Reactome | OMA1 cleaves DELE1

OMA1 cleaves DELE1

Stable Identifier

R-HSA-9840408

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial inner membrane

ReviewStatus

5/5

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OMA1 activated by depolarization of the mitochondrial inner membrane cleaves DELE1 in the N-terminal region (Fessler et al. 2020, Guo et al. 2020, Cheng et al. 2022, Fessler et al. 2022). Whereas the N-terminal region of uncleaved DELE1 is anchored in the mitochondrial inner membrane (Guo et al. 2020, Fessler et al. 2022), the C-terminal fragment of DELE1 is released into the cytosol where it activates the kinase activity of EIF2AK1 (HRI) to phosphorylate the EIF2S1 subunit of the eIF2 complex (Fessler et al. 2020, Guo et al. 2020, Cheng et al. 2022). OMA1 activity is negatively regulated by interaction with the PHB2:STOML2 complex (Cheng et al. 2022). An intermediate length processing product of DELE1 is observed in the mitochondrial matrix (Fessler et al. 2022) leading to the hypothesis that DELE1 is completely imported into the matrix and degraded by LONP1 in unstressed mitochondria (Fessler et al. 2022, Sekine et al. 2023). Upon mitochondrial stress, import of DELE1 into the matrix is blocked and OMA1 at the inner membrane cleaves the N-terminal region of DELE1 resulting in release of the C-terminal fragment into the cytosol (Fessler et al. 2022, Sekine et al. 2023). The PHB2:STOML2 complex interacts with OMA1 and inhibits cleavage of DELE1 (Cheng et al. 2022).

Literature References

PubMed ID	Title	Journal	Year
35388015	DELE1 tracks perturbed protein import and processing in human mitochondria Fessler, E, Jae, LT, Krumwiede, L	Nat Commun	2022
32132707	Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway Unger, BA, Tian, R, Liu, Y, Xu, K, Lin, YT, Guo, X, Kampmann, M, Correia, MA, Wiita, AP, Aviles, G	Nature	2020
32132706	A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol Schmitt, S, Mancilla, IA, Fessler, E, Meyer-Bender, MF, Jae, LT, Eckl, EM, Philippou-Massier, J, Zischka, H, Krebs, S, Hanf, M	Nature	2020
35163244	The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer Wang, B, Kong, Q, Sun, L, Dong, D, Yu, H, Cheng, M, Shen, L	Int J Mol Sci	2022
37327776	A mitochondrial iron-responsive pathway regulated by DELE1 Sekine, Y, Fessler, E, Houston, R, Jae, LT, Sekine, S, Narendra, DP, Eckl, EM	Mol Cell	2023