Mitochondrial protein lysine acetylation (K-ac)

Mitochondrial protein lysine acetylation is a widespread post-translational modification that serves as a critical regulator of metabolic flux and energy production within the cell (He et al., 2012). Unlike nuclear histone acetylation, mitochondrial acetylation often occurs non-enzymatically due to the high concentration of acetyl-CoA and the alkaline pH of the mitochondrial matrix, which increases the reactivity of lysine residues (Wagner & Hirschey, 2014). This modification generally inhibits the activity of key enzymes in the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and the urea cycle, thereby acting as a sensor for carbon stress. The primary enzymatic regulator of this state is Sirtuin 3 (SIRT3), an NAD+-dependent deacetylase that removes acetyl groups to maintain mitochondrial efficiency and redox balance (Goudarzi, 2019). Dysregulation of this process, typically manifesting as hyperacetylation, is strongly associated with metabolic syndrome, cardiovascular diseases, and age-related neurodegeneration (Baeza et al., 2016). Therapeutic interventions focus on activating sirtuins or modulating NAD+ levels to reduce the burden of acetylated residues and restore mitochondrial function (Hirschey et al., 2011). Consequently, while the residues themselves are the site of modification, the therapeutic target is usually the regulatory enzyme SIRT3.

Other names

Acetylated lysine residues on mitochondrial protein substratesMitochondrial acetylomeLysine acetylation of mitochondrial proteinsMitochondrial K-acetylation

Modulation of mitochondrial protein function through enzymatic deacetylation (primarily by SIRT3) or non-enzymatic chemical acetylation.