Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2016, Vol. 7 Issue (2) : 150-162     DOI: 10.14336/AD.2015.0820
Review Article |
The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases
Redmann Matthew1,2, Darley-Usmar Victor1,2, Zhang Jianhua1,2,3,*
1Center for Free Radical Biology,
2Department of Pathology, University of Alabama at Birmingham,
3Department of Veterans Affairs, Birmingham VA Medical Center, Birmingham, Alabama 35294, USA
Download: PDF(964 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks     Supporting Info

Redox and proteotoxic stress contributes to age-dependent accumulation of dysfunctional mitochondria and protein aggregates, and is associated with neurodegeneration. The free radical theory of aging inspired many studies using reactive species scavengers such as alpha-tocopherol, ascorbate and coenzyme Q to suppress the initiation of oxidative stress. However, clinical trials have had limited success in the treatment of neurodegenerative diseases. We ascribe this to the emerging literature which suggests that the oxidative stress hypothesis does not encompass the role of reactive species in cell signaling and therefore the interception with reactive species with antioxidant supplementation may result in disruption of redox signaling. In addition, the accumulation of redox modified proteins or organelles cannot be reversed by oxidant intercepting antioxidants and must then be removed by alternative mechanisms. We have proposed that autophagy serves this essential function in removing damaged or dysfunctional proteins and organelles thus preserving neuronal function and survival. In this review, we will highlight observations regarding the impact of autophagy regulation on cellular bioenergetics and survival in response to reactive species or reactive species generating compounds, and in response to proteotoxic stress.

Keywords oxidative stress      reductive stress      mitochondrial dysfunction      prions      α-synuclein      neurodegenerative diseases     
Corresponding Authors: Zhang Jianhua   
About author:

These authors equally contribute this work

Issue Date: 01 April 2016
E-mail this article
E-mail Alert
Articles by authors
Redmann Matthew
Darley-Usmar Victor
Zhang Jianhua
Cite this article:   
Redmann Matthew,Darley-Usmar Victor,Zhang Jianhua. The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases[J]. Aging and disease, 2016, 7(2): 150-162.
URL:     OR
Figure 1.  Autophagy serves as an essential neuroprotective pathway in response to mitochondrial dysfunction and oxidative stress. In neurodegenerative diseases, AD, PD, and stroke, mitochondrial dysfunction accumulates due to aging, genetic abnormalities, environmental damage (such as pesticides), or neuroinflammation (which induces excessive production of nitric oxide, among others), resulting in decreased oxidative phosphorylation, and accumulation of mtDNA damage. There are also increases in protein damage, including protein oxidation and formation of HNE-protein adducts. Whether absolute levels of ROS are directly correlated with aging process is debatable. Emerging evidence indicated that transient or moderate ROS elevation may trigger response in ER stress and mitochondrial unfolded protein response pathways, as well as adaptations mediated by HIF, NRF2 and other transcription factor-regulated mechanisms (such as Apaf1 and Caspase-9 dependent mitochondria to nuclear signaling). Therefore, a systemic decrease of ROS is unlikely to be the best approach to delay aging and age related neurodegeneration. Clearance of damaged proteins and organelles are dependent on the autophagy process, which involve double membrane vesicles encircling these damaged intracellular materials and sending them to be degraded. It has been hypothesized that dysfunction of autophagy promotes neurodegeneration and enhancement of autophagy may be neuroprotective.
Figure 2.  Autophagy may be used to attenuate α-synuclein secretion and inter-cellular propagation. α-synuclein fibrils (PFF) (red circles) recruit endogenous α-synuclein (aSyn) (yellow circles) to form aggregates and induce neuron death. Aggregates can also be released and propagate to neighboring cells and further pathological damage to the brain. Enhanced lysosomal efficiency/hydrolytic capacity through increased Cathepsin D or enhanced autophagosome production through trehalose treatment may promote the sequestering and degradation of toxic α-synuclein species.
[1] Finkel T,Holbrook NJ (2000). Oxidants, oxidative stress and the biology of ageing. Nature, 408:239-247.
[2] Salmon AB, Richardson A, Perez VI (2010). Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med, 48:642-655.
[3] Houtkooper RH, Williams RW, Auwerx J (2010). Metabolic networks of longevity. Cell, 142:9-14.
[4] Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott Get al (2013). Mitonuclear protein imbalance as a conserved longevity mechanism. Nature, 497:451-457.
[5] Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VCet al (2014). The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab, 19:418-430.
[6] Yun J,Finkel T (2014). Mitohormesis. Cell Metab, 19:757-766.
[7] Detmer SA,Chan DC (2007). Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol, 8:870-879.
[8] Malkus KA, Tsika E, Ischiropoulos H (2009). Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle. Mol Neurodegener, 4:24.
[9] Parker WD Jr., Parks JK, Swerdlow RH (2008). Complex I deficiency in Parkinson's disease frontal cortex. Brain Res, 1189:215-218.
[10] Schapira AH (2008). Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol, 7:97-109.
[11] Muller WE, Eckert A, Kurz C, Eckert GP, Leuner K (2010). Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease--therapeutic aspects. Mol Neurobiol, 41:159-171.
[12] Querfurth HW,LaFerla FM (2010). Alzheimer's disease. N Engl J Med, 362:329-344.
[13] Santos RX, Correia SC, Wang X, Perry G, Smith MA, Moreira PIet al (2010). A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease. J Alzheimers Dis, 20 Suppl 2:S401-S412.
[14] Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach Met al (2008). Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging.
[15] Crouch PJ, Cimdins K, Duce JA, Bush AI, Trounce IA (2007). Mitochondria in aging and Alzheimer's disease. Rejuvenation Res, 10:349-357.
[16] Moreira PI, Santos MS, Oliveira CR (2007). Alzheimer's disease: a lesson from mitochondrial dysfunction. Antioxid Redox Signal, 9:1621-1630.
[17] Joselin AP, Hewitt SJ, Callaghan SM, Kim RH, Chung YH, Mak TWet al (2012). ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum Mol Genet, 21:4888-4903.
[18] Crifo C, Capuozzo E, Siems W, Salerno C (2005). Inhibition of ion transport ATPases by HNE. Biofactors, 24:137-140.
[19] Crifo C, Siems W, Soro S, Salerno C (2005). Inhibition of defective adenylosuccinate lyase by HNE: a neurological disease that may be affected by oxidative stress. Biofactors, 24:131-136.
[20] Siems W, Grune T, Sommerburg O, Flohe L, Cadenas E (2005). HNE and Further Lipid Peroxidation Products. Biofactors, 24:1-4.
[21] Castellani RJ, Perry G, Siedlak SL, Nunomura A, Shimohama S, Zhang Jet al (2002). Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans. Neurosci Lett, 319:25-28.
[22] Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA (1997). 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem, 68:2092-2097.
[23] Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T (2008). Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS ONE, 3:e1433.
[24] Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SDet al (2003). D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest, 112:892-901.
[25] Reeves MB, Davies AA, McSharry BP, Wilkinson GW, Sinclair JH (2007). Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. Science, 316:1345-1348.
[26] Storch A, Jost WH, Vieregge P, Spiegel J, Greulich W, Durner Jet al (2007). Randomized, double-blind, placebo-controlled trial on symptomatic effects of coenzyme Q(10) in Parkinson disease. Arch Neurol, 64:938-944.
[27] Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JLet al (1995). Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet, 11:376-381.
[28] Wilkins HM, Kirchhof D, Manning E, Joseph JW, Linseman DA (2013). Mitochondrial glutathione transport is a key determinant of neuronal susceptibility to oxidative and nitrosative stress. J Biol Chem, 288:5091-5101.
[29] Hill BG, Benavides GA, Lancaster JR Jr., Ballinger S, Dell'italia L, Zhang Jet al (2012). Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem, 393:1485-1512.
[30] Harman D (1956). Aging: a theory based on free radical and radiation chemistry. J Gerontol, 11:298-300.
[31] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013). The hallmarks of aging. Cell, 153:1194-1217.
[32] Ristow M,Schmeisser K (2014). Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS). Dose Response, 12:288-341.
[33] Durieux J, Wolff S, Dillin A (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell, 144:79-91.
[34] Yang W,Hekimi S (2010). A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol, 8:e1000556.
[35] Yee C, Yang W, Hekimi S (2014). The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell, 157:897-909.
[36] Lee SJ, Hwang AB, Kenyon C (2010). Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol, 20:2131-2136.
[37] Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow Det al (2012). Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab, 15:451-465.
[38] Van Raamsdonk JM,Hekimi S (2009). Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet, 5:e1000361.
[39] Cabreiro F, Ackerman D, Doonan R, Araiz C, Back P, Papp Det al (2011). Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med, 51:1575-1582.
[40] Van Raamsdonk JM,Hekimi S (2012). Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci U S A, 109:5785-5790.
[41] Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr., Dionne L, Lu Net al (1996). Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci U S A, 93:9782-9787.
[42] Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong Ret al (2006). Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med, 40:1993-2004.
[43] 43. Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang Het al (2010). Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J, 24:1376-1390.
[44] Flood DG, Reaume AG, Gruner JA, Hoffman EK, Hirsch JD, Lin YGet al (1999). Hindlimb motor neurons require Cu/Zn superoxide dismutase for maintenance of neuromuscular junctions. Am J Pathol, 155:663-672.
[45] Larkin LM, Davis CS, Sims-Robinson C, Kostrominova TY, Van RH, Richardson Aet al (2011). Skeletal muscle weakness due to deficiency of CuZn-superoxide dismutase is associated with loss of functional innervation. Am J Physiol Regul Integr Comp Physiol, 301:R1400-R1407.
[46] Sims-Robinson C, Bakeman A, Rosko A, Glasser R, Feldman EL (2015). The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain. Mol Neurobiol. In press.
[47] Perez VI, Van RH, Bokov A, Epstein CJ, Vijg J, Richardson A (2009). The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell, 8:73-75.
[48] Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CEet al (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429:417-423.
[49] Itsara LS, Kennedy SR, Fox EJ, Yu S, Hewitt JJ, Sanchez-Contreras Met al (2014). Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations. PLoS Genet, 10:e1003974.
[50] Lin TK, Hughes G, Muratovska A, Blaikie FH, Brookes PS, Darley-Usmar Vet al (2002). Specific modification of mitochondrial protein thiols in response to oxidative stress: a proteomics approach. J Biol Chem, 277:17048-17056.
[51] Higdon A, Diers AR, Oh JY, Landar A, Darley-Usmar VM (2012). Cell signalling by reactive lipid species: new concepts and molecular mechanisms. Biochem J, 442:453-464.
[52] Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Orr AL, Brand MD (2013). Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biol, 1:304-312.
[53] Takacs-Vellai K, Vellai T, Puoti A, Passannante M, Wicky C, Streit Aet al (2005). Inactivation of the autophagy gene bec-1 triggers apoptotic cell death in C. elegans. Curr Biol, 15:1513-1517.
[54] Juhasz G, Erdi B, Sass M, Neufeld TP (2007). Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev, 21:3061-3066.
[55] Toth ML, Sigmond T, Borsos E, Barna J, Erdelyi P, Takacs-Vellai Ket al (2008). Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy, 4:330-338.
[56] Wu JJ, Quijano C, Chen E, Liu H, Cao L, Fergusson MMet al (2009). Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Albany NY), 1:425-437.
[57] Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken HH, Becker Det al (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE, 4:e5777.
[58] 58. Gautier CA, Kitada T, Shen J (2008). Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci U S A, 105:11364-11369.
[59] Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey Ket al (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460:392-395.
[60] Vellai T, Takacs-Vellai K, Sass M, Klionsky DJ (2009). The regulation of aging: does autophagy underlie longevity? Trends Cell Biol, 19:487-494.
[61] Vellai T (2009). Autophagy genes and ageing. Cell Death Differ, 16:94-102.
[62] Madeo F, Tavernarakis N, Kroemer G (2010). Can autophagy promote longevity? Nat Cell Biol, 12:842-846.
[63] Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras Ket al (2010). Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis, 1:e10.
[64] Bjedov I,Partridge L (2011). A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans, 39:460-465.
[65] Mai S, Muster B, Bereiter-Hahn J, Jendrach M (2012). Autophagy proteins LC3B, ATG5 and ATG12 participate in quality control after mitochondrial damage and influence lifespan. Autophagy, 8:47-62.
[66] Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TIet al (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun, 4:2300.
[67] Li J, Kim SG, Blenis J (2014). Rapamycin: one drug, many effects. Cell Metab, 19:373-379.
[68] Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DMet al (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science, 335:1638-1643.
[69] Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LBet al (2012). Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience, 223:102-113.
[70] Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig Eet al (2012). Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell, 11:326-335.
[71] Richardson A (2013). Rapamycin, anti-aging, and avoiding the fate of Tithonus. J Clin Invest, 123:3204-3206.
[72] Lin AL, Zheng W, Halloran JJ, Burbank RR, Hussong SA, Hart MJet al (2013). Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb Blood Flow Metab, 33:1412-1421.
[73] Richardson A, Galvan V, Lin AL, Oddo S (2014). How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story. Exp Gerontol.
[74] Liu Y, Diaz V, Fernandez E, Strong R, Ye L, Baur JAet al (2014). Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging (Albany NY), 6:742-754.
[75] Fok WC, Chen Y, Bokov A, Zhang Y, Salmon AB, Diaz Vet al (2014). Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS ONE, 9:e83988.
[76] Zhang Y, Bokov A, Gelfond J, Soto V, Ikeno Y, Hubbard Get al (2014). Rapamycin extends life and health in C57BL/6 mice. J Gerontol A Biol Sci Med Sci, 69:119-130.
[77] Tardif S, Ross C, Bergman P, Fernandez E, Javors M, Salmon Aet al (2015). Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. J Gerontol A Biol Sci Med Sci, 70:577-588.
[78] Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han Met al (2014). Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell, 13:468-477.
[79] Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell, 6:95-110.
[80] Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AIet al (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science, 326:140-144.
[81] Mortiboys H, Thomas KJ, Koopman WJ, Klaffke S, bou-Sleiman P, Olpin Set al (2008). Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol, 64:555-565.
[82] Jolly RD, Brown S, Das AM, Walkley SU (2002). Mitochondrial dysfunction in the neuronal ceroid-lipofuscinoses (Batten disease). Neurochem Int, 40:565-571.
[83] Rouschop KM, Ramaekers CH, Schaaf MB, Keulers TG, Savelkouls KG, Lambin Pet al (2009). Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother Oncol, 92:411-416.
[84] Park BC, Park SH, Paek SH, Park SY, Kwak MK, Choi HGet al (2008). Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells. Toxicol Lett, 178:52-60.
[85] Farombi EO (2006). Genotoxicity of chloroquine in rat liver cells: protective role of free radical scavengers. Cell Biol Toxicol, 22:159-167.
[86] Park J, Choi K, Jeong E, Kwon D, Benveniste EN, Choi C (2004). Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia, 47:9-20.
[87] Yamasaki R, Zhang J, Koshiishi I, Sastradipura Suniarti DF, Wu Z, Peters Cet al (2007). Involvement of lysosomal storage-induced p38 MAP kinase activation in the overproduction of nitric oxide by microglia in cathepsin D-deficient mice. Mol Cell Neurosci, 35:573-584.
[88] Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WHet al (2008). Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci, 28:6926-6937.
[89] Koike M, Shibata M, Waguri S, Yoshimura K, Tanida I, Kominami Eet al (2005). Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Am J Pathol, 167:1713-1728.
[90] Nakanishi H, Zhang J, Koike M, Nishioku T, Okamoto Y, Kominami Eet al (2001). Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice. J Neurosci, 21:7526-7533.
[91] Saftig P, Hetman M, Schmahl W, Weber K, Heine L, Mossmann Het al (1995). Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J, 14:3599-3608.
[92] Koike M, Nakanishi H, Saftig P, Ezaki J, Isahara K, Ohsawa Yet al (2000). Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J Neurosci, 20:6898-6906.
[93] Cuervo AM,Dice JF (2000). When lysosomes get old. Exp Gerontol, 35:119-131.
[94] Chu Y, Dodiya H, Aebischer P, Olanow CW, Kordower JH (2009). Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions. Neurobio Dis, 35:385-398.
[95] Zhou H, Cao F, Wang Z, Yu ZX, Nguyen HP, Evans Jet al (2003). Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity. J Cell Biol, 163:109-118.
[96] Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno Met al (2011). Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. Brain, 134:258-277.
[97] Tizon B, Sahoo S, Yu H, Gauthier S, Kumar AR, Mohan Pet al (2010). Induction of autophagy by cystatin C: a mechanism that protects murine primary cortical neurons and neuronal cell lines. PLoS ONE, 5:e9819.
[98] Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen Jet al (2006). Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron, 51:703-714.
[99] Dranka BP, Benavides GA, Diers AR, Giordano S, Zelickson BR, Reily Cet al (2011). Assessing bioenergetic function in response to oxidative stress by metabolic profiling. Free Radic Biol Med, 51:1621-1635.
[100] Salabei JK, Gibb AA, Hill BG (2014). Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis. Nat Protoc, 9:421-438.
[101] Ballinger SW, Patterson C, Yan CN, Doan R, Burow DL, Young CGet al (2000). Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res, 86:960-966.
[102] Ballinger SW, Van HB, Jin GF, Conklin CA, Godley BF (1999). Hydrogen peroxide causes significant mitochondrial DNA damage in human RPE cells. Exp Eye Res, 68:765-772.
[103] Ballinger SW, Bouder TG, Davis GS, Judice SA, Nicklas JA, Albertini RJ (1996). Mitochondrial genome damage associated with cigarette smoking. Cancer Res, 56:5692-5697.
[104] Wallace DC, Lott MT, Shoffner JM, Ballinger S (1994). Mitochondrial DNA mutations in epilepsy and neurological disease. Epilepsia, 35 Suppl 1:S43-S50.
[105] Ballinger SW, Shoffner JM, Hedaya EV, Trounce I, Polak MA, Koontz DAet al (1992). Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nat Genet, 1:11-15.
[106] Kalyanaraman B, Darley-Usmar V, Davies KJ, Dennery PA, Forman HJ, Grisham MBet al (2012). Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. Free Radic Biol Med, 52:1-6.
[107] Bailey SM, Andringa KK, Landar A, rley-Usmar VM (2008). Proteomic approaches to identify and characterize alterations to the mitochondrial proteome in alcoholic liver disease. Methods Mol Biol, 447:369-380.
[108] Higdon AN, Benavides GA, Chacko BK, Ouyang X, Johnson MS, Landar Aet al (2012). Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy. Am J Physiol Heart Circ Physiol, 302:H1394-H1409.
[109] Mitchell T, Johnson MS, Ouyang X, Chacko BK, Mitra K, Lei Xet al (2013). Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita+/Ins2-derived beta-cells. Am J Physiol Endocrinol Metab, 305:E585-E599.
[110] Benavides GA, Liang Q, Dodson M, Darley-Usmar V, Zhang J (2013). Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons. Free Radic Biol Med, 65:1215-1228.
[111] Liang Q, Benavides GA, Vassilopoulos A, Gius D, Darley-Usmar V, Zhang J (2013). Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts. Biochem J, 454:249-257.
[112] Boyer-Guittaut M, Poillet L, Liang Q, Bole-Richard E, Ouyang X, Benavides GAet al (2014). The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells. Autophagy, 10:986-1003.
[113] Levonen AL, Hill BG, Kansanen E, Zhang J, Darley-Usmar VM (2014). Redox regulation of antioxidants, autophagy, and the response to stress: Implications for electrophile therapeutics. Free Radic Biol Med, 71C:196-207.
[114] Mitchell T, Chacko B, Ballinger SW, Bailey SM, Zhang J, Darley-Usmar V (2013). Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics. Biochem Soc Trans, 41:127-133.
[115] Jegga AG, Schneider L, Ouyang X, Zhang J (2011). Systems biology of the autophagy-lysosomal pathway. Autophagy, 7:477-489.
[116] Jaber N, Dou Z, Chen JS, Catanzaro J, Jiang YP, Ballou LMet al (2012). Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci U S A, 109:2003-2008.
[117] Jaber N, Dou Z, Lin RZ, Zhang J, Zong WX (2012). Mammalian PIK3C3/VPS34: the key to autophagic processing in liver and heart. Autophagy, 8:707-708.
[118] Wani WY, Boyer-Guittaut M, Dodson M, Chatham J, Darley-Usmar V, Zhang J (2015). Regulation of autophagy by protein post-translational modification. Lab Invest, 95:14-25.
[119] Schneider L, Giordano S, Zelickson BR, Johnson S, Benavides A, Ouyang Xet al (2011). Differentiation of SH-SY5Y cells to a neuronal phenotype changes cellular bioenergetics and the response to oxidative stress. Free Radic Biol Med, 51:2007-2017.
[120] Giordano S, Lee J, Darley-Usmar VM, Zhang J (2012). Distinct Effects of Rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on Cellular Bioenergetics and Cell Death. PLoS ONE, 7:e44610.
[121] Dodson M, Liang Q, Johnson MS, Redmann M, Fineberg N, Darley-Usmar VMet al (2013). Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells. Autophagy, 9:1996-2008.
[122] Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS (2001). Environmental risk factors and Parkinson's disease: a metaanalysis. Environ Res, 86:122-127.
[123] Priyadarshi A, Khuder SA, Schaub EA, Shrivastava S (2000). A meta-analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology, 21:435-440.
[124] van der MM, Brouwer M, Kromhout H, Nijssen P, Huss A, Vermeulen R (2012). Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results. Environ Health Perspect, 120:340-347.
[125] Pezzoli G,Cereda E (2013). Exposure to pesticides or solvents and risk of Parkinson disease. Neurology, 80:2035-2041.
[126] Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci, 3:1301-1306.
[127] Inden M, Kitamura Y, Abe M, Tamaki A, Takata K, Taniguchi T (2011). Parkinsonian rotenone mouse model: reevaluation of long-term administration of rotenone in C57BL/6 mice. Biol Pharm Bull, 34:92-96.
[128] Giordano S, Dodson M, Ravi S, Redmann M, Ouyang X, Darley Usmar VMet al (2014). Bioenergetic adaptation in response to autophagy regulators during rotenone exposure. J Neurochem, 131:625-633.
[129] Lee HJ, Cho ED, Lee KW, Kim JH, Cho SG, Lee SJ (2013). Autophagic failure promotes the exocytosis and intercellular transfer of alpha-synuclein. Exp Mol Med, 45:e22.
[130] Liang Q, Ouyang X, Schneider L, Zhang J (2011). Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons. Mol Neurodegener, 6:37.
[131] Tanik SA, Schultheiss CE, Volpicelli-Daley LA, Brunden KR, Lee VM (2013). Lewy body-like alpha-synuclein aggregates resist degradation and impair macroautophagy. J Biol Chem, 288:15194-15210.
[132] Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A (2013). TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc Natl Acad Sci U S A, 110:E1817-E1826.
[133] Kilpatrick K, Zeng Y, Hancock T, Segatori L (2015). Genetic and Chemical Activation of TFEB Mediates Clearance of Aggregated alpha-Synuclein. PLoS ONE, 10:e0120819.
[134] Tsujimura A, Taguchi K, Watanabe Y, Tatebe H, Tokuda T, Mizuno Tet al (2014). Lysosomal enzyme cathepsin B enhances the aggregate forming activity of exogenous alpha-synuclein fibrils. Neurobiol Dis, 73C:244-253.
[135] Schapira AH,Gegg M (2011). Mitochondrial contribution to Parkinson's disease pathogenesis. Parkinsons Dis, 2011:159160.
[136] Murphy MP (2009). How mitochondria produce reactive oxygen species. Biochem J, 417:1-13.
[137] Keeney PM, Xie J, Capaldi RA, Bennett JP, Jr. (2006). Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J Neurosci, 26:5256-5264.
[138] Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008). Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem, 283:9089-9100.
[139] Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory Met al (2000). alpha-synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol, 157:401-410.
[140] Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NAet al (2006). Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci, 26:41-50.
[141] Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun Let al (2009). Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron, 64:807-827.
[142] Liu G, Zhang C, Yin J, Li X, Cheng F, Li Yet al (2009). alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett, 454:187-192.
[143] Chinta SJ, Mallajosyula JK, Rane A, Andersen JK (2010). Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett, 486:235-239.
[144] Zhu Y, Duan C, Lu L, Gao H, Zhao C, Yu Set al (2011). alpha-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator. Int J Biochem Cell Biol, 43:732-741.
[145] Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami Ket al (2011). Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem, 286:20710-20726.
[146] Sarafian TA, Ryan CM, Souda P, Masliah E, Kar UK, Vinters HVet al (2013). Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human alpha-synuclein. PLoS ONE, 8:e63557.
[147] Mejias R, Villadiego J, Pintado CO, Vime PJ, Gao L, Toledo-Aral JJet al (2006). Neuroprotection by transgenic expression of glucose-6-phosphate dehydrogenase in dopaminergic nigrostriatal neurons of mice. J Neurosci, 26:4500-4508.
[148] Ebadi M, Brown-Borg H, El RH, Singh BB, Garrett S, Shavali Set al (2005). Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Res Mol Brain Res, 134:67-75.
[149] Yacoubian TA,Standaert DG (2009). Targets for neuroprotection in Parkinson's disease. Biochim Biophys Acta, 1792:676-687.
[150] Giordano S, Darley-Usmar V, Zhang J (2014). Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. Redox Biol, 2:82-90.
[1] Wei Zhuang,Lifeng Yue,Xiaofang Dang,Fei Chen,Yuewen Gong,Xiaolan Lin,Yumin Luo. Rosenroot (Rhodiola): Potential Applications in Aging-related Diseases[J]. Aging and disease, 2019, 10(1): 134-146.
[2] Antonina Luca, Carmela Calandra, Maria Luca. Molecular Bases of Alzheimer’s Disease and Neurodegeneration: The Role of Neuroglia[J]. Aging and disease, 2018, 9(6): 1134-1152.
[3] Changhong Ren, Hang Wu, Dongjie Li, Yong Yang, Yuan Gao, Yunneng Jizhang, Dachuan Liu, Xunming Ji, Xuxiang Zhang. Remote Ischemic Conditioning Protects Diabetic Retinopathy in Streptozotocin-induced Diabetic Rats via Anti-Inflammation and Antioxidation[J]. Aging and disease, 2018, 9(6): 1122-1133.
[4] Yong-Fei Zhao, Qiong Zhang, Jian-Feng Zhang, Zhi-Yin Lou, Hen-Bing Zu, Zi-Gao Wang, Wei-Cheng Zeng, Kai Yao, Bao-Guo Xiao. The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson’s Disease[J]. Aging and disease, 2018, 9(5): 785-797.
[5] Eckert Schamim H, Gaca Janett, Kolesova Nathalie, Friedland Kristina, Eckert Gunter P, Muller Walter E. Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease[J]. Aging and disease, 2018, 9(4): 729-744.
[6] Morroni Fabiana, Sita Giulia, Graziosi Agnese, Turrini Eleonora, Fimognari Carmela, Tarozzi Andrea, Hrelia Patrizia. Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway[J]. Aging and disease, 2018, 9(4): 605-622.
[7] Shen Ting, You Yuyi, Joseph Chitra, Mirzaei Mehdi, Klistorner Alexander, Graham Stuart L., Gupta Vivek. BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders[J]. Aging and disease, 2018, 9(3): 523-536.
[8] Zhang Meng, Deng Yong-Ning, Zhang Jing-Yi, Liu Jie, Li Yan-Bo, Su Hua, Qu Qiu-Min. SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway[J]. Aging and disease, 2018, 9(2): 273-286.
[9] Mari L. Sbardelotto,Giulia S. Pedroso,Fernanda T. Pereira,Helen R. Soratto,Stella MS. Brescianini,Pauline S. Effting,Anand Thirupathi,Renata T. Nesi,Paulo CL. Silveira,Ricardo A. Pinho. The Effects of Physical Training are Varied and Occur in an Exercise Type-Dependent Manner in Elderly Men[J]. A&D, 2017, 8(6): 887-898.
[10] Gao Guofen, Zhang Nan, Wang Yue-Qi, Wu Qiong, Yu Peng, Shi Zhen-Hua, Duan Xiang-Lin, Zhao Bao-Lu, Wu Wen-Shuang, Yan-Zhong Chang. Mitochondrial Ferritin Protects Hydrogen Peroxide-Induced Neuronal Cell Damage[J]. Aging and disease, 2017, 8(4): 458-470.
[11] Szybińska Aleksandra, Leśniakx Leśniak. P53 Dysfunction in Neurodegenerative Diseases - The Cause or Effect of Pathological Changes?[J]. Aging and disease, 2017, 8(4): 506-518.
[12] Zheng Hong, Wu Jinzi, Jin Zhen, Yan Liang-Jun. Potential Biochemical Mechanisms of Lung Injury in Diabetes[J]. Aging and disease, 2017, 8(1): 7-16.
[13] Kyung Soo Kim,Jin Wook Kwak,Su Jin Lim,Yong Kyun Park,Hoon Shik Yang,Hyun Jik Kim. Oxidative Stress-induced Telomere Length Shortening of Circulating Leukocyte in Patients with Obstructive Sleep Apnea[J]. A&D, 2016, 7(5): 604-613.
[14] Amelia Maria Gaman,Adriana Uzoni,Aurel Popa-Wagner,Anghel Andrei,Eugen-Bogdan Petcu. The Role of Oxidative Stress in Etiopathogenesis of Chemotherapy Induced Cognitive Impairment (CICI)-“Chemobrain”[J]. A&D, 2016, 7(3): 307-317.
[15] Haiping Zhao,Ziping Han,Xunming Ji,Yumin Luo. Epigenetic Regulation of Oxidative Stress in Ischemic Stroke[J]. A&D, 2016, 7(3): 295-306.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd