Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration

Abstract

Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1–7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets. SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD+ directly links their activity to the metabolic status of the cell. High NAD+ levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan. SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases. In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme. The goal of this review is to summarize emerging data supporting a neuroprotective action of SIRT3 against Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

SIRT3 Deacetylates Ceramide Synthases

“…The results of our studies demonstrating a critical role of SIRT3 in mitochondrial ROS generation after cerebral IR do not contradict the evidence of SIRT3 involvement in cellular antioxidant defense system (76). SIRT3 interacts and directly deacetylates hepatic SOD2, a primary mitochondrial antioxidant enzyme, enhancing its ability to scavenge ROS in response to caloric restriction (59).…”

“…10, A and B). In light of the oxidative stress-ameliorative effects assigned to SIRT3 function in caloric restriction studies and the protective effect of overexpressed SIRT3 in neural cells (41,42), stimulation of SIRT3 activity has been proposed to reduce mitochondrial deficits associated with cerebral oxidative stress and neurodegeneration (76). However, our studies showing that Sirt3 gene ablation protected mitochondria against cerebral IR-induced damage suggest that small molecule inhibitors of SIRT3 activity could be beneficial in the stroke treatment.…”

New Gene Profiling in Determination of Breast Cancer Recurrence and Prognosis in Iranian Women

“…In other words, SIRT3 expression levels were higher in the metastatic group as to the non-metastatic cohort. Over expression of SIRT3 in the metastatic samples may suggest its contribution to survival and dissemination of aggressive tumors (Kincaid and Bossy-Wetzel, 2013).…”

Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity

“…Sirtuins can be activated under certain stress conditions such as starvation and caloric restriction [254][255][256] to increase the efficiency of metabolism to cope with metabolic stress. However, sirtuins are usually less active under overnutrition conditions such as diabetes because of overproduction of NADH that can inhibit sirtuins activity [257,258].…”