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SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

 Junghee Lee  ;  Yunha Kim  ;  Tian Liu  ;  Yu Jin Hwang  ;  Seung Jae Hyeon  ;  Hyeonjoo Im  ;  Kyungeun Lee  ;  Victor E. Alvarez  ;  Ann C. McKee  ;  Soo-Jong Um  ;  Manwook Hur  ;  Inhee Mook-Jung  ;  Neil W. Kowall  ;  Hoon Ryu 
 AGING CELL, Vol.17(1) : e12679, 2018 
Journal Title
Issue Date
Alzheimer's disease ; SIRT3 ; gene expression ; mitochondria ; p53
Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD-dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac-p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53-induced mitochondrial dysfunction and neuronal damage in a deacetylase activity-dependent manner. Notably, mitochondrially targeted p53 (mito-p53) directly reduced mitochondria DNA-encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53-ChIP analysis verified the presence of p53-binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito-p53 activity. Our results indicate that SIRT3 dysfunction leads to p53-mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Hur, Man Wook(허만욱) ORCID logo https://orcid.org/0000-0002-3416-1334
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