An integrated perspective and functional impact of the mitochondrial acetylome

Abstract

Growing evidence suggests that a range of reversible protein post-translational modifications such as acetylation regulates mitochondria signalling, impacting cellular homeostasis. However, the extent of this type of regulation in the control of mitochondria functionality is just beginning to be discovered, aided by the availability of high-resolution mass spectrometers and bioinformatic tools. Data mining from literature on protein acetylation profiling focused on mitochondria isolated from tissues retrieved more than 1395 distinct proteins, corresponding to more than 4858 acetylation sites. ClueGo analysis of identified proteins highlighted oxidative phosphorylation, tricarboxylic acid cycle, fatty acid oxidation and amino acid metabolism as the biological processes more prone to regulation through acetylation. This review also examines the physiological relevance of protein acetylation on the molecular pathways harbored in mitochondria under distinct pathophysiological conditions as caloric restriction and alcohol-induced liver damage. This integrative perspective will certainly help to envisage future studies targeting the regulation of mitochondrial functionality.

Keywords::

• alcohol-induced liver damage
• caloric restriction
• lysine acetylation
• mass spectrometry
• mitochondria
• proteome
• signaling
• sirtuins

Acknowledgements

This work was supported by Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA research unit (project PEst-C/QUI/UI0062/2013), research projects (PTDC/DES/114122/2009, PTDC/DES/104567/2008 and COMPETE, FCOMP-01-0124-FEDER-014707) to CENTRO-07-ST24-FEDER-002034 (co-financiated by QREN, Mais Centro-Programa Operacional Regional do Centro e União Europeia/Fundo Europeu de Desenvolvimento Regional) and RNEM.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Protein acetylation is known to modulate mitochondrial dynamics in a similar way as protein phosphorylation.

• Protein acetylation profiling of isolated mitochondria relies on enrichment approaches based on immunoaffinity selection or immunoprecipitation.

• Label-free quantitative methods are more suitable strategies for mitochondrial acetylome analysis than labeling methods.

• Few studies have performed mass spectrometry-based profiling of mitochondrial protein acetylation and all targeted liver.

• Data mining of data from studies focused on isolated mitochondria highlights oxidative phosphorylation and metabolism as the main biological processes regulated by protein acetylation.

• Unlike for phosphoproteomics, there is no straightforward predictor tool of the probable acetyltransferases/deacetylases involved in protein acetylation.

• Most of the studies on mitochondrial acetylome dynamics focus sirtuin 3, whose deacetylase activity is known to regulate this organelle’s functionality.

• General control of amino acid synthesis 5-like 1 is the only protein acetyltransferase reported to be harbored in mitochondria, being involved in its proteome regulation, particularly the activity of electron transport chain.

• A large-scale inventory of modified proteins in mitochondria is needed to expand the knowledge on this organelle dynamics.

Notes