Mitochondrial OPA1 cleavage is reversibly activated by differentiation of H9c2 cardiomyoblasts

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 (Delta psi m): when Delta psi m is intact, long OPA1 isoforms (L-OPA1) carry out inner membrane fusion. Upon loss of Delta psi m, 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 LOPA1 isoforms of H9c2 cardiomyoblasts are retained under loss of Delta psi m, 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 Delta psi m induces robust, and reversible, cleavage of L-OPA1 and subsequent OMA1 degradation. These findings indicate that a potent developmental switch regulates Delta psi m-sensitive OPA1 cleavage, suggesting novel developmental and regulatory mechanisms for OPA1 homeostasis.

Automated summary

This study found that in cardiomyoblasts, differentiation to a cardiac-like phenotype via treatment with retinoic acid results in robust cleavage and degradation of long OPA1 isoforms (L-OPA1) under loss of mitochondrial transmembrane potential, suggesting a novel developmental regulatory mechanism for OPA1 cleavage.