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Review
. 2014 Sep 2;5:301.
doi: 10.3389/fphys.2014.00301. eCollection 2014.

Metabolism Leaves Its Mark on the Powerhouse: Recent Progress in Post-Translational Modifications of Lysine in Mitochondria

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Free PMC article
Review

Metabolism Leaves Its Mark on the Powerhouse: Recent Progress in Post-Translational Modifications of Lysine in Mitochondria

Kyriakos N Papanicolaou et al. Front Physiol. .
Free PMC article

Abstract

Lysine modifications have been studied extensively in the nucleus, where they play pivotal roles in gene regulation and constitute one of the pillars of epigenetics. In the cytoplasm, they are critical to proteostasis. However, in the last decade we have also witnessed the emergence of mitochondria as a prime locus for post-translational modification (PTM) of lysine thanks, in large measure, to evolving proteomic techniques. Here, we review recent work on evolving set of PTM that arise from the direct reaction of lysine residues with energized metabolic thioester-coenzyme A intermediates, including acetylation, succinylation, malonylation, and glutarylation. We highlight the evolutionary conservation, kinetics, stoichiometry, and cross-talk between members of this emerging family of PTMs. We examine the impact on target protein function and regulation by mitochondrial sirtuins. Finally, we spotlight work in the heart and cardiac mitochondria, and consider the roles acetylation and other newly-found modifications may play in heart disease.

Keywords: Sirt3; Sirt5; acetylation; glutarylation; heart; malonylation; sirtuin; succinylation.

Figures

Figure 1
Figure 1
Proposed model for the increased mitochondrial protein acetylation detected in the absence of Ndufs4, CypD, and frataxin (gene deficiencies shown in red). CypD facilitates Ca++ efflux and when absent, mitochondria exhibit higher than normal [Ca++]. This upregulates matrix dehydrogenases (e.g., TCA cycle dehydrogenases and PDH). Dehydrogenase activation enhances generation of NADH, altering the balance to higher ratios of [NADH:NAD+]. Complex I normally converts NADH back to NAD+ but in the absence of Ndufs4 this conversion is blocked. Defects in complex I activity may also arise in the absence of Fe-S cluster biogenesis, a mitochondrial process regulated by frataxin. Although described independently (Wagner et al., ; Karamanlidis et al., ; Nguyen et al., 2013), the three conditions are similar in that they exhibit an increase in protein acetylation which may be at least in part attributable to elevation of [NADH:NAD+] ratios and lowering of Sirt3 activity. It remains to be determined whether mechanisms other than Sirt3 inhibition (e.g., elevation of acetyl-CoA) also contribute to increased acetylation in these models.
Figure 2
Figure 2
Diagram showing metabolic intermediates produced in mitochondria and utilized in protein lysine modifications. The inset table highlights the structural similarities and differences among the various acyl-CoA species. Lysine acetylation, propionylation, malonylation, and succinylation have been found to dynamically change in mammalian mitochondria, while other acylation variants (e.g., butyrylation, crotonylation) await further experimental characterization.
Figure 3
Figure 3
Role of Sirt3 and Sirt5 in the catalysis of protein deacylation in the presence of NAD+. Sirt3 has specificity for acetylated lysines (K-Ac) whereas Sirt5 has broader specificity and it can accommodate malonylated and succinylated substrates (K-Ma and K-Su respectively). In all cases, NAD+ is consumed to release nicotinamide while the ADP-Ribose (ADPR) moiety serves as the final acceptor of the acyl group (O-Ac-, O-Ma-, and O-Su-ADPR respectively). The acyl-modified and de-modified site is also shown.

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