Abstract
Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.
Highlights
Frequent cisplatin resistance seriously limits the treatment of ovarian cancer
The results showed that the mitochondria in the control group were filamentous and connected into a network, and those in the group treated with cisplatin alone were still filamentous, whereas those in the group treated with FCCP alone were in the intermediate transition state between filamentous and of PARL was reduced, and optic atrophy 1 (OPA1) and phosphoglycerate mutase 5 (PGAM5) were cleaved in the group treated with FCCP alone and in that receiving the combined treatment (Figure 2a–d)
Another study showed that the expression of S-OMA1 (40 KDa) increased during apoptosis [31], which was contrary to our results
Summary
Frequent cisplatin resistance seriously limits the treatment of ovarian cancer. Ovarian cancer cells exposed to cisplatin often change the tumor microenvironment [1], enhance metastatic properties [2], and adjust signal pathways [3], and they become resistant to drugs. A multidisciplinary approach to explore the molecular mechanism of improving the efficacy of cisplatin is needed [4]. Coordination of the MIM and MOM is thought to be the premise for mitochondrial-mediated apoptosis [8]. Exploring the coordination of MIM and MOM may provide new clues that could increase responses to chemotherapeutics such as cisplatin in ovarian cancer
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