Abstract
The multiple dysfunctional changes associated with a brain affected with Alzheimer’s disease (AD) makes the understanding of primary pathogenic mechanisms challenging. Mitochondrial dysfunction has been associated with almost every neurodegenerative disease and neurodegenerative-related event. Alzheimer’s disease is no exception with data suggesting mitochondrial malfunctions ranging from improper organelle dynamics, defective oxidative phosphorylation (OXPHOS), oxidative stress, and harmful beta amyloid (Aβ) associations with the mitochondria. A major change often associated with AD is impairment of the electron transport chain at complex IV: cytochrome c oxidase (COX). This mini-review concentrates on recent work by our group that sheds light on the role COX deficiency plays in the pathophysiology of AD using a transgenic mouse model. Results suggest that neuronal COX deficiency does not increase oxidative stress and nor increases amyloidal formations in vivo. Conclusions from this work also suggest that Aβ formation is a cause of COX deficiency as opposed to the consequence.
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Anandatheerthavarada HK, Biswas G, Robin MA, Avadhani NG (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161:41–54
Atamna H, Boyle K (2006) Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer’s disease. Proc Natl Acad Sci U S A 103:3381–3386
Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517
Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80:91–100
Chagnon P, Betard C, Robitaille Y, Cholette A, Gauvreau D (1995) Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases. Neuroreport 6:711–715
Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA (2009) S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Science 324:102–105
Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC (1992) Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2:324–329
Coskun PE, Beal MF, Wallace DC (2004) Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A 101:10726–10731
Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068
Diaz F, Thomas CK, Garcia S, Hernandez D, Moraes CT (2005) Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency. Hum Mol Genet 14:2737–2748
Diaz F, Fukui H, Garcia S, Moraes CT (2006) Cytochrome c oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol Cell Biol 26:4872–4881
Dragatsis I, Zeitlin S (2000) CaMKIIalpha-Cre transgene expression and recombination patterns in the mouse brain. Genesis 26:133–135
Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097–1105
Fukui H, Diaz F, Garcia S, Moraes CT (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 104:14163–14168
Hong MG, Myers AJ, Magnusson PK, Prince JA (2008) Transcriptome-wide assessment of human brain and lymphocyte senescence. PLoS One 3:e3024
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–165
Lansbury PT, Lashuel HA (2006) A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443:774–779
Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF (2002) High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer’s disease brain. Hum Mol Genet 11:133–145
Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW (1993) Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci U S A 90:7951–7955
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452
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
Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 408:982–985
Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 63:2179–2184
Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, Zaccheo D, Odetti P, Strocchi P, Marinari UM, Tabaton M, Pronzato MA (2000) Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 268:642–646
Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M, Jennings G, Knolker HJ, Simons K (2008) Efficient inhibition of the Alzheimer’s disease beta-secretase by membrane targeting. Science 320:520–523
Rhein V, Baysang G, Rao S, Meier F, Bonert A, Muller-Spahn F, Eckert A (2009) Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 29:1063–1071
Suissa S, Wang Z, Poole J, Wittkopp S, Feder J, Shutt TE, Wallace DC, Shadel GS, Mishmar D (2009) Ancient mtDNA genetic variants modulate mtDNA transcription and replication. PLoS Genet 5:e1000474
Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10:279–288
Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A 105:19318–19323
Xu S, Zhong M, Zhang L, Wang Y, Zhou Z, Wenyan Zhang YH, Yang X, Wei A, Pei L, Yu Z (2009) Overexpression of Tfam protects mitochondria against beta-amyloid-induced oxidative damage in SH-SY5Y cells. Febs J
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Pickrell, A.M., Fukui, H. & Moraes, C.T. The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. J Bioenerg Biomembr 41, 453–456 (2009). https://doi.org/10.1007/s10863-009-9245-3
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DOI: https://doi.org/10.1007/s10863-009-9245-3