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Sirtuin 3‐ and Diet‐Mediated Regulation of Mitochondrial Function During Aging
Author(s) -
Dhillon Rashpal S.,
Ginkel Paul R.,
Fu Vivian,
Prolla Tomas A.,
Denu John M.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.941.6
Subject(s) - sirt3 , sirtuin , mitochondrion , biology , sirt2 , senescence , oxidative phosphorylation , acetylation , oxidative stress , microbiology and biotechnology , nad+ kinase , sirtuin 1 , phenotype , endocrinology , biochemistry , enzyme , downregulation and upregulation , gene
Aging is a multifactorial process that results in the gradual damage of a number of cellular systems. Specifically, the decline of mitochondrial function due to hyperacetylation has been implicated in numerous metabolic defects, including senescence. The NAD + ‐dependent mitochondrial deacetylase, sirtuin 3 (SIRT3) has a marked impact on mitochondrial acetylation status and may be responsible for attenuating oxidative stress. Furthermore, caloric restriction, which induces SIRT3 expression, has been linked to increased longevity. However, the impact of acetylation on mitochondrial function over the lifespan of an organism remains largely unknown. Here, we used a multi‐tissue approach to establish the role of SIRT3 and acetylation status in governing aging phenotypes by comparing mitochondrial function and structure in aging mice. C57BL/6 mice in the SIRT3 +/+ and −/− condition were fed a control or calorically‐restricted diet, and sampled at 5, 15, and 25 months of age. Gastrocnemius, brain, liver and heart were measured for respiratory capacity, complex enzyme kinetics, mitochondrial morphology, mtDNA content, and the protein expression of key SIRT3 targets. Metabolomic profiling of the liver was used to assess the impact of electron transport impairments on substrate utilization and accumulation. To determine possible mechanisms for the aging phenotypes observed in the present study, we examined expression levels of ATP‐dependent mitochondrial proteases. Generally, all tissues had markedly different respiratory responses to the treatment condition. However, oxygen flux through complex II revealed a significant SIRT3‐CR “rescue” effect at old age in most tissues. These results suggest that the deficiencies in oxidative phosphorylation may be driven by an impaired function at respiratory complexes caused by reduced protein content or complex activity. Mitochondrial structure, as determined by electron microscopy, revealed differences amongst groups, dependent on both genotype and diet. Overall, our findings suggest that SIRT3 in conjunction with caloric restriction may play a pivotal role in the age‐related response of the mitochondrial respiratory chain to aging in a tissue‐specific manner. Support or Funding Information National Institute of Health, National Institute on Aging