Mechanisms and Dynamics of Protein Acetylation in Mitochondria

Abstract

Reversible protein acetylation is a major regulatory mechanism for controlling protein function. Through genetic manipulations, dietary perturbations, and new proteomic technologies, the diverse functions of protein acetylation are coming into focus. Protein acetylation in mitochondria has taken center stage, revealing that 63% of mitochondrially localized proteins contain lysine acetylation sites. We summarize the field and discuss salient topics that cover spurious versus targeted acetylation, the role of SIRT3 deacetylation, nonenzymatic acetylation, and molecular models for regulatory acetylations that display high and low stoichiometry.

Keywords: acetylation; acylation; metabolic regulation; mitochondria; nonenzymatic; stoichiometry.

Figure 1. Acetylated Proteins in the Context of Global Metabolism

A large proportion of metabolic enzymes are acetylated. Mitochondrial proteins (in blue) and cytoplasmic proteins (in green) that have been found acetylated in M. musculus are overlaid on the KEGG Metabolic Pathways reference pathway. The labeled pathways have had between 8% and 30% of their total lysines acetylated [46,98].

Figure 2. Timeline of Detected Acetylated Peptides per Publication, 2006–2015

The number of acetylated peptides reported per acetyl-proteome study, grouped by year. Included experiments used liquid chromatography coupled mass spectrometry (LC-MS) to query the acetylation on the proteome level with the data type indicated by fill color. “Identification” studies report a list of peptides, “quantification” studies report the change in relative abundance in an acetyl-peptide between two experimental conditions, and “stoichiometry” studies report the ratio of acetyl-peptide to the amount of acetyl-peptide plus the unmodified corresponding peptide. The papers include experiments performed in the following organisms: M. musculus, H. sapiens, S. enterica, D. melanogaster, S. cerevisiae, R. norvegicus, and E. Coli.

Figure 3. Overview of proteins in mitochondrial metabolism with functional consequence caused by reversible acetylation

Representative mitochondrial metabolic proteins that contain known regulatory acetylation site(s) are depicted. The pathways represented display only those enzymes or subunits that contain acetylation site(s), which cause a functional consequence on enzymatic activity (See Table 1).

Figure 4. Described and Potential Lysine Acylations

Lysine has been shown to be modified by a number of acyl-groups (in blue), which are often donated from the corresponding acyl-CoA. Acetylation, succinylation [99], propionylation [100], butyrylation [70,101], malonylation [54], glutrarylation [53], myristoylation [102], and crotonylation [103] are among lysine modifications previously discovered. Other acyl-CoAs that are present in the mitochondria are likely to also modify lysines (in green), particularly if the acylation process is primarily nonenzymatically driven.