Updated publication reference for PubMed record(s): 26998524. Mitochondrial proteomics was used to identify energy metabolic derangements that occur during the early stages of heart failure in well-defined mouse models. Levels of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme in ketone oxidation, was upregulated. 13C-substrate flux studies and metabolomic profiling confirmed that the hypertrophied and early stage failing heart shifts to ketone bodies as a fuel source in the context of reduced oxidation of fatty acids, the chief substrate for the normal heart. This fuel shift is associated with an expansion of the acetyl pool and reduced levels of NAD+ levels resulting in increased mitochondrial protein acetylation. Myocardium of humans with heart failure also exhibited mitochondrial protein hyperacetylation. We propose that a shift to ketones as a fuel source leads to maladaptive bioenergetic consequences during the development of heart failure.