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Review
. 2013 Sep 6:5:48.
doi: 10.3389/fnagi.2013.00048.

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

Brad Kincaid  1 , Ella Bossy-Wetzel
Affiliations
Review

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

Brad Kincaid et al. Front Aging Neurosci. .

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.

Keywords: SIRT3; aging; antioxidants; caloric restriction; mitochondria; neurodegeneration; neuroprotection.

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Figures

FIGURE 1
FIGURE 1
Cellular stress activates SIRT3. Energy deficits resulting from calorie restriction, exercise, and fasting cause the cellular AMP:ATP ratio to increase. Increased levels of AMP trigger activation of AMPK, initiating a signaling cascade promoting SIRT3 expression. SIRT3 promotes activation of antioxidant systems, fatty acid oxidation, and neuroprotection. A positive feedback mechanism is also initiated via the deacetylation and activation of LKB1 by SIRT3, further promoting activation of AMPK. AMPK, AMP-activated protein kinase; CREB, cyclic AMP response element-binding protein; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; LKB1, liver kinase B1; AMP, adenosine-5′-monophosphate; ATP, adenosine-5′-triphosphate.
FIGURE 2
FIGURE 2
SIRT3 promotes ROS defense systems. SIRT3 deacetylates and activates MnSOD and IDH2, increasing their activity. MnSOD scavenges superoxide produced by the respiratory complexes, converting it to hydrogen peroxide which is further converted to water. Activation of IDH2 by SIRT3 increases its activity, thus producing more NADPH for use by glutathione reductase. GR converts oxidized glutathione to its reduced form, which is further used by GPX to convert the reactive hydrogen peroxide into water. O2, molecular oxygen; O2•−, superoxide; MnSOD, manganese superoxide dismutase; H2O2, hydrogen peroxide; CAT, catalase; GPX, glutathione peroxidase; GSH, reduced glutathione; GSSG, oxidized glutathione; GR, glutathione reductase; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; IDH2, isocitrate dehydrogenase 2.
FIGURE 3
FIGURE 3
Hormetic response curve. Within the hormetic zone, mild or moderate doses of ROS, calorie restriction, and exercise may increase stress resistance and promote cell survival by invoking transcription of stress response genes such as Sirt3. Alternatively, high levels of cellular stress can cause damaging effects leading to cell death. NOEL, no observed effect level; CR, calorie restriction; ROS, reactive oxygen species.
FIGURE 4
FIGURE 4
Bona fide and suggested SIRT3 substrates.
See this image and copyright information in PMC

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