Updated FTP location. Acyl CoA metabolites derived from catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translation modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong correlative connection between mitochondrial hyperacylation and disease; however, the functional consequences of these modifications remain uncertain. Here, we used a comprehensive respiratory diagnostics platform to evaluate three disparate mouse models of mitochondrial hyperacylation in heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), the SIRT5 demalonylase/desuccinylase, or the SIRT3 deacetylase. In each case, elevated acylation was accompanied by surprisingly marginal respiratory phenotypes. Of the >30 mitochondrial energy fluxes evaluated, the only outcome observed consistently across models was ~15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that have minimal impact on mitochondrial bioenergetics. See Fisher-Wellman et. al. 2018 for further experimental details, reagents, and references.