MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid β-Oxidation

Micropeptide regulator of beta-oxidation (MOXI) is a conserved muscle-enriched protein encoded by an RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondria! membrane where it associates with the mitochondria! trifunctional protein, an enzyme complex that plays a critical role in fatty acid 13-oxidation. Isolated heart and skeletal muscle mitochondria from MOXI knockout mice exhibit a diminished ability to metabolize fatty acids, while transgenic MOXI overexpression leads to enhanced 13-oxidation. Additionally, hearts from MOXI knockout mice preferentially oxidize carbohydrates over fatty acids in an isolated perfused heart system compared to wild-type (WT) animals. MOXI knockout mice also exhibit a profound reduction in exercise capacity, highlighting the role of MOXI in metabolic control. The functional characterization of MOXI provides insight into the regulation of mitochondria! metabolism and energy homeostasis and underscores the regulatory potential of additional micropeptides that have yet to be identified.