MOXI Is a Mitochondrial Micropeptide That Enhances Fatty Acid β-Oxidation
Catherine A. Makarewich,
Kedryn K. Baskin,
Amir Z. Munir,
Svetlana Bezprozvannaya,
Gaurav Sharma,
Chalermchai Khemtong,
Akansha M. Shah,
John R. McAnally,
Craig R. Malloy,
Luke I. Szweda,
Rhonda Bassel-Duby,
Eric N. Olson
Affiliations
Catherine A. Makarewich
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kedryn K. Baskin
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Amir Z. Munir
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Svetlana Bezprozvannaya
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Gaurav Sharma
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chalermchai Khemtong
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Akansha M. Shah
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
John R. McAnally
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Craig R. Malloy
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Luke I. Szweda
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Rhonda Bassel-Duby
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Eric N. Olson
Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Summary: Micropeptide regulator of β-oxidation (MOXI) is a conserved muscle-enriched protein encoded by an RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondrial membrane where it associates with the mitochondrial trifunctional protein, an enzyme complex that plays a critical role in fatty acid β-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 β-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 mitochondrial metabolism and energy homeostasis and underscores the regulatory potential of additional micropeptides that have yet to be identified. : Micropeptide regulator of β-oxidation (MOXI) is encoded by a muscle-enriched RNA transcript misannotated as non-coding. MOXI localizes to the inner mitochondrial membrane where it interacts with the trifunctional protein to modulate fatty acid β-oxidation and exercise capacity. Keywords: micropeptide, fatty acid oxidation, metabolism, mitochondria, trifunctional protein, noncoding RNA
