The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice

Catherine A. Makarewich, Amir Z. Munir, Svetlana Bezprozvannaya, Aaron M. Gibson, Soo Young Kim, Misty S. Martin-Sandoval, Thomas P. Mathews, Luke I. Szweda, Rhonda Bassel-Duby, Eric N. Olson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function.

Original languageEnglish (US)
Article numbere2120476119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number6
DOIs
StatePublished - Feb 8 2022

Keywords

  • Cardiac
  • Microprotein
  • Mitochondria
  • Oxidative phosphorylation

ASJC Scopus subject areas

  • General

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