Open AccessSIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
Author(s) -
Lee Junghee,
Kim Yunha,
Liu Tian,
Hwang Yu Jin,
Hyeon Seung Jae,
Im Hyeonjoo,
Lee Kyungeun,
Alvarez Victor E.,
McKee Ann C.,
Um SooJong,
Hur Manwook,
MookJung Inhee,
Kowall Neil W.,
Ryu Hoon
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12679
Subject(s) - sirt3 , biology , neurodegeneration , mitochondrion , mitochondrial dna , sirt2 , mitochondrial ros , alzheimer's disease , microbiology and biotechnology , dna damage , reactive oxygen species , sirtuin , gene , genetics , medicine , disease , acetylation , dna
Summary 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 SIRT 3 and mitochondrial function and neuronal activity in AD . SIRT 3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT 3 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 ND 2 and ND 4 gene expression resulting in increased reactive oxygen species ( ROS ) and reduced mitochondrial oxygen consumption. ND 2 and ND 4 gene expressions were significantly decreased in patients with AD . p53‐Ch IP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD . SIRT 3 overexpression restored the expression of ND 2 and ND 4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT 3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD . Therapeutic modulation of SIRT 3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD .