Network of the mitochondrial sirtuins (SIRT3–5). Mitochondria can metabolize fuels, such as fatty acids, amino acids, and pyruvate, derived from glucose. Electrons pass through electron transport complexes (I–IV), generating a proton gradient that is used to drive ATP synthase to generate ATP. SIRT3 binds to complex I, regulating its activity and energy levels in the cell. SIRT3 also binds and deacetylates acetyl-CoA synthetase 2 (AceCS2) and glutamate dehydrogenase (GDH), activating their enzymatic activities. SIRT4 binds and represses GDH activity via ADP-ribosylation. SIRT5 deacetylates and activates carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting step of the urea cycle.