC, Box 478, Norco, CA, 92860, USA

    Gregory M. Fahy

  2. BioTime, Inc., 1301 Harbor Bay Parkway, Alameda, CA, 94502, USA

    Michael D. West

  3. Institute of Molecular Biology Department of Chemistry and Biochemistry Young Hall, University of California, Los Angeles, CA, 90095-1569, USA

    L. Stephen Coles

  4. Critical Care Research, Inc., 10743 Civic Center Drive, Rancho Cucamonga, CA, 91730, USA

    Steven B. Harris

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Smigrodzki, R., Portell, F.R. (2010). Mitochondrial Manipulation as a Treatment for Aging. In: Fahy, G.M., West, M.D., Coles, L.S., Harris, S.B. (eds) The Future of Aging. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3999-6_16

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