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Review
. 2017 Apr;23(4):320-331.
doi: 10.1016/j.molmed.2017.02.005. Epub 2017 Mar 10.

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Robert A H van de Ven  1 , Daniel Santos  2 , Marcia C Haigis  3
Affiliations
Review

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Robert A H van de Ven et al. Trends Mol Med. 2017 Apr.

Abstract

Advancing age is the major risk factor for the development of chronic diseases and is accompanied by changes in metabolic processes and mitochondrial dysfunction. Mitochondrial sirtuins (SIRT3-5) are part of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyl transferases. The dependence on NAD+ links sirtuin enzymatic activity to the metabolic state of the cell, poising them as stress sensors. Recent insights have revealed that SIRT3-5 orchestrate stress responses through coordinated regulation of substrate clusters rather than of a few key metabolic enzymes. Additionally, mitochondrial sirtuin function has been implicated in the protection against age-related pathologies, including neurodegeneration, cardiopathologies, and insulin resistance. In this review, we highlight the molecular targets of SIRT3-5 and discuss their involvement in aging and age-related pathologies.

Keywords: aging; metabolism; mitochondrial sirtuins; sirtuin networks; stress response.

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Figures

Figure 1
Figure 1. Mitochondrial Sirtuins Are NAD+-Dependent Deacylases and ADP-Ribosyl Transferases
A. mitochondrial sirtuins remove acyl moieties by positioning NAD+ to nucleophilically attack the acylated lysine. As a result, NAD+ is cleaved and 2′-O-acyl-ADP ribose and nicotinamide are formed in the process. The best characterized acyl modifications removed by mitochondrial sirtuins are shown in the inset. B. SIRT4 catalyzes the transfer of ADP-ribose from NAD+ to arginine, cysteine, serine and threonine substrates. Here, NAD+ is used by SIRT4 to nucleophilically attack the substrate yielding nicotinamide as a byproduct.
Figure 2
Figure 2. Mitochondrial Sirtuins Coordinate the Stress Response Through Control of Substrate Networks
Recent research has revealed that mitochondrial sirtuins regulate networks of mitochondrial proteins [9]. Shown are the different mitochondrial programs (bold italic) that are under the control of SIRT3, SIRT4 and SIRT5. Note the diversity of substrates and interaction partners, most notably for SIRT3, and the overlap between substrates and functional groups of substrates between sirtuins. The proteins shown are either experimentally validated as substrates or high-confidence sirtuin interacting proteins. For the complete mitochondrial sirtuin networks, see [9].
Figure 3
Figure 3. Loss of SIRT3, SIRT4 and SIRT5 Can Cause Age-Related Pathologies
Loss of SIRT3 (red), SIRT4 (blue) and SIRT5 (green) have been associated with the development of age-related diseases including cardiopathologies, insulin resistance, reduced immune function and neurodegeneration. The major phenotype associated with loss of the specific mitochondrial sirtuin is described per organ system together with the identified substrates (italicized) responsible for the development of the disease. See the section “Mitochondrial Sirtuins Protects Against Age-Related Diseases” for more detail on the different sirtuin substrates and phenotypes associated with loss of sirtuin function. WAT: white adipose tissue, CNS: central nervous system. PNS: pheriperal nervous system.
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