The <i>i</i>-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission

TLDR

Mitochondrial fusion and structure depend on the dynamin‑like GTPase OPA1, whose activity is regulated by proteolytic processing. YME1L and OMA1 constitutively cleave OPA1 at two sites to generate long and short forms that support fusion, while stress‑induced OMA1 cleavage produces only short isoforms that inhibit fusion and promote fragmentation; the study examined how these forms function in cells deficient for YME1L, OMA1, or both. Deleting Oma1 in YME1L‑deficient cells restored mitochondrial tubulation, cristae morphology, and apoptotic resistance, showing that long OPA1 forms drive fusion while short forms promote fission and associate with ER–mitochondria contacts, indicating that OPA1 processing is not required for fusion but is essential for mitochondrial integrity and quality control.

Abstract

Mitochondrial fusion and structure depend on the dynamin-like GTPase OPA1, whose activity is regulated by proteolytic processing. Constitutive OPA1 cleavage by YME1L and OMA1 at two distinct sites leads to the accumulation of both long and short forms of OPA1 and maintains mitochondrial fusion. Stress-induced OPA1 processing by OMA1 converts OPA1 completely into short isoforms, inhibits fusion, and triggers mitochondrial fragmentation. Here, we have analyzed the function of different OPA1 forms in cells lacking YME1L, OMA1, or both. Unexpectedly, deletion of Oma1 restored mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in cells lacking YME1L. Long OPA1 forms were sufficient to mediate mitochondrial fusion in these cells. Expression of short OPA1 forms promoted mitochondrial fragmentation, which indicates that they are associated with fission. Consistently, GTPase-inactive, short OPA1 forms partially colocalize with ER–mitochondria contact sites and the mitochondrial fission machinery. Thus, OPA1 processing is dispensable for fusion but coordinates the dynamic behavior of mitochondria and is crucial for mitochondrial integrity and quality control.