2. Academic Validation
  3. Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency

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

  • Cell Rep. 2018 Jun 26;23(13):3710-3720.e8. doi: 10.1016/j.celrep.2018.06.002.
Colleen S Stein 1,  Pooja Jadiya 2,  Xiaoming Zhang 1,  Jared M McLendon 1,  Gabrielle M Abouassaly 1,  Nathan H Witmer 1,  Ethan J Anderson 3,  John W Elrod 2,  Ryan L Boudreau 4
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 2 Center of Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
  • 3 Department of Pharmaceutical Sciences and Experimental Therapeutics, Fraternal Order of Eagles Diabetes Research Center, Abboud Cardiovascular Research Center, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
  • 4 Department of Internal Medicine, Fraternal Order of Eagles Diabetes Research Center, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address: [email protected].
PMID: 29949756 DOI: 10.1016/j.celrep.2018.06.002
Abstract

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

Keywords

ROS; assembly factor; fatty acid oxidation; micropeptide; microprotein; mitochondria; mitochondrial calcium; respirasome; sORF; supercomplexes.

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