Targeted OMA1 therapies for cancer

Abstract

The mitochondrial inner membrane proteins OMA1 and OPA1 belong to the BAX/BAK1‐dependent apoptotic signaling pathway, which can be regulated by tumor protein p53 and the prohibitins PHB and PHB2 in the context of neoplastic disease. For the most part these proteins have been studied separate from each other. Here, I argue that the OMA1 mechanism of action represents the missing link between p53 and cytochrome c release. The mitochondrial fusion protein OPA1 is cleaved by OMA1 in a stress‐dependent manner generating S‐OPA1. Excessive S‐OPA1 can facilitate outer membrane permeabilization upon BAX/BAK1 activation through its membrane shaping properties. p53 helps outer membrane permeabilization in a 2‐step process. First, cytosolic p53 activates BAX/BAK1 at the mitochondrial surface. Then, in a second step, p53 binds to prohibitin thereby releasing the restraint on OMA1. This activates OMA1, which cleaves OPA1 and promotes cytochrome c release. Clearly, OMA1 and OPA1 are not root causes for cancer. Yet many cancer cells rely on this pathway for survival, which can explain why loss of p53 function promotes tumor growth and confers resistance to chemotherapies.

Resveratrol protects retinal ganglion cells against ischemia induced damage by increasing Opa1 expression

“…Mitochondrial fusion is determined by the tightly regulated L-Opa1/S-Opa1 ratio, where L-Opa1 facilitated mitochondrial inner membrane fusion and S-Opa1 promoted mitochondrial fission. Excessive mitochondrial fission can induce mitochondrion fragmentation, resulting in mitochondrial dysfunction and cell death (62)(63)(64)(65)(66). Under physiological conditions, Oma1 is degraded by sufficient ATP and Yme-1 serves a pivotal role in promoting mitochondrial fusion whilst inhibiting apoptosis by generating L-Opa1.…”

Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

“…Studies have displayed a significant decrease in the expression of Opa1 along with high mitochondrial fragmentation in hepatocellular carcinoma (118). Tumor suppressor p53 is involved in Oma1-mediated L-Opa1 processing and mitochondrial fragmentation in ovarian and cervical cancer cells (119), the role of which is further supported by the close relationship between S-Opa1 and the p53 signaling pathway (120). Interestingly, in mouse adult fibroblasts (MAFs), Opa1 interacts with mitochondrial F1F0-ATP synthase, favors ATP synthase oligomerization, and finally, protects mitochondria from respiratory chain inhibition by modulating crista shape (89).…”

OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development

“…Interestingly, recent studies revealed another piece of evidence that stress‐activated OMA1 mediates the cleavage of DELE1, which then relays mitochondrial stress to the cytosol (Fessler et al , 2020; Guo et al , 2020). So far, the role of OMA1 in cancer is complicated, depending on the type of cancer, the disease stage, the treatment, and many other factors (Jiang et al , 2014; Alavi, 2019; Amini et al , 2019; Daverey et al , 2019), and the underlying mechanism of OMA1 in regulating tumorigenesis and progression remains largely unknown.…”