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

Colleen S Stein; Pooja Jadiya; Xiaoming Zhang; Jared M McLendon; Gabrielle M Abouassaly; Nathan H Witmer; Ethan J Anderson; John W Elrod; Ryan L Boudreau

doi:10.1016/j.celrep.2018.06.002

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

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

Colleen S Stein, Pooja Jadiya, Xiaoming Zhang, Jared M McLendon, Gabrielle M Abouassaly, Nathan H Witmer, Ethan J Anderson, John W Elrod and Ryan L Boudreau

Cell reports (Cambridge), Vol.23(13), pp.3710-3720.e8

06/26/2018

DOI: 10.1016/j.celrep.2018.06.002

PMCID: PMC6091870

PMID: 29949756

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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. [Display omitted] •LINC00116 encodes a single-pass transmembrane protein known as mitoregulin (Mtln)•Mtln appears to be a sticky inner mitochondrial membrane protein that binds cardiolipin•Mtln levels influence mitochondrial respiration, ROS, and Ca2+ retention capacity•Mtln-KO mice exhibit deficiencies in FAO, mCa2+ retention, and supercomplexes Stein et al. show that the long non-coding RNA LINC00116 encodes a highly conserved single-pass transmembrane protein named mitoregulin (Mtln). Studies in cells and mice demonstrate that Mtln localizes to inner mitochondrial membranes, where it interacts with several complexes to influence mitochondrial membrane potential, respiration, Ca2+ retention capacity, ROS, and supercomplex levels.

sORF

assembly factor

mitochondria

microprotein

ROS

supercomplexes

micropeptide

respirasome

fatty acid oxidation

mitochondrial calcium

Details

Title: Subtitle: Mitoregulin: A lncRNA-Encoded Microprotein that Supports Mitochondrial Supercomplexes and Respiratory Efficiency
Creators: Colleen S Stein - 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
Pooja Jadiya - Center of Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
Xiaoming Zhang - 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
Jared M McLendon - 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
Gabrielle M Abouassaly - 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
Nathan H Witmer - 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
Ethan J Anderson - 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
John W Elrod - Center of Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
Ryan L Boudreau - 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
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.23(13), pp.3710-3720.e8
DOI: 10.1016/j.celrep.2018.06.002
PMID: 29949756
PMCID: PMC6091870
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000968, name: American Heart Association, award: 14SDG18590008; name: Roy J. Carver Trust; name: Fraternal Order of Eagles Diabetes Research Center; name: NIH NHLBI and NIA, award: HL136954, HL123966, DA037830, HL122863, AG057006; name: Abboud Cardiovascular Research Center NIH T32, award: HL007121
Language: English
Date published: 06/26/2018
Academic Unit: Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984065488502771

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