Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling

Abstract

Sirtuins are a highly conserved family of proteins whose activity can prolong the lifespan of model organisms such as yeast, worms and flies. Mammals contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondria, dynamic organelles that function as the primary site of oxidative metabolism and play crucial roles in apoptosis and intracellular signaling. Recent findings have shed light on how the mitochondrial sirtuins function in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis and intracellular signaling.

Figure 1. Network of mitochondrial sirtuins

Mitochondria can metabolize fuels, such as fatty acids, amino acids, and pyruvate, derived from glucose. Electrons pass through electron transport complexes (I-IV; red) generating a proton gradient, which is used to drive ATP synthase (AS; red) to generate ATP. SIRT3 (gold) binds complexes I and II, regulating cellular energy levels in the cell [43, 55]. Moreover, SIRT3 binds and deacetylates acetyl-CoA synthetase 2 (AceCS2) [39, 40] and glutamate dehydrogenase (GDH) [33, 47], thereby activating their enzymatic activities. SIRT3 also binds and activates long-chain acyl-CoA dehydrogenase (LCAD) [46]. SIRT4 (light purple) binds and represses GDH activity via ADP-ribosylation [21]. In the rate-limiting step of the urea cycle, SIRT5 (light blue) deacetylates and activates carbamoyl phosphate synthetase 1 (CPS1) [48, 49].

Figure 2. Structure and alignment of sirtuins

Three dimensional structures of the sirtuin core domains from yeast Sir2 (DOI: 10.2210/pdb2hjh/pdb), mammalian SIRT2 [66], SIRT3 [32] and SIRT5 [34] were generated using UCSF Chimera [67]. In each structure, the catalytic histidine residue is highlighted in pink, and the N and C termini are shown in navy. Reference sequences for yeast Sir2 and mammalian SIRT1-5 were aligned by ClustalW and the region surrounding the catalytic core is shown with highly conserved amino acid residues shaded in blue and the catalytic histidine residue boxed in pink.

Figure 3. Mitochondria at nexus of cellular signaling

Mitochondria and mitochondrial sirtuins play a central role in intra- and extra-cellular signaling. Circulating fatty acids and acetate provide whole body energy homeostasis. The mitochondrial metabolites NAD⁺, NADH, ATP, Ca²⁺, ROS, ketone bodies, and acetyl-CoA participate in intracellular signaling.