Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency

• DOI: 10.1016/j.celrep.2018.06.002
• Publication Date: 2018-06-26T17:03:44Z
• Authors: Colleen S. Stein; Pooja Jadiya; Xiaoming Zhang; Jared M. McLendon; Gabrielle M. Abou...; Nathan H. Witmer; Ethan J. Anderson; John W. Elrod; Ryan L. Boudreau
• Keywords: QH301-705.5; Cardiolipins; Article; Mitochondrial Proteins; Mice; 03 medical and health sciences; Animals; Humans; Amino Acid Sequence; Biology (General); RNA, Small Interfering; Mice, Knockout; 0303 health sciences; Fatty Acids; Mitochondria; Electron Transport Chain Complex Proteins; Mitochondrial Membranes; Calcium; RNA Interference; RNA, Long Noncoding; Reactive Oxygen Species; Oxidation-Reduction; Sequence Alignment; HeLa Cells; Protein Binding

Highlights•LINC00116 encodes a single-pass transmembrane protein known as mitoregulin (Mtln)•Mtln appears to be sticky inner mitochondrial membrane that binds cardiolipin•Mtln levels influence respiration, ROS, and Ca2+ retention capacity•Mtln-KO mice exhibit deficiencies in FAO, mCa2+ retention, supercomplexesSummaryMitochondria are composed of many small proteins control synthesis, complex assembly, metabolism, ion reactive oxygen species (ROS) handling. We show skeletal muscle- heart-enriched long non-coding RNA, LINC00116, highly conserved 56-amino-acid microprotein we named (Mtln). Mtln localizes the membrane, where it cardiolipin influences assembly. In cultured cells, overexpression increases potential, respiration rates, capacity while decreasing ROS matrix-free Ca2+. Mtln-knockout display perturbations respiratory (super)complex formation activity, fatty acid oxidation, tricarboxylic (TCA) cycle enzymes, capacity. Blue-native gel electrophoresis revealed co-migrates alongside several complexes, including I assembly module, V, supercomplexes. Under denaturing conditions, remains high-molecular-weight supporting its role molecular tether enhances efficiency by bolstering and/or stability.Graphical abstract