Mitochondrial dysfunction in Alzheimer's disease and the rationale for bioenergetics based therapies

Aging and Disease

Volumn 7, Issue 2, 2016, Pages 201-214

  Onyango, Isaac G ^a   Dennis, Jameel ^a   Khan, Shaharyah M ^a  

^a Gencia Corporation   (United States)

Author keywords

Alzheimer's disease; Mitochondria; Mitochondrial biogenesis; Mitophagy; Neuroinflammation; Oxidative stress

Indexed keywords

ACETYLCYSTEINE; ADENOSINE TRIPHOSPHATE; AFLATOXIN B1; CATALASE; CRYOPYRIN; CYCLIN D1; CYTOCHROME C; CYTOCHROME C OXIDASE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; GLUCOSE TRANSPORTER 4; GLUTATHIONE; HISTONE DEACETYLASE 6; INTERLEUKIN 23; MITOCHONDRIAL DNA; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; MITOCHONDRIAL RNA; MITOCHONDRIAL TRANSCRIPTION FACTOR A; NITRIC OXIDE; PROTEIN BCL 2; PROTEIN P53; REACTIVE OXYGEN METABOLITE; SIRTUIN 1; SUPEROXIDE DISMUTASE; TRANSCRIPTION FACTOR NRF2;

ALZHEIMER DISEASE; ANTIOXIDANT RESPONSIVE ELEMENT; APOPTOSIS; BIOENERGY; CALORIC RESTRICTION; CELL CYCLE ARREST; CYTOKINE PRODUCTION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; EXERCISE; GENE EXPRESSION; GLUCOSE METABOLISM; HUMAN; LIPID METABOLISM; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MITOPHAGY; NERVE CELL PLASTICITY; NONHUMAN; OXIDATIVE PHOSPHORYLATION; REVIEW; SIGNAL TRANSDUCTION; SUMOYLATION; UBIQUITINATION; UNFOLDED PROTEIN RESPONSE;

EID: 85001882183     PISSN: None     EISSN: 21525250     Source Type: Journal    
DOI: 10.14336/AD.2015.1007     Document Type: Review

References (205)

1. Swerdlow RH, Burns JM, Khan SM (2014). The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta, 1842:1219-1231
2. Fukui H, Moraes CT (2008). The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis? Trends Neurosci, 31:251-256
3. Picone P, Nuzzo D, Caruana L, Scafidi V, Di Carlo M (2014). Mitochondrial Dysfunction: Different Routes to Alzheimer's Disease Therapy. Oxidative Medicine and Cellular Longevity. Oxid Med Cell Longev, 2014:780179.
4. Scarpulla RC (2008). Transcriptional paradigms in mammalian mitochondrial biogenesis and function. . Physiol Rev, 88: 611-638.
5. Mosconi L, Brys M, Switalski R, Mistur R, Glodzik L, Pirraglia E, et al. (2007). Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. Proc Natl Acad Sci U S A, 104: 19067-19072.
6. Murray J, Tsui WH, Li Y, McHugh P, Williams S, Cummings M, et al. (2014). FDG and Amyloid PET in Cognitively Normal Individuals at Risk for Late-Onset Alzheimer's Disease. Adv J Mol Imaging, 4: 15-26.
7. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. (2001). Mitochondrial abnormalities in Alzheimer's disease. J Neurosci, 21: 3017-3023
8. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, et al. (2007). Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy, 3: 614-615.
9. Parker WDJ, Parks JK (1995). Cytochrome c oxidase in Alzheimer's disease brain: purification and characterization. Neurology, 45: 482-486
10. Gibson GE, Sheu KF, Blass JP (1998). Abnormalities of mitochondrial enzymes in Alzheimer disease. J NeuralTransm, 105: 855-870.
11. Maurer I, Zierz S, Moller HJ (2000). A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiol Aging, 21: 455-462
12. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, et al. (2008). Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci USA, 105: 19318-19323.
13. Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH (2011). Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet, 20: 4515-4529.
14. Manczak M, Calkins MJ, Reddy PH (2011). Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: impli-cations for neuronal damage. Hum Mol Genet, 20: 2495-2509.
15. Keller JN, Pang Z, Geddes JW, Begley JG, Germeyer A, Waeg G, et al. (1997). Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J Neurochem, 69: 273-284
16. Abramov AY, Canevari L, Duchen MR (2004). Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci, 24: 565-575
17. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006). Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet, 15: 1437-1449
18. Mattson MP, Partin J, Begley JG (1998). Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res, 807: 167-176.
19. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, et al. (2004). ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science, 304: 448-452
20. Reddy PH (2008). Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med, 10: 291-315
21. Calkins MJ, Manczak M, Reddy PH (2012). Mitochondria-targeted antiox-idant SS31 prevents amyloid beta-induced mitochondrial abnormalities and synaptic degeneration in Alzheimer's disease. Pharmaceuticals, 5:1103-1119.
22. Eckert GP, Renner K, Eckert SH, Eckmann J, Hagl S, Abdel-Kader RM, et al. (2012). Mitochondrial dysfunction a pharmacological target in Alzheimer's disease. Mol Neurobiol, 46: 136-150
23. Reddy PH, Tripathi R, Troung Q, Tirumala K, Reddy TP, Anekonda V, et al. (2012). Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics. Biochim Biophys Acta, 1822: 639-649
24. Ryan MT, Hoogenraad NJ (2007). Mitochondrial-nuclear communications. Annu Rev Biochem, 76: 701-722.
25. Liu X, Hajnóczky G (2011). Altered fusion dynamics underlie unique morphological changes in mitochondria during hypoxia-reoxygenation stress. Cell Death Differ, 18: 1561-1572
26. Chan DC (2007). Mitochondrial dynamics in disease. N Engl J Med, 356: 1707-1709
27. Medeiros DM (2008). Assessing mitochondria biogenesis. Methods, 46: 288-294
28. Onyango IG, Lu J, Rodova M, Lezi E, Crafter AB, Swerdlow RH (2010). Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta, 1802: 228-234.
29. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J (2008). Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. . Stroke, 39:3057-3063
30. Medeiros DM (2008). Assessing mitochondria biogenesis. Methods, 46: 288-294
31. Kelly DP, Scarpulla RC (2004). Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev, 18: 357-368
32. Canto C, Auwerx J (2011). NAD+ as a signaling molecule modulating metabolism. Cold Spring Harb Symp Quant Biol, 76: 291-298.
33. Gleyzer N, Vercauteren K, Scarpulla RC (2005). Control of Mitochondrial Transcription Specificity Factors (TFB1M and TFB2M) by Nuclear Respiratory Factors (NRF-1 and NRF-2) and PGC-1 Family Coactivators. Molecular and Cellular Biology, 25: 1354-1366
34. Bruni F, Polosa PL, Gadaleta MN, Cantatore P, Roberti M (2010). Nuclear Respiratory Factor 2 Induces the Expression of Many but Not All Human Proteins Acting in Mitochondrial DNA Transcription and Replication. J Bio Chem, 285: 3939-3948.
35. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. Embo J, 27: 433-446
36. Youle RJ, Narendra DP (2011). Mechanisms of mitophagy. Nat Rev Mol Biol, 12: 9-14
37. Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, et al. (2009). PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol, 66: 352-361.
38. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. (2001). Mitochondrial abnormalities in Alzheimer's disease. J Neurosci, 21: 3017-3023
39. Sheng B, Wang X, Su B, Lee HG, Casadesus G, Perry G, et al. (2012). Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer's disease. J Neurochem, 120: 419-429.
40. Dominy JE, Lee YS, Gerhart-Hines Z, Puigserver P (2010). Nutrient-dependent regulation of PGC-1a's acetylation state and metabolic function through the enzy-matic activities of Sirt1/GCN5. Biochim Biophys Acta, 1804: 1676-1683
41. Rasbach KA, Schnellmann RG (2007). Signaling of mitochondrial biogenesis following oxidant injury. J Biol Chem, 282: 2355-2362.
42. Rohas LM, St-Pierre J, Uldry M, Jager S, Handschin C, Spiegelman BM (2007). A fundamental system of cellular energy homeostasis regulated by PGC-1a. Proc Natl Acad Sci U S A, 104: 7933-7938.
43. Bell EL, Guarente L (2011). The SirT3 divining rod points to oxidative stress. Mol Cell, 42: 561-568
44. Shin JH, Ko HS, Kang HS, Lee YK, Lee YI, Pletinkova O (2011). PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell, 144: 689-702
45. Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007). Selective degradation of mitochondria by mitophagy. Arch Biochem. Biophys, 462: 245-253
46. Scherz-Shouval R, Elazar Z (2011). Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci, 36: 30-38
47. Narendra DP, Youle RJ (2011). Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid. Redox Signal, 14: 1929-1938
48. Narendra D, Kane LA, Hauser DN, Fearnley IM, Youle RJ (2010). p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both. Autophagy, 6: 1090-1106
49. Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010). Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol, 191: 933-942
50. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science, 304: 1158-1160
51. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, et al. (2010). PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol, 12: 119-131
52. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. (2007). p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem, 282: 24131-24145
53. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, et al. (2012). Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol, 14: 177-185
54. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, et al. (2010). Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep, 11: 45-51
55. Ding WX, Yin XM (2012). Mitophagy, mechanisms, pathophysiological roles, and analysis. Biol Chem, 393: 547-564
56. Fu M, St-Pierre P, Shankar J, Wang PT, Joshi B, Nabi IR (2013). Regulation of mitophagy by the Gp78 E3 ubiquitin ligase. Mol Biol Cell, 24: 1153-1162.
57. Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C, et al. (2012). The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab, 16: 613-624
58. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, et al. (2000). Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem, 275: 16023-16029
59. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Overvatn A, et al. (2010). p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem, 285: 22576-22591
60. Cheng X, Siow RC, Mann GE (2011). Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway. Antioxid Redox Signal, 14: 469-487
61. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT (2010). Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal, 13: 1713-1748.
62. Kensler TW, Wakabayashi N, Biswal S (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol. Toxicol, 47: 89-116
63. East DA, Fagiani F, Crosby J, Georgakopoulos ND, Bertrand H M. S, et al. (2014). PMI: A Δψm Independent Pharmacological Regulator of Mitophagy. Chemistry & Biology, 21: 1585-1596
64. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J (2010). PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A, 107: 378-383
65. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D (2011). PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochon-drial motility. Cell, 147: 893-906.
66. Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, et al. (2009). S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science, 324: 102-105
67. Lee JY, Koga H, Kawaguchi Y, Tang W, Wong E, Gao YS (2010). HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J, 29: 969-980
68. Lee JY, Nagano Y, Taylor JP, Lim KL, Yao TP (2010). Disease-causing mutations in Parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. J Cell Biol, 189: 671-679.
69. de Castro IP, Martins LM, Tufi R (2010). Mitochondrial quality control and neurological disease: an emerging connection. Expert Rev Mol Med, 12: e12
70. Karbowski M, Neutzner A (2012). Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol, 123: 157-171
71. Horn SR, Thomenius MJ, Johnson ES, Freel CD, Wu JQ, Coloff JL (2011). Regulation of mitochondrial morphology by APC/CCdh1-mediated control of Drp1 stability. Mol Biol Cell, 22: 1207-1216
72. Kashatus DF, Lim KH, Brady DC, Pershing NL, Cox AD, Counter CM (2011). RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol, 13: 1108-1115
73. Twig G, Hyde B, Shirihai OS (2008). Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochim Biophys Acta, 1777: 1092-1097
74. Martinou JC, Youle RJ (2011). Mitochondria in apoptosis:Bcl-2 family members and mitochondrial dynamics. Dev Cell, 21: 92-101
75. Autret A, Martin SJ (2009). Emerging role for members of the Bl-2 family in mito-chondrial morphogenesis. Mol Cell, 36: 355-363
76. Youle RJ, van der Bliek AM (2012). Mitochondrial fission, fusion and stress. Science, 337: 1062-1065.
77. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT (2011). MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO reports, 12: 565-573
78. Bossy B, Petrilli A, Klinglmayr E, Chen J, Lütz-Meindl U, Knott AB, et al. (2010). S-Nitrosylation of DRP1 does not affect enzymatic activity and is not specific to Alzheimer's disease. Journal of Alzheimer's disease, 20: S513-526
79. Nakamura T, Lipton SA (2011). Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases. Cell Death Differ, 18: 1478-1486.
80. Sauvanet C, Duvezin-Caubet S, di Rago JP, Rojo M (2010). Energetic requirements and bioenergetic modulation of mitochondrial morphology and dynamics. Semin Cell Dev Biol, 21: 558-565
81. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S, Schwarzenbacher R (2010). Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell, 142: 889-901
82. Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R (2008). Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci U S A, 105: 2169-2174
83. Wang H, Lim PJ, Karbowski M, Monteiro MJ (2008). Effects of overexpression of Huntingtin proteins on mitochondrial integrity. Hum Mol Genet, 18: 737-752
84. Hamblet NS, Ragland B, Ali M, Conyers B, Castora FJ (2006). Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II, and III genes detected in Alzheimer's disease using single-strand conformation polymorphism. Electrophoresis, 27: 398-408
85. Chandrasekaran K, Hatanpää K, Brady DR, Rapoport SI (1996). Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease. Exp Neurol, 142: 80-88
86. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, et al. (2008). Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell, 14: 193-204.
87. Brooks C, Wei Q, Cho SG, Dong Z (2009). Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models. J Clin Invest, 119: 1275-1285.
88. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ (2010). Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation, 121: 2012-2022
89. Park SW, Kim KY, Lindsey JD, Dai Y, Heo H, Nguyen DH, et al. (2011). Selective Inhibitor of Drp1, Mdivi-1, Increases Retinal Ganglion Cell Survival in Acute Ischemic Mouse Retina. Invest Ophthalmol Vis Sci, 52: 2837-2843.
90. Cui M, Tang X, Christian WV, Yoon Y, Tieu K (2010). Perturbations in mitochondrial dynamics induced by human mutant PINK1 can be rescued by the mitochondrial division inhibitor mdivi-1. J Biol Chem, 285: 11740-11752
91. Madamanchi NR, Runge MS (2007). Mitochondrial dysfunction in atherosclerosis. Circ Res, 100: 460-473.
92. Ohashi S, Nishio A, Nakamura H, Kido M, Ueno S, Uza N, et al. (2006). Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis. Am J Physiol Gastrointest Liver Physiol, 290: G772-781
93. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007). Free radicals and antioxidants in normal physiological functions and human disease Int J Biochem Cell Biol , 39: 44-84.
94. Ramsden DB, Ho PW-L, Ho JW-M, al e (2012). Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction. Brain and Behavior, 2: 468-478.
95. (2001). Δψm dependent and independent production of reactive oxygen species by rat brain mitochondria. J Neurochem, 79: 266-277
96. Brennan JP, Southworth R, Medina RA, Davidson SM, Duchen MR, Shattock MJ (2006). "Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation." Cardiovas Res, 72: 313-321.
97. Skulachev VP (1998). Uncoupling: new approaches to an old problem of bioenergetics. Biochim Biophys Acta, 1363: 100-124
98. Korshunov SS, Skulachev VP, Starkov AA (1997). High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett, 416: 15-18.
99. Brookes PS (2005). Mitochondrial H(+) leak and ROS generation: an odd couple. . Free Radic Biol Med, 38: 12-23
100. Brand MD, Buckingham JA, Esteves T (2004). Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production. Biochem Soc Symp, 203-213
101. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, et al. (2009). Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol aging, 30: 1574-1586
102. Reddy PH (2009). Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease. Exp Neurol, 2, 218: 286-292
103. Xie H, Guan J, Borrelli LA, Xu J, Serrano-Pozo A, Bacskai BJ (2013). Mitochondrial Alterations near Amyloid Plaques in an Alzheimer's Disease Mouse Model. J Neurosci, 33: 17042-17051
104. Deshpande A, Mina E, Glabe C, Busciglio J (2006). Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J Neurosci, 26: 6011-6018
105. Cabezas-Opazo FA, Vergara-Pulgar K, Pérez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA (2015). Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer's Disease. Oxid Med Cell Longev, 2015:509654
106. Aon MA, Cortassa S, O'Rourke B (2010). Redox-optimized ROS balance: A unifying hypothesis. Biochim Biophys Acta, 1797: 865-877
107. Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart J, et al. (2002). Superoxide activates mitochondrial uncoupling proteins. Nature, 415: 96-99
108. Murphy MP, Echtay KS, Blaikie FH, Asin-Cayuela J, Cocheme HM, Gree K, et al. (2003). Superoxide activates uncoupling proteins by generating carbon-centered radicals and initiating lipid peroxidation. J Biol Chem, 278: 48534-48545
109. Brookes PS, Land JM, Clark JB, Heales SJ (1998). Peroxynitrite and brain mitochondria: evidence for increased proton leak. J Neurochem, 70: 2195-2202.
110. Miwa S, Brand MD (2003). Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem Soc Trans, 311: 1300-1301.
111. Jezek P, Engstova H, Zackova M (1998). Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Biochim Biophys Acta, 1365: 319-327
112. Skulachev VP (1991). Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation. FEBS Lett, 294: 158-162
113. Pecqueur C, Alves-Guerra MC, Gelly C (2001). Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem, 276: 8705-8712
114. Ricquier D, Bouillaud F (2000). The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J, 345: 161-179
115. Andreyev A, Bondareva TO, Dedukhova VI (1988). Carboxyatractylate inhibits the uncoupling effect of free fatty acids. FEBS Lett, 226: 265-269
116. Hoerter J, Gonzalez-Barroso MD, Couplan E (2004). Mitochondrial uncoupling protein 1 expressed in the heart of transgenic mice protects against ischemic-reperfusion damage. Circulation, 110: 528-533
117. McLeod CJ, Aziz A, Hoyt RFJ, McCoy JPJ, Sack MN (2005). Uncoupling proteins 2 and 3 function in concert to augment tolerance to cardiac ischemia. J Biol Chem, 280: 33470-33476
118. Hamanaka RB, Chandel NS (2010). Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci, 35: 505-513
119. Mammucari C, Rizzuto R (2010). Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev, 131: 536-543
120. Ristow M, Zarse K, Oberbach A, et al. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A, 106: 8665-8670
121. Ristow M, Zarse K (2010). How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol, 45: 410-418
122. Kenyon CJ (2010). The genetics of ageing. Nature, 464: 504-512
123. Schulz TJ, et al (2007). Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab, 6: 280-293
124. Yun J, Finkel T (2014). Mitohormesis. Cell Metab, 19: 757-766
125. Feng J, Bussière F, Hekimi S (2001). Mitochondrial electron transport is a key determinant of life span inCaenorhabditis elegans. Dev Cell, 1: 633-644
126. Copeland JM, Cho J, Lo TJ, Hur J, Bahadorani S, Arabyan T, et al. (2009). Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr Biol, 19: 1591-1598
127. Dell'agnello C, Leo S, Agostino A, Szabadkai G, Tiveron C, Zulian A, et al. (2007). Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration inSurf1 knockout mice. Hum Mol Genet, 16: 431-444
128. Durieux J, Wolff S, Dillin A (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell, 144: 79-91
129. Bennett CF, Kaeberlein M (2014). The mitochondrial unfolded protein response and increased longevity: cause, consequence, or correlation? Exp Gerontol, 56: 42-46
130. Bennett CF, Vander Wende H, Simko M, Klum S, Barfield S, Choi H, et al. (2014). Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans. Nat Commun, 5: 3483
131. Artal-Sanz M, Tavernarakis N (2009). Prohibitin and mitochondrial biology. Endocrinol Metab, 20: 394-401
132. Dirks AJ, Leeuwenburgh C (2006). Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev, 127: 1-7
133. Sohal RS, Ku HH, Agarwal S, Forster MJ, Lal H (1994). Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev, 74: 121-133
134. Melov S, Hinerfeld D, Esposito L, Wallace DC (1997). Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age. Nucleic Acids Research, 25: 974-982.
135. Mattson MP (2012). Energy Intake and Exercise as Determinants of Brain Health and Vulnerability to Injury and Disease. Cell metabolism, 16: 706-722.
136. Gillette-Guyonnet S, Secher M, Vellas B (2013). Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol, 75: 738-755.
137. Fulton D, Gratton JP, McCabe TJ (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature, 399: 597-601
138. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ (2003). Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem, 278: 45021-45026.
139. Nisoli E, Tonello C, Cardile A (2005). Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science, 310: 314-317
140. Rashid G, Bernheim J, Green J, Benchetrit S (2007). Parathyroid hormone stimulates the endothelial nitric oxide synthase through protein kinase A and C pathways. Nephrol Dial Transplant., 22: 2831-2837.
141. Ritchie SA, Kohlhaas CF, Boyd AR, Yalla KC, Walsh K, Connell JM, et al. (2010). Insulin-stimulated phosphorylation of endothelial nitric oxide synthase at serine-615 contributes to nitric oxide synthesis. Biochem J, 426: 85-90
142. Cerqueiram FM, Laurindo FR, Kowaltowski AJ (2011). Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, akt and mitochondrial biogenesis. PLoS One, 6:e18433
143. Nisoli E, Clementi E, Paolucci C (2003). Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science, 299: 896-899
144. Nisoli E, Falcone S, Tonello C (2004). Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci U S A, 101: 16507-16512
145. Hu Z, Chen J, Wei Q, Xia Y (2008). Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J Biol Chem, 283: 25256-25263
146. Zhou X, Bohlen HG, Unthank JL, S.J. M (2009). Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide. Am J Physiol Heart Circ Physiol, 297: H2227-2233.
147. Civitarese AE, Carling S, Heilbronn L (2007). Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med, 4:e76
148. Lee IH, Cao L, Mostoslavsky R (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A, 105: 3374-3379.
149. Wohlgemuth SE, Julian D, Akin DE, al. e (2007). Autophagy in the heart and liver during normal aging and calorie restriction. Rejuvenation Res, 10: 281-292.
150. Donati A, Cavallini G, Paradiso C (2001). Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J Gerontol A Biol Sci Med Sci, 56: B375-383.
151. Bergamini E, Cavallini G, Donati A, Gori Z (2007). The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction. Ann N Y Acad Sci, 11145: 69-78
152. Simonsen A, Cumming RC, Brech A, al. e (2008). Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy, 4: 176-184.
153. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM (2011). Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol, 111: 1066-1071
154. Little JP, Safdar A, Wilkin GP, Tarnopolsky MA, Gibala MJ (2010). A practical model of low-volume high-intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms. J Physiol, 588: 1011-1022
155. Little JP, Safdar A, Cermak N, Tarnopolsky MA, Gibala MJ (2010). Acute endurance exercise increases the nuclear abundance of PGC-1alpha in trained human skeletal muscle. Am J Physiol Regul Integr Comp Physiol, 298: R912-917
156. Safdar A, Little JP, Stokl AJ, al. e (2011). Exercise Increases Mitochondrial PGC-1{alpha} Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis. J Biol Chem, 286: 10605-10617
157. Menshikova EV, Ritov VB, Fairfull L (2006). Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci, 61: 534-540
158. Vina J, Gomez-Cabrera MC, Borras C, Froio T, Sanchis-Gomar F, Martinez-Bello VE, et al. (2009). Mitochondrial biogenesis in exercise and in ageing. Adv Drug Deliv Rev, 61: 1369-1374
159. Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, et al. (2003). Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes, 52: 1888-1896
160. Ghosh S, Lertwattanarak R, Lefort N (2011). Reduction in reactive oxygen species production by mitochondria from elderly subjects with normal and impaired glucose tolerance. Diabetes, 60: 2051-2060.
161. Psilander N, Frank P, Flockhart M, Sahlin K (2013). Exercise with low glycogen increases PGC-1α gene expression in human skeletal muscle. European Journal of Applied Physiology, 113: 951-963
162. Lefevre M, Redman LM, Heilbronn LK, Smith JV, Martin CK, Rood JC, et al. (2009). Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 203: 206-213.
163. Gomez-Cabrera MC, Domenech E, M. R (2008). Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr, 87: 142-149.
164. Sena LA, Chandel NS (2012). Physiological roles of mitochondrial reactive oxygen species. Mol Cell, 48: 158-167
165. Havens CG, Ho H, Yoshioka N, Dowdy SF (2006). Regulation of late G1/S phase tran-sition and APCCdh1 by reactive oxygen. Mol Cell Biol, 26: 4701-4711
166. Balaban RS, Nemoto S, Finkel T (2005). Mitochondria, oxidants and aging. Cell, 120: 483-495
167. Tormos KV, Anso E, Hamanaka RB, Eisenbart J, Joseph J, Kalyanaraman B, et al. (2011). Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab, 14: 537-544
168. Fu Z, Tindall DJ (2008). FOXOs, cancer and regulation of apoptosis. Oncogene, 27: 2312-2319.
169. Kops GJ, Dansen TB, Polderman E, Saarloos I, Wirtz KWA, PJC (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature, 419: 316-321
170. Mihaylova MM, Shaw RJ (2011). The AMPK signaling pathway coordinates cell growth, autophagy and metabolism. Nat Rev Cell Biol, 13: 1016-1023
171. Alto NM, Soderling J, Scott JD (2002). Rab32 is an A-kinase anchoring protein and participates in mitochondrial dynamics. J Cell Sci, 158: 659-6810
172. Bera AK, Ghosh S, Das S (1995). Mitochondrial VDAC can be phosphorylated by cyclic AMP-dependent protein kinase. Biochem Biophys Res Commun, 209: 213-217
173. Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C (2008). Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res, 103: 983-9110.
174. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW (2004). Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest, 113: 1535-4910
175. Kumar S, Bharti A, Mishra NC, Raina D, Kharbanda S, Saxena S (2001). Targeting of the c-Abl tyrosine kinase to mitochondria in the necrotic cell death response to oxidative stress. J Biol Chem, 276: 17281-17510
176. Majumder PK, Mishra NC, Sun X, Bharti A, Kharbanda S, Saxena S (2001). Targeting of protein kinase C delta to mitochondria in the oxidative stress response. Cell Growth Differ, 12: 465-470
177. Robey RB, Hay N (2009). Is Akt the "Warburg kinase"?-Akt energy metabolism interactions and oncogenesis. Semin Cancer Biol, 19: 25-31
178. Maurer U, Chavret C, Wagman AS, Dejardin E, Green DR (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell, 21: 749-6010
179. Martel C, Allouche M, Esposti DD, Fanelli E, Boursier C, Henry C (2013). Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology, 57: 93-102
180. Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998). Glycogen synthase kinase-3 beta regulates cyclin D1 proteolysis and subcellular localisation. Genes Dev, 12: 3499-3511
181. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P (1996). Binding of GSK3B to the APC-b-catenin complex and regulation of complex assembly. Science, 272: 1023-1610.
182. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, et al. (2004). A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol, 6: 308-318
183. Kim J, Kundu M, Viollet B, Guan KL (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol, 13: 132-141
184. Carlucci A, Adornetto A, Scorziello A, Viggiano D, Foca M, Cuomo O (2008). Proteolysis of AKAP121 regulates mitochondrial activity during cellular hypoxia and brain ischaemia. EMBO J, 27: 1073-8410.
185. Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C (2006). Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Mol Biol Cell, 17: 263-7110.
186. Miyazaki T, Neff L, Tanaka S, Horne WC, R. B (2003). Regulation of cytochrome c oxidase activity by c-Src in osteoclasts. J Cell Biol, 160: 709-718
187. Tibaldi E, Brunati AM, Massimino ML, Stringaro A, Colone M, Agostinelli E, et al. (2008). Src-Tyrosine kinases are major agents in mitochondrial tyrosine phosphorylation. J Cell Biochem, 104: 840-910
188. Hardie DG (2011). AMP-activated protein kinase-an energy sensor that regulates all aspects of cell function. Genes Dev, 25: 1895-1908
189. Jäger S, Handschin C, St-Pierre J, B.M. S (2007). AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A,104: 12017-12022.
190. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, et al. (2002). AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A, 99: 15983-15987
191. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science, 331: 456-461
192. Petersen AJ, Rimkus SA, Wassarman DA (2012). ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc Natl Acad Sci U S A, 109: E656-E664
193. Valentin-Vega YA, MacLean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, et al. (2012). Mitochondrial dysfunction in ataxia-telangiectasia Blood, 119: 1490-5001
194. Fulop T, Le Page A, Fortin C, Witkowski JM, Dupuis G, Larbi A (2014). Cellular signaling in the aging immune system. Curr Opin Immunol, 29: 105-111.
195. Fulop T, Witkowski JM, Pawelec G, Alan C, Larbi A (2014). On the immunological theory of aging. Interdiscip Top Gerontol, 39: 163-176.
196. Bektas A, Zhang Y, Lehmann E, Wood WH, Becker KG, Madara K, et al. (2014). Age-associated changes in basal NF-κB function in human CD4+ T lymphocytes via dysregulation of PI3 kinase. Aging, 6: 957-969
197. Reynolds LM, Taylor JR, Ding J, Lohman K, Johnson C, Siscovick D, et al. (2014). Age-related variations in the methylome associated with gene expression in human monocytes and T cells. Nat Commun, 5:5366
198. Weinberg SE, Chandel NS (2015). Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol, 11: 9-15.
199. Mocchegiani E, Giacconi R, Cipriano C, et al. (2004). The variations during the circadian cycle of liver CD1d-unrestricted NK1.1+TCR gamma/delta+ cells lead to successful ageing. Role of metallothionein/IL-6/gp130/PARP-1 interplay in very old mice. Exp Gerontol. 39:775-88.
200. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. (2000). Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 908: 244-254.
201. Fulop T, Larbi A, Wikby A, Mocchegiani E, Hirokawa K, Pawelec G (2005). Dysregulation of T-cell function in the elderly:scientific basis and clinical implications. Drugs Aging, 22: 589-603
202. Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, et al. (2015). Neuroinflammation in Alzheimer's disease. Lancet Neurol, 14: 388-405.
203. Anderson KM, Olson KE, Estes KA, Flanagan K, Gendelman HE, Mosley RL (2014). Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders. Transl Neurodegener, 3: 25
204. Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, et al. (2011). Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer's disease. Brain Behav Immun, 25: 539-547
205. Maciolek JA, Pasternak JA, Wilson HL (2014). Metabolism of activated T lymphocytes. Curr Opin Immunol, 27: 60-74