SIRT3 Regulates Mitochondrial Translation by Modulating MRPL12 Binding to Ribosome

The reversible acetylation of mitochondrial proteins regulates mitochondrial function in response to caloric intake. Generally, the acetylation of many metabolic enzymes occurs when levels of acetyl‐CoA are high, and reduces the activity of many enzymes responsible for the oxidation of acetyl‐CoA. We recently discovered that the acetylation of a mitochondrial ribosomal protein, MRPL10, is critical for the synthesis of mitochondrially‐encoded components of oxidative phosphorylation complexes. We also established a link between the SIRT3‐dependent deacetylation of MRPL10 and a decline in mitochondrial protein synthesis/translation. Here, we provide a mechanism for the role of reversible MRPL10 acetylation on protein synthesis. In this mechanism, deacetylation of MRPL10 reduces MRPL12 binding to ribosomes in mouse cell lines expressing SIRT3, while its acetylation stabilizes MRPL12 binding to the ribosome in the absence of SIRT3. Additionally, we reveal that nicotinamide, a feedback inhibitor of SIRT3, stabilizes MRPL12 and EF‐G binding to ribosomes in the presence of a non‐hydrolysable GTP analog in vitro. We suggest that the reversible acetylation of MRPL10 regulates mitochondrial translation, and consequently, oxidative phosphorylation by modulating MRPL12 binding to the mitochondrial L7/L12 stalk, an essential component of the ribosome in all organisms. Supported by NIH grant R01GM071034 (E.C.K.).