8.A.150.  The Mitochondrial Metalloendopeptidase OMA1 (OMA1) Family

Oma1 is a metalloprotease of 524 aas and probably 4 TMSs in a 2 + 2 TMS arrangement in the center of the protein (Alavi 2020). It is part of the quality control system in the inner membrane of mitochondria (Head et al. 2009, Desmurs et al. 2015) where it is activated in response to various mitochondrial stresses, leading to the proteolytic cleavage of target proteins, such as OPA1, UQCC3 and DELE1 (Fessler et al. 2020, Guo et al. 2020). Following stress conditions that induce loss of the mitochondrial membrane potential, OMA1 mediates cleavage of OPA1 at the S1 position, leading to OPA1 inactivation and negative regulation of mitochondrial fusion (Jiang et al. 2014). It also acts as a regulator of apoptosis: upon BAK and BAX aggregation, it mediates cleavage of OPA1, leading to the remodeling of mitochondrial cristae and allowing the release of cytochrome c from mitochondrial cristae. It may cleave UQCC3 in response to mitochondrial depolarization (Desmurs et al. 2015). OMA1 acts as an activator of the integrated stress response (ISR): in response to mitochondrial stress, and it mediates cleavage of DELE1 to generate the processed form of DELE1 (S-DELE1), which translocates to the cytosol and activates EIF2AK1/HRI to trigger the ISR (Fessler et al. 2020, Guo et al. 2020). Its role in mitochondrial quality control is essential for regulating lipid metabolism as well as for maintaining body temperature and energy expenditure under cold-stress conditions. It binds cardiolipin, possibly regulating its own turnover.



This family belongs to the CAAX Superfamily.

 

References:

Alavi, M.V. (2020). OMA1-An integral membrane protease? Biochim. Biophys. Acta. Proteins Proteom 1869: 140558. [Epub: Ahead of Print]

Desmurs, M., M. Foti, E. Raemy, F.M. Vaz, J.C. Martinou, A. Bairoch, and L. Lane. (2015). C11orf83, a mitochondrial cardiolipin-binding protein involved in bc1 complex assembly and supercomplex stabilization. Mol. Cell Biol. 35: 1139-1156.

Fessler, E., E.M. Eckl, S. Schmitt, I.A. Mancilla, M.F. Meyer-Bender, M. Hanf, J. Philippou-Massier, S. Krebs, H. Zischka, and L.T. Jae. (2020). A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579: 433-437.

Guo, X., G. Aviles, Y. Liu, R. Tian, B.A. Unger, Y.T. Lin, A.P. Wiita, K. Xu, M.A. Correia, and M. Kampmann. (2020). Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 579: 427-432.

Head, B., L. Griparic, M. Amiri, S. Gandre-Babbe, and A.M. van der Bliek. (2009). Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J. Cell Biol. 187: 959-966.

Jiang, X., H. Jiang, Z. Shen, and X. Wang. (2014). Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis. Proc. Natl. Acad. Sci. USA 111: 14782-14787.

Examples:

TC#NameOrganismal TypeExample
8.A.150.1.1

OMA1 protease of 524 aas and 4 TMS in a central 2 + 2 TMSs arrangement. (See family description for properties and functions).

OMA1 of Homo sapiens

 
8.A.150.1.2

M48 family metallopeptidase of 246 aas and 3 or 4 TMSs in a probable 1 + 1 (or 2) + 1 TMS arrangement.

M48 metalloprotease of Helicobacter apodemus

 
8.A.150.1.3

M48 family metalloprotease of 380 aas and possibly 3 TMSs.

M48 metalloprotease of Methanobrevibacter smithii

 
8.A.150.1.4

M48 family metallopeptidase of 281 aas and 3 or 4 TMSs in a 1 (or 2) + 2 TMS arrangement.

Peptidase of Idiomarina xiamenensis