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Review
. 2019 Nov 1;145(9):2330-2341.
doi: 10.1002/ijc.32177. Epub 2019 Feb 21.

Targeted OMA1 therapies for cancer

Marcel V Alavi  1
Affiliations
Review

Targeted OMA1 therapies for cancer

Marcel V Alavi. Int J 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.

Keywords: OMA1; OPA1; apoptosis; chemotherapy; mitochondria; outer membrane permeabilization; prohibitin; tumor protein p53.

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