Mitochondrial protein acetylation regulates metabolism

Abstract

Changes in cellular nutrient availability or energy status induce global changes in mitochondrial protein acetylation. Over one-third of all proteins in the mitochondria are acetylated, of which the majority are involved in some aspect of energy metabolism. Mitochondrial protein acetylation is regulated by SIRT3 (sirtuin 3), a member of the sirtuin family of NAD+-dependent protein deacetylases that has recently been identified as a key modulator of energy homoeostasis. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, have altered function, and contribute to mitochondrial dysfunction. This chapter presents a review of the functional impact of mitochondrial protein acetylation, and its regulation by SIRT3.

Figure 1. SIRT3 is a mitochondrial NAD⁺-dependent protein deacetylase

SIRT3 is encoded in the nucleus and imported into the mitochondrial matrix. SIRT3 uses NAD⁺ as a cofactor and removes acetyl groups from protein lysine residues within mitochondrial proteins, rendering the protein deacetylated. Ac, acetyl group.

Figure 2. Protein acetylation is abundant in the mitochondria

(A) Several proteomic datasets were integrated to identify all acetylated proteins. Redundant acetylated proteins were removed and datasets were filtered on mitochondrial proteins in mice and humans. The PubMed logo is reproduced with the permission of the National Library of Medicine. (B) Acetylated mitochondrial proteins were counted and tallied for unique sites of acetylation (percentage of mitochondrial proteins containing a number of acetylated sites compared with all acetylated mitochondrial proteins).

Figure 3. Metabolic pathways are highly acetylated

(A) Summary of all annotated mitochondrial functions and their levels of acetylation; each box represents one annotated function by GO term; the size of the box indicates the number of proteins labelled with common annotation; the colour of the box indicates the percentage of acetylated proteins in the annotated pathway (light blue, ≤25%; medium blue, 26–50%; dark blue, 51–75%; and very dark blue, ≥76%). (B) Representative schematic diagram of oxidative phosphorylation (Complex I–V) showing unacetylated (blue) and acetylated (orange) proteins. ROS, reactive oxygen species.