Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin

Abstract

Mitochondria are highly dynamic organelles that undergo frequent fusion and fission. Optic atrophy 1 (OPA1) is an essential GTPase protein for both mitochondrial inner membrane (IM) fusion and cristae morphology. Under mitochondria-stress conditions, membrane-anchored L-OPA1 is proteolytically cleaved to form peripheral S-OPA1, leading to the selection of damaged mitochondria for mitophagy. However, molecular details of the selective mitochondrial fusion are less well understood. Here, we showed that L-OPA1 and cardiolipin (CL) cooperate in heterotypic mitochondrial IM fusion. We reconstituted an in vitro membrane fusion reaction using purified human L-OPA1 protein expressed in silkworm, and found that L-OPA1 on one side of the membrane and CL on the other side are sufficient for fusion. GTP-independent membrane tethering through L-OPA1 and CL primes the subsequent GTP-hydrolysis-dependent fusion, which can be modulated by the presence of S-OPA1. These results unveil the most minimal intracellular membrane fusion machinery. In contrast, independent of CL, a homotypic trans-OPA1 interaction mediates membrane tethering, thereby supporting the cristae structure. Thus, multiple OPA1 functions are modulated by local CL conditions for regulation of mitochondrial morphology and quality control.

The role of nonbilayer phospholipids in mitochondrial structure and function

“…Consistent with its biophysical characteristics, CL is critical for fusion of the inner membrane via its interaction with the dynamin‐related protein OPA1, a GTPase, which mediates inner membrane fusion. A recent study has shown that the membrane fusion of OPA1‐containing liposomes is dependent on the presence and abundance of CL . In this elegant study, the authors demonstrated that when donor and acceptor liposomes containing high concentrations of CL (~ 25% of total phospholipids) and Opa1 are mixed, maximum lipid mixing and membrane fusion is observed.…”

Melatonin attenuates myocardial ischemia‐reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK‐OPA1 signaling pathways

“…At the molecular levels, mitochondrial fusion is primarily regulated by optic atrophy 1 (OPA1), which is predominately embedded in the mitochondrial membranes. Although the molecular mechanisms of mitochondrial fusion and mitophagy through OPA1 remain a matter of intense debate, increased OPA1 has been reported to be associated with active mitochondrial fusion and mitophagy by promoting the fusion of the inner mitochondrial membrane . In the atrial tissues of patients undergoing coronary artery bypass graft surgery, OPA1 is downregulated, and this process is connected with mitophagy delay .…”

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…OPA1 undergoes proteolytic processing leading to the balanced accumulation of short (S‐) and membrane‐anchored long forms (L‐) of OPA1 (MacVicar & Langer, ). Whereas either L‐OPA1 or S‐OPA1 is sufficient to preserve cristae structure and respiration (Anand et al , ; Del Dotto et al , ; Lee et al , ), L‐OPA1 is required to mediate mitochondrial fusion (Tondera et al , ; Ban et al , ; Chen & Chan, ). Two IM proteases can cleave L‐OPA1 at neighboring sites and limit fusion: the stress‐activated peptidase OMA1 (Ehses et al , ; Head et al , ) and the ATP‐dependent i ‐AAA protease YME1L (Griparic et al , ; Song et al , ).…”