The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function

Abstract

It is unclear how the mitochondrial fusion protein Optic atrophy 1 (OPA1), which inhibits cristae remodeling, protects from mitochondrial dysfunction. Here we identify the mitochondrial F1Fo-ATP synthase as the effector of OPA1 in mitochondrial protection. In OPA1 overexpressing cells, the loss of proton electrochemical gradient caused by respiratory chain complex III inhibition is blunted and this protection is abolished by the ATP synthase inhibitor oligomycin. Mechanistically, OPA1 and ATP synthase can interact, but recombinant OPA1 fails to promote oligomerization of purified ATP synthase reconstituted in liposomes, suggesting that OPA1 favors ATP synthase oligomerization and reversal activity by modulating cristae shape. When ATP synthase oligomers are genetically destabilized by silencing the key dimerization subunit e, OPA1 is no longer able to preserve mitochondrial function and cell viability upon complex III inhibition. Thus, OPA1 protects mitochondria from respiratory chain inhibition by stabilizing cristae shape and favoring ATP synthase oligomerization.

Opa1overexpression protects from early onsetMpv17-/--related mouse kidney disease

“…Mechanistically, the correction of mitochondrial ultrastructure was likely mediated by ATP synthase stabilization, as shown by our 1D-BNGE Western-blot data, showing the accumulation of free F 1 ATP-synthase particles in Mpv17 -/-, which were absent in Mpv17 -/-::Opa1 tg kidneys. These results are also in agreement with recent published data (Quintana-Cabrera et al, 2018). The normalization of mitochondrial ultrastructure explains the reduced apoptosis in Mpv17 -/-::Opa1 tg vs. Mpv17 -/kidneys and podocytes.…”

“…Mitochondrial cristae are controlled by a molecular network formed by the mitochondrial contact site and cristae organizing system (MICOS), the F 1 F o -ATP synthase, the IMM pleiotropic OPA1 protein, and the non-bilayer-forming phospholipids cardiolipin and phosphatidylethanolamine (Colina-Tenorio et al, 2020). OPA1 has been shown to be epistatic to MICOS (Glytsou et al, 2016), and that its protective effect against mitochondrial dysfunction is mediated by ATP synthase oligomerization (Quintana-Cabrera et al, 2018).…”

Sirt3 Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by Opa1 Gene Transfer

“…To provide further functional data on mitochondrial activity in cardiomyocytes transfected with mutOpa1, we evaluated the expression of ATP synthase subunit e (ATP5I) that is required for ATP synthase dimerization and proper functioning (38). As shown in Figure 7D and F, we found that SIRT3 silencing in iPSC-derived cardiomyocytes significantly reduced ATP5I protein expression compared with siNULL-transfected cells.…”

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 .…”

“…Although the molecular mechanisms of mitochondrial fusion and mitophagy through OPA1 remain a matter of intense debate, 27 increased OPA1 has been reported to be associated with active mitochondrial fusion and mitophagy by promoting the fusion of the inner mitochondrial membrane. 28,29 In the atrial tissues of patients undergoing coronary artery bypass graft surgery, OPA1 is downregulated, and this process is connected with mitophagy delay. 30 Furthermore, decreased OPA1 is associated with the progression of autoimmune myocarditis via the repression of mitochondrial fusion.…”