title: The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease.
abstract: β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Li Fang
authors.initials: LF
authors.lastname: Ng
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore; Yale-NUS College, 6 College Avenue East, Singapore 138614, Singapore. Electronic address: bchjg@nus.edu.sg.
authors.forename: Jan
authors.initials: J
authors.lastname: Gruber
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Irwin K
authors.initials: IK
authors.lastname: Cheah
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Chong Kiat
authors.initials: CK
authors.lastname: Goo
authors.affiliation: Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
authors.forename: Wei Fun
authors.initials: WF
authors.lastname: Cheong
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Kim Ping
authors.initials: KP
authors.lastname: Sit
authors.affiliation: Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Barry
authors.initials: B
authors.lastname: Halliwell
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000819:agonists / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008136:Longevity / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019076:Transgenes; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone; D000255:Adenosine Triphosphate
keywords: Alzheimer disease; Caenorhabditis elegans; Cardiolipin; Complex IV; Cytochrome c oxidase; Electron transport chain; Free radicals; Healthspan; Lifespan; MitoQ; Mitochondria-targeted antioxidants; Oxidative stress; β-Amyloid peptides