Skip to main content
SpringerLink
Log in

Role of SIRT3 and Mitochondrial Dysfunction in Neurodegeneration

  • Protocol
  • First Online:
Neurodegenerative Diseases Biomarkers

Part of the book series: Neuromethods ((NM,volume 173))

  • 1428 Accesses

Abstract

Loss of function of Sirtuin-3 (SIRT3) has been associated with multiple neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Given the involvement of SIRT3 in maintaining healthy mitochondrial respiration and redox homeostasis, it is widely speculated that reduction of this mitochondrial enzyme contributes to the pathogenesis of these neurodegenerative disorders. More recently, SIRT3 activation has also been shown in model organisms and human cells to be an effective strategy to slow the progression of neurodegeneration. In this chapter, we describe the roles of SIRT3 in regulating cellular metabolism, and review recent research on the roles of SIRT3 in neurodegeneration. Finally, we provide a list of biochemical assays for the investigation of SIRT3 levels and activities in cultured cells.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Berger F, Lau C, Dahlmann M, Ziegler M (2005) Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. J Biol Chem 280(43):36334–36341. https://doi.org/10.1074/jbc.M508660200

    Article  CAS  PubMed  Google Scholar 

  2. Haigis MC, Sinclair DA (2010) Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol 5:253–295. https://doi.org/10.1146/annurev.pathol.4.110807.092250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lombard DB, Alt FW, Cheng HL, Bunkenborg J, Streeper RS, Mostoslavsky R, Kim J, Yancopoulos G, Valenzuela D, Murphy A, Yang Y, Chen Y, Hirschey MD, Bronson RT, Haigis M, Guarente LP, Farese RV Jr, Weissman S, Verdin E, Schwer B (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27(24):8807–8814. https://doi.org/10.1128/MCB.01636-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Onyango P, Celic I, Mccaffery JM, Boeke JD, Feinberg AP (2002) SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci U S A 99(21):13653–13658. https://doi.org/10.1073/pnas.222538099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, Shortreed MR, Prolla T, Markley JL, Smith LM, Zhao S, Guan KL, Denu JM (2011) Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 41(2):139–149. https://doi.org/10.1016/j.molcel.2011.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hiromasa Y, Fujisawa T, Aso Y, Roche TE (2004) Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. J Biol Chem 279(8):6921–6933. https://doi.org/10.1074/jbc.M308172200

    Article  CAS  PubMed  Google Scholar 

  7. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119(9):2758–2771. https://doi.org/10.1172/JCI39162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27(16):2276–2288. https://doi.org/10.1038/onc.2008.21

    Article  CAS  PubMed  Google Scholar 

  9. Van Der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8(6):440–450. https://doi.org/10.1038/nrm2190

    Article  CAS  PubMed  Google Scholar 

  10. Hurst LD, Williams EJ, Pal C (2002) Natural selection promotes the conservation of linkage of co-expressed genes. Trends Genet 18(12):604–606. https://doi.org/10.1016/s0168-9525(02)02813-5

    Article  CAS  PubMed  Google Scholar 

  11. Mcdonnell E, Peterson BS, Bomze HM, Hirschey MD (2015) SIRT3 regulates progression and development of diseases of aging. Trends Endocrinol Metab 26(9):486–492. https://doi.org/10.1016/j.tem.2015.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brown K, Xie S, Qiu X, Mohrin M, Shin J, Liu Y, Zhang D, Scadden DT, Chen D (2013) SIRT3 reverses aging-associated degeneration. Cell Rep 3(2):319–327. https://doi.org/10.1016/j.celrep.2013.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fritz KS, Galligan JJ, Hirschey MD, Verdin E, Petersen DR (2012) Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J Proteome Res 11(3):1633–1643. https://doi.org/10.1021/pr2008384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, Carson JJ, Tonelli M, Balloon AJ, Higbee AJ, Westphall MS, Pagliarini DJ, Prolla TA, Assadi-Porter F, Roy S, Denu JM, Coon JJ (2013) Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol Cell 49(1):186–199. https://doi.org/10.1016/j.molcel.2012.10.024

    Article  CAS  PubMed  Google Scholar 

  15. Ahn BH, Kim HS, Song S, Lee IH, Liu J, Vassilopoulos A, Deng CX, Finkel T (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A 105(38):14447–14452. https://doi.org/10.1073/pnas.0803790105

    Article  PubMed  PubMed Central  Google Scholar 

  16. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 12(6):662–667. https://doi.org/10.1016/j.cmet.2010.11.015

    Article  CAS  PubMed  Google Scholar 

  17. Bharathi SS, Zhang Y, Mohsen AW, Uppala R, Balasubramani M, Schreiber E, Uechi G, Beck ME, Rardin MJ, Vockley J, Verdin E, Gibson BW, Hirschey MD, Goetzman ES (2013) Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J Biol Chem 288(47):33837–33847. https://doi.org/10.1074/jbc.M113.510354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kim H, Kim S, Choi JE, Han D, Koh SM, Kim HS, Kaang BK (2019) Decreased neuron number and synaptic plasticity in SIRT3-knockout mice with poor remote memory. Neurochem Res 44(3):676–682. https://doi.org/10.1007/s11064-017-2417-3

    Article  CAS  PubMed  Google Scholar 

  19. Kausar S, Wang F, Cui H (2018) The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells 7(12). https://doi.org/10.3390/cells7120274

  20. Eisner V, Picard M, Hajnoczky G (2018) Mitochondrial dynamics in adaptive and maladaptive cellular stress responses. Nat Cell Biol 20(7):755–765. https://doi.org/10.1038/s41556-018-0133-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tseng AH, Shieh SS, Wang DL (2013) SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med 63:222–234. https://doi.org/10.1016/j.freeradbiomed.2013.05.002

    Article  CAS  PubMed  Google Scholar 

  22. Samant SA, Zhang HJ, Hong Z, Pillai VB, Sundaresan NR, Wolfgeher D, Archer SL, Chan DC, Gupta MP (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34(5):807–819. https://doi.org/10.1128/MCB.01483-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ranhotra HS (2009) Up-regulation of orphan nuclear estrogen-related receptor alpha expression during long-term caloric restriction in mice. Mol Cell Biochem 332(1–2):59–65. https://doi.org/10.1007/s11010-009-0174-6

    Article  CAS  PubMed  Google Scholar 

  24. Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5(7):e11707. https://doi.org/10.1371/journal.pone.0011707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI (2001) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281(6):E1340–E1346. https://doi.org/10.1152/ajpendo.2001.281.6.E1340

    Article  CAS  PubMed  Google Scholar 

  26. Pillai VB, Sundaresan NR, Kim G, Gupta M, Rajamohan SB, Pillai JB, Samant S, Ravindra PV, Isbatan A, Gupta MP (2010) Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem 285(5):3133–3144. https://doi.org/10.1074/jbc.M109.077271

    Article  CAS  PubMed  Google Scholar 

  27. Thomson DM, Herway ST, Fillmore N, Kim H, Brown JD, Barrow JR (1985) Winder WW (2008) AMP-activated protein kinase phosphorylates transcription factors of the CREB family. J Appl Physiol 104(2):429–438. https://doi.org/10.1152/japplphysiol.00900.2007

    Article  Google Scholar 

  28. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D (2003) LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 13(22):2004–2008. https://doi.org/10.1016/j.cub.2003.10.031

    Article  CAS  PubMed  Google Scholar 

  29. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI (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(25):15983–15987. https://doi.org/10.1073/pnas.252625599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408(6809):239–247. https://doi.org/10.1038/35041687

    Article  CAS  PubMed  Google Scholar 

  31. Sawada M, Carlson JC (1987) Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Ageing Dev 41(1–2):125–137. https://doi.org/10.1016/0047-6374(87)90057-1

    Article  CAS  PubMed  Google Scholar 

  32. Baloh RH, Schmidt RE, Pestronk A, Milbrandt J (2007) Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 27(2):422–430. https://doi.org/10.1523/JNEUROSCI.4798-06.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reynolds IJ, Malaiyandi LM, Coash M, Rintoul GL (2004) Mitochondrial trafficking in neurons: a key variable in neurodegeneration? J Bioenerg Biomembr 36(4):283–286. https://doi.org/10.1023/B:JOBB.0000041754.78313.c2

    Article  CAS  PubMed  Google Scholar 

  34. Tao R, Coleman MC, Pennington JD, Ozden O, Park SH, Jiang H, Kim HS, Flynn CR, Hill S, Hayes Mcdonald W, Olivier AK, Spitz DR, Gius D (2010) Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell 40(6):893–904. https://doi.org/10.1016/j.molcel.2010.12.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tao R, Vassilopoulos A, Parisiadou L, Yan Y, Gius D (2014) Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid Redox Signal 20(10):1646–1654. https://doi.org/10.1089/ars.2013.5482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, Tanokura M, Denu JM, Prolla TA (2010) Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143(5):802–812. https://doi.org/10.1016/j.cell.2010.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV Jr, Alt FW, Kahn CR, Verdin E (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285):121–125. https://doi.org/10.1038/nature08778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bause AS, Haigis MC (2013) SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol 48(7):634–639. https://doi.org/10.1016/j.exger.2012.08.007

    Article  CAS  PubMed  Google Scholar 

  39. Yang W, Nagasawa K, Munch C, Xu Y, Satterstrom K, Jeong S, Hayes SD, Jedrychowski MP, Vyas FS, Zaganjor E, Guarani V, Ringel AE, Gygi SP, Harper JW, Haigis MC (2016) Mitochondrial sirtuin network reveals dynamic SIRT3-dependent deacetylation in response to membrane depolarization. Cell 167(4):985–1000.e1021. https://doi.org/10.1016/j.cell.2016.10.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jing E, O’neill BT, Rardin MJ, Kleinridders A, Ilkeyeva OR, Ussar S, Bain JR, Lee KY, Verdin EM, Newgard CB (2013) Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation. Diabetes 62(10):3404–3417. https://doi.org/10.2337/db12-1650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kincaid B, Bossy-Wetzel E (2013) Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci 5:48. https://doi.org/10.3389/fnagi.2013.00048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schwer B, Verdin E (2008) Conserved metabolic regulatory functions of sirtuins. Cell Metab 7(2):104–112. https://doi.org/10.1016/j.cmet.2007.11.006

    Article  CAS  PubMed  Google Scholar 

  43. Dong K, Pelle E, Yarosh DB, Pernodet N (2012) Sirtuin 4 identification in normal human epidermal keratinocytes and its relation to sirtuin 3 and energy metabolism under normal conditions and UVB-induced stress. Exp Dermatol 21(3):231–233. https://doi.org/10.1111/j.1600-0625.2011.01439.x

    Article  CAS  PubMed  Google Scholar 

  44. Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF, Steegborn C (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382(3):790–801. https://doi.org/10.1016/j.jmb.2008.07.048

    Article  CAS  PubMed  Google Scholar 

  45. Verdin E, Hirschey MD, Finley LW, Haigis MC (2010) Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci 35(12):669–675. https://doi.org/10.1016/j.tibs.2010.07.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fujino T, Kondo J, Ishikawa M, Morikawa K, Yamamoto TT (2001) Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J Biol Chem 276(14):11420–11426. https://doi.org/10.1074/jbc.M008782200

    Article  CAS  PubMed  Google Scholar 

  47. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E (2010) SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12(6):654–661. https://doi.org/10.1016/j.cmet.2010.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hallows WC, Lee S, Denu JM (2006) Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A 103(27):10230–10235. https://doi.org/10.1073/pnas.0604392103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schwer B, Bunkenborg J, Verdin RO, Andersen JS, Verdin E (2006) Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc Natl Acad Sci U S A 103(27):10224–10229. https://doi.org/10.1073/pnas.0603968103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Alzheimer’s A (2015) 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 11(3):332–384. https://doi.org/10.1016/j.jalz.2015.02.003

    Article  Google Scholar 

  51. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ (2012) National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1):1–13. https://doi.org/10.1016/j.jalz.2011.10.007

    Article  PubMed  PubMed Central  Google Scholar 

  52. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15(9):1437–1449. https://doi.org/10.1093/hmg/ddl066

    Article  CAS  PubMed  Google Scholar 

  53. Mungarro-Menchaca X, Ferrera P, Moran J, Arias C (2002) beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine. J Neurosci Res 68(1):89–96. https://doi.org/10.1002/jnr.10193

    Article  CAS  PubMed  Google Scholar 

  54. Calkins MJ, Reddy PH (2011) Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons. Biochim Biophys Acta 1812(4):507–513. https://doi.org/10.1016/j.bbadis.2011.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ludewig S, Korte M (2017) Novel insights into the physiological function of the APP (gene) family and its proteolytic fragments in synaptic plasticity. Front Mol Neurosci 9:161. https://doi.org/10.3389/fnmol.2016.00161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Han P, Tang Z, Yin J, Maalouf M, Beach TG, Reiman EM, Shi J (2014) Pituitary adenylate cyclase-activating polypeptide protects against beta-amyloid toxicity. Neurobiol Aging 35(9):2064–2071. https://doi.org/10.1016/j.neurobiolaging.2014.03.022

    Article  CAS  PubMed  Google Scholar 

  57. Lee J, Kim Y, Liu T, Hwang YJ, Hyeon SJ, Im H, Lee K, Alvarez VE, Mckee AC, Um SJ, Hur M, Mook-Jung I, Kowall NW, Ryu H (2018) SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease. Aging Cell 17(1):e12679. https://doi.org/10.1111/acel.12679

    Article  CAS  Google Scholar 

  58. Li S, Yin J, Nielsen M, Beach TG, Guo L, Shi J (2019) Sirtuin 3 mediates tau deacetylation. J Alzheimers Dis 69(2):355–362. https://doi.org/10.3233/JAD-190014

    Article  CAS  PubMed  Google Scholar 

  59. Yin J, Han P, Song M, Nielsen M, Beach TG, Serrano GE, Liang WS, Caselli RJ, Shi J (2018) Amyloid-beta increases tau by mediating sirtuin 3 in Alzheimer’s disease. Mol Neurobiol 55(11):8592–8601. https://doi.org/10.1007/s12035-018-0977-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang W, Zou Y, Zhang M, Zhao N, Tian Q, Gu M, Liu W, Shi R, Lü Y, Yu W (2015) Mitochondrial Sirt3 expression is decreased in APP/PS1 double transgenic mouse model of Alzheimer’s disease. Neurochem Res 40(8):1576–1582. https://doi.org/10.1007/s11064-015-1630-1

    Article  CAS  PubMed  Google Scholar 

  61. Weir HJ, Murray TK, Kehoe PG, Love S, Verdin EM, O’neill MJ, Lane JD, Balthasar N (2012) CNS SIRT3 expression is altered by reactive oxygen species and in Alzheimer’s disease. PLoS One 7(11):e48225. https://doi.org/10.1371/journal.pone.0048225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ansari A, Rahman MS, Saha SK, Saikot FK, Deep A, Kim KH (2017) Function of the SIRT 3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging Cell 16(1):4–16. https://doi.org/10.1111/acel.12538

    Article  CAS  PubMed  Google Scholar 

  63. Yin J, Nielsen M, Carcione T, Li S, Shi J (2019) Apolipoprotein E regulates mitochondrial function through the PGC-1a-sirtuin 3 pathway. Aging (Albany NY) 11(23):11148-11156. https://doi.org/10.18632/aging.102516

  64. Ramesh S, Govindarajulu M, Lynd T, Briggs G, Adamek D, Jones E, Heiner J, Majrashi M, Moore T, Amin R, Suppiramaniam V, Dhanasekaran M (2018) SIRT3 activator Honokiol attenuates beta-Amyloid by modulating amyloidogenic pathway. PLoS One 13(1):e0190350. https://doi.org/10.1371/journal.pone.0190350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li H, Jia J, Wang W, Hou T, Tian Y, Wu Q, Xu L, Wei Y, Wang X (2018) Honokiol alleviates cognitive deficits of Alzheimer’s disease (PS1 V97L) transgenic mice by activating mitochondrial SIRT3. J Alzheimers Dis 64(1):291–302. https://doi.org/10.3233/jad-180126

    Article  CAS  PubMed  Google Scholar 

  66. Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O’Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA (2018) NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115(8):E1876–E1885. https://doi.org/10.1073/pnas.1718819115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Blesa J, Phani S, Jackson-Lewis V, Przedborski S (2012) Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012:845618. https://doi.org/10.1155/2012/845618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Savitt JM, Dawson VL, Dawson TM (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 116(7):1744–1754. https://doi.org/10.1172/JCI29178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909. https://doi.org/10.1016/s0896-6273(03)00568-3

    Article  CAS  PubMed  Google Scholar 

  70. Liu L, Peritore C, Ginsberg J, Kayhan M, Donmez G (2015) SIRT3 attenuates MPTP-induced nigrostriatal degeneration via enhancing mitochondrial antioxidant capacity. Neurochem Res 40(3):600–608. https://doi.org/10.1007/s11064-014-1507-8

    Article  CAS  PubMed  Google Scholar 

  71. Zhang X, Ren X, Zhang Q, Li Z, Ma S, Bao J, Li Z, Bai X, Zheng L, Zhang Z, Shang S, Zhang C, Wang C, Cao L, Wang Q, Ji J (2016) PGC-1alpha/ERRalpha-Sirt3 pathway regulates DAergic neuronal death by directly deacetylating SOD2 and ATP synthase beta. Antioxid Redox Signal 24(6):312–328. https://doi.org/10.1089/ars.2015.6403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang JY, Deng YN, Zhang M, Su H, Qu QM (2016) SIRT3 acts as a neuroprotective agent in rotenone-induced Parkinson cell model. Neurochem Res 41(7):1761–1773. https://doi.org/10.1007/s11064-016-1892-2

    Article  CAS  PubMed  Google Scholar 

  73. Cui XX, Li X, Dong SY, Guo YJ, Liu T, Wu YC (2017) SIRT3 deacetylated and increased citrate synthase activity in PD model. Biochem Biophys Res Commun 484(4):767–773. https://doi.org/10.1016/j.bbrc.2017.01.163

    Article  CAS  PubMed  Google Scholar 

  74. Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH (2008) Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. J Neurosci 28(47):12305–12317. https://doi.org/10.1523/JNEUROSCI.3088-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gleave JA, Arathoon LR, Trinh D, Lizal KE, Giguere N, Barber JH, Najarali Z, Khan MH, Thiele SL, Semmen MS (2017) Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism. Neurobiol Dis 106:133–146. https://doi.org/10.1016/j.nbd.2017.06.009

    Article  CAS  PubMed  Google Scholar 

  76. Park J-H, Burgess JD, Faroqi AH, Demeo NN, Fiesel FC, Springer W, Delenclos M, Mclean PJ (2020) Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway. Mol Neurodegener 15(1):1–19

    Article  Google Scholar 

  77. West A, Brummel BE, Braun AR, Rhoades E, Sachs JN (2016) Membrane remodeling and mechanics: experiments and simulations of alpha-Synuclein. Biochim Biophys Acta 1858(7 Pt B):1594–1609. https://doi.org/10.1016/j.bbamem.2016.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Patterson VL, Zullo AJ, Koenig C, Stoessel S, Jo H, Liu X, Han J, Choi M, Dewan AT, Thomas JL, Kuan CY, Hoh J (2014) Neural-specific deletion of Htra2 causes cerebellar neurodegeneration and defective processing of mitochondrial OPA1. PLoS One 9(12):e115789. https://doi.org/10.1371/journal.pone.0115789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stafa K, Tsika E, Moser R, Musso A, Glauser L, Jones A, Biskup S, Xiong Y, Bandopadhyay R, Dawson VL, Dawson TM, Moore DJ (2014) Functional interaction of Parkinson’s disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet 23(8):2055–2077. https://doi.org/10.1093/hmg/ddt600

    Article  CAS  PubMed  Google Scholar 

  80. Deng H, Dodson MW, Huang H, Guo M (2008) The Parkinson’s disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila. Proc Natl Acad Sci U S A 105(38):14503–14508. https://doi.org/10.1073/pnas.0803998105

    Article  PubMed  PubMed Central  Google Scholar 

  81. Thomas RE, Andrews LA, Burman JL, Lin W-Y, Pallanck LJ (2014) PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet 10(5):e1004279. https://doi.org/10.1371/journal.pgen.1004279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pickrell AM, Youle RJ (2015) The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85(2):257–273. https://doi.org/10.1016/j.neuron.2014.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang W, Huang Y, Huang RQ, Huang CG, Wang WH, Gu JM, Dong Y (2016) SIRT3 expression decreases with reactive oxygen species generation in rat cortical neurons during early brain injury induced by experimental subarachnoid hemorrhage. Biomed Res Int 2016:8263926. https://doi.org/10.1155/2016/8263926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Arrasate M, Finkbeiner S (2012) Protein aggregates in Huntington’s disease. Exp Neurol 238(1):1–11. https://doi.org/10.1016/j.expneurol.2011.12.013

    Article  CAS  PubMed  Google Scholar 

  85. Myers RH (2004) Huntington’s disease genetics. NeuroRx 1(2):255–262. https://doi.org/10.1602/neurorx.1.2.255

    Article  PubMed  PubMed Central  Google Scholar 

  86. Valor LM (2015) Transcription, epigenetics and ameliorative strategies in Huntington’s disease: a genome-wide perspective. Mol Neurobiol 51(1):406–423. https://doi.org/10.1007/s12035-014-8715-8

    Article  CAS  PubMed  Google Scholar 

  87. Raymond LA, Andre VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS (2011) Pathophysiology of Huntington’s disease: time-dependent alterations in synaptic and receptor function. Neuroscience 198:252–273. https://doi.org/10.1016/j.neuroscience.2011.08.052

    Article  CAS  PubMed  Google Scholar 

  88. Nasir J, Floresco SB, O’kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR (1995) Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81(5):811–823. https://doi.org/10.1016/0092-8674(95)90542-1

    Article  CAS  PubMed  Google Scholar 

  89. Fu J, Jin J, Cichewicz RH, Hageman SA, Ellis TK, Xiang L, Peng Q, Jiang M, Arbez N, Hotaling K, Ross CA, Duan W (2012) Trans-(−)-epsilon-Viniferin increases mitochondrial sirtuin 3 (SIRT3), activates AMP-activated protein kinase (AMPK), and protects cells in models of Huntington disease. J Biol Chem 287(29):24460–24472. https://doi.org/10.1074/jbc.M112.382226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Herskovits AZ, Guarente L (2013) Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res 23(6):746–758. https://doi.org/10.1038/cr.2013.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Browne SE, Beal MF (2004) The energetics of Huntington’s disease. Neurochem Res 29(3):531–546. https://doi.org/10.1023/b:nere.0000014824.04728.dd

    Article  CAS  PubMed  Google Scholar 

  92. Jodeiri Farshbaf M, Ghaedi K (2017) Huntington’s disease and mitochondria. Neurotox Res 32(3):518–529. https://doi.org/10.1007/s12640-017-9766-1

    Article  CAS  PubMed  Google Scholar 

  93. Kim J, Moody JP, Edgerly CK, Bordiuk OL, Cormier K, Smith K, Beal MF, Ferrante RJ (2010) Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum Mol Genet 19(20):3919–3935. https://doi.org/10.1093/hmg/ddq306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y, Poquiz P, Tjong J, Pouladi MA, Hayden MR, Masliah E, Ellisman M, Rouiller I, Schwarzenbacher R, Bossy B, Perkins G, Bossy-Wetzel E (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17(3):377–382. https://doi.org/10.1038/nm.2313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Valdmanis PN, Rouleau GA (2008) Genetics of familial amyotrophic lateral sclerosis. Neurology 70(2):144–152. https://doi.org/10.1212/01.wnl.0000296811.19811.db

    Article  PubMed  Google Scholar 

  96. Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, Liu Y, Wan R, Marosi K, Misiak M, Bohr VA, Mattson MP (2016) Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab 23(1):128–142. https://doi.org/10.1016/j.cmet.2015.10.013

    Article  CAS  PubMed  Google Scholar 

  97. Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH Jr (2004) Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron 43(1):19–30. https://doi.org/10.1016/j.neuron.2004.06.021

    Article  CAS  PubMed  Google Scholar 

  98. Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E (2013) Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1alpha. Neurobiol Dis 51:72–81. https://doi.org/10.1016/j.nbd.2012.07.004

    Article  CAS  PubMed  Google Scholar 

  99. Harlan BA, Pehar M, Sharma DR, Beeson G, Beeson CC, Vargas MR (2016) Enhancing NAD+ salvage pathway reverts the toxicity of primary astrocytes expressing amyotrophic lateral sclerosis-linked mutant superoxide dismutase 1 (SOD1). J Biol Chem 291(20):10836–10846. https://doi.org/10.1074/jbc.M115.698779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hor J-H, Santosa MM, Lim VJW, Xuan Ho B, Taylor A, Khong ZJ, Ravits J, Fan Y, Liou Y-C, Soh B-S, Ng S-Y (2021) ALS motor neurons exhibit hallmark metabolic defects that are rescued by SIRT3 activation. Cell Death Differ 28(4): 1379–1397. https://doi.org/10.1038/s41418-020-00664-0.

  101. Jawaid A, Murthy SB, Wilson AM, Qureshi SU, Amro MJ, Wheaton M, Simpson E, Harati Y, Strutt AM, York MK, Schulz PE (2010) A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS. Amyotroph Lateral Scler 11(6):542–548. https://doi.org/10.3109/17482968.2010.482592

    Article  PubMed  Google Scholar 

  102. Peter RS, Rosenbohm A, Dupuis L, Brehme T, Kassubek J, Rothenbacher D, Nagel G, Ludolph AC (2017) Life course body mass index and risk and prognosis of amyotrophic lateral sclerosis: results from the ALS registry Swabia. Eur J Epidemiol 32(10):901–908. https://doi.org/10.1007/s10654-017-0318-z

    Article  PubMed  Google Scholar 

  103. Parodi-Rullan RM, Chapa-Dubocq XR, Javadov S (2018) Acetylation of mitochondrial proteins in the heart: the role of SIRT3. Front Physiol 9:1094. https://doi.org/10.3389/fphys.2018.01094

    Article  PubMed  PubMed Central  Google Scholar 

  104. Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM (1999) Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol 46(5):787–790. https://doi.org/10.1002/1531-8249(199911)46:5<787::aid-ana17>3.0.co;2-8

    Article  CAS  PubMed  Google Scholar 

  105. Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA (2002) Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem 80(4):616–625. https://doi.org/10.1046/j.0022-3042.2001.00731.x

    Article  CAS  PubMed  Google Scholar 

  106. Lassmann H, Van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8(11):647–656. https://doi.org/10.1038/nrneurol.2012.168

    Article  CAS  PubMed  Google Scholar 

  107. Friese MA, Schattling B, Fugger L (2014) Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 10(4):225–238. https://doi.org/10.1038/nrneurol.2014.37

    Article  CAS  PubMed  Google Scholar 

  108. Zundorf G, Reiser G (2011) Calcium dysregulation and homeostasis of neural calcium in the molecular mechanisms of neurodegenerative diseases provide multiple targets for neuroprotection. Antioxid Redox Signal 14(7):1275–1288. https://doi.org/10.1089/ars.2010.3359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rice CM, Sun M, Kemp K, Gray E, Wilkins A, Scolding NJ (2012) Mitochondrial sirtuins—a new therapeutic target for repair and protection in multiple sclerosis. Eur J Neurosci 35(12):1887–1893. https://doi.org/10.1111/j.1460-9568.2012.08150.x

    Article  CAS  PubMed  Google Scholar 

  110. Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ (2011) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 69(3):481–492. https://doi.org/10.1002/ana.22109

    Article  CAS  PubMed  Google Scholar 

  111. D’aquila P, Rose G, Panno ML, Passarino G, Bellizzi D (2012) SIRT3 gene expression: a link between inherited mitochondrial DNA variants and oxidative stress. Gene 497(2):323–329. https://doi.org/10.1016/j.gene.2012.01.042

    Article  CAS  PubMed  Google Scholar 

  112. Inkster B, Strijbis EM, Vounou M, Kappos L, Radue EW, Matthews PM, Uitdehaag BM, Barkhof F, Polman CH, Montana G, Geurts JJ (2013) Histone deacetylase gene variants predict brain volume changes in multiple sclerosis. Neurobiol Aging 34(1):238–247. https://doi.org/10.1016/j.neurobiolaging.2012.07.007

    Article  CAS  PubMed  Google Scholar 

  113. Khodaei F, Rashedinia M, Heidari R, Rezaei M, Khoshnoud MJ (2019) Ellagic acid improves muscle dysfunction in cuprizone-induced demyelinated mice via mitochondrial Sirt3 regulation. Life Sci 237:116954. https://doi.org/10.1016/j.lfs.2019.116954

    Article  CAS  PubMed  Google Scholar 

  114. Satterstrom FK, Haigis MC (2014) Luciferase-based reporter to monitor the transcriptional activity of the SIRT3 promoter. Methods Enzymol 543:141–163. https://doi.org/10.1016/B978-0-12-801329-8.00007-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH image to ImageJ: 25 years of image analysis. Nat Methods 9(7):671–675. https://doi.org/10.1038/nmeth.2089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Guan X, Lin P, Knoll E, Chakrabarti R (2014) Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS One 9(9):e107729. https://doi.org/10.1371/journal.pone.0107729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Camacho-Pereira J, Tarrago MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN (2016) CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab 23(6):1127–1139. https://doi.org/10.1016/j.cmet.2016.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Jin-Hui Hor and Munirah Mohamad Santosa contributed equally with all other contributors.

Authors and Affiliations

  1. Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore, Singapore

    Jin-Hui Hor, Munirah Mohamad Santosa & Shi-Yan Ng

  2. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Jin-Hui Hor

  3. Yong Loo Lin School of Medicine (Physiology), National University of Singapore, Singapore, Singapore

    Munirah Mohamad Santosa & Shi-Yan Ng

  4. National Neuroscience Institute, Singapore, Singapore

    Shi-Yan Ng

Authors
  1. Jin-Hui Hor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Munirah Mohamad Santosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shi-Yan Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shi-Yan Ng .

Editor information

Editors and Affiliations

  1. Department of Anatomy, University of Otago, Dunedin, New Zealand

    Philip V. Peplow

  2. Department of Pharmacology, Department of Medicine, Reno School of Medicine, University of Nevada, Reno, NV, USA

    Bridget Martinez

  3. Department of Neurosurgery, George Washington University, West Chester, PA, USA

    Thomas A. Gennarelli

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Hor, JH., Santosa, M.M., Ng, SY. (2022). Role of SIRT3 and Mitochondrial Dysfunction in Neurodegeneration . In: Peplow, P.V., Martinez, B., Gennarelli, T.A. (eds) Neurodegenerative Diseases Biomarkers. Neuromethods, vol 173. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1712-0_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-1712-0_5

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1711-3

  • Online ISBN: 978-1-0716-1712-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation