Mitochondrial OPA1 cleavage is reversibly activated by differentiation of H9c2 cardiomyoblasts

Mitochondrion. 2021 Mar;57:88-96. doi: 10.1016/j.mito.2020.12.007. Epub 2020 Dec 29.

Abstract

Optic atrophy-1 (OPA1) is a dynamin-like GTPase localized to the mitochondrial inner membrane, playing key roles in inner membrane fusion and cristae maintenance. OPA1 is regulated by the mitochondrial transmembrane potential (Δψm): when Δψm is intact, long OPA1 isoforms (L-OPA1) carry out inner membrane fusion. Upon loss of Δψm, L-OPA1 isoforms are proteolytically cleaved to short (S-OPA1) isoforms by the stress-inducible OMA1 metalloprotease, causing collapse of the mitochondrial network and promoting apoptosis. Here, we show that L-OPA1 isoforms of H9c2 cardiomyoblasts are retained under loss of Δψm, despite the presence of OMA1. However, when H9c2s are differentiated to a more cardiac-like phenotype via treatment with retinoic acid (RA) in low serum media, loss of Δ ψm induces robust, and reversible, cleavage of L-OPA1 and subsequent OMA1 degradation. These findings indicate that a potent developmental switch regulates Δ ψm-sensitive OPA1 cleavage, suggesting novel developmental and regulatory mechanisms for OPA1 homeostasis.

Keywords: Cardiac; Cultured cell; Differentiation; Mitochondria; OMA1; OPA1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Line, Tumor
  • GTP Phosphohydrolases / metabolism*
  • Humans
  • Membrane Potentials
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism
  • Mice
  • Mitochondria, Heart / metabolism*
  • Mitochondrial Membranes / metabolism
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism
  • Rats
  • Tretinoin / pharmacology*

Substances

  • Tretinoin
  • Metalloendopeptidases
  • GTP Phosphohydrolases
  • Opa1 protein, rat