Mitochondrial metabolism, sirtuins, and aging

Abstract

The sirtuins are a family of proteins that act predominantly as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases. In mammals seven sirtuin family members exist, including three members, Sirt3, Sirt4, and Sirt5, that localize exclusively within the mitochondria. Although originally linked to life-span regulation in simple organisms, this family of proteins appears to have various and diverse functions in higher organisms. One particular property that is reviewed here is the regulation of mitochondrial number, turnover, and activity by various mitochondrial and nonmitochondrial sirtuins. An emerging consensus from these recent studies is that sirtuins may act as metabolic sensors, using intracellular metabolites such as NAD and short-chain carbon fragments such as acetyl coenzyme A to modulate mitochondrial function to match nutrient supply.

Figures

Figure 1.

Regulation of PGC-1α acetylation and activity by Sirt1. The transcriptional coactivator and regulator of mitochondrial biogenesis PGC-1α is, at least in part, regulated by lysine acetylation. In the setting of low nutrient availability, the intracellular and particularly the nuclear levels of NAD are believed to increase and lead to activation of Sirt1 enzymatic activity. This leads to PGC-1α deacetylation, resulting in increased PGC-1α activity and hence, ultimately, in an increase in mitochondrial number.

Figure 2.

A role for Sirt3 in metabolic adaptation and stress defense in the setting of low nutrients. The sirtuin family member Sirt3 is the predominant mitochondrial deacetylase. Multiple targets of Sirt3 have been described. These targets involve enzymes linked to substrate utilization as well as core components of the electron transport chain. In addition, Sirt3 has been linked to a wide array of other stress-related programs including the maintenance of redox homeostasis. See text for additional details.