Cellular response to mitochondrial stress

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Homo sapiens
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Mitochondrial stress caused by depolarization of the mitochondrial inner membrane, inhibition of proton flux across the mitochondrial inner membrane, or insufficient protein import capacity caused by inhibition of ATP synthase or iron deficiency is communicated to the cytosol and nucleus, resulting in decreased protein production and increased transcription of chaperones and metabolic genes among others. This pathway is known as the mitochondrial stress response and is a part of mitochondrial signaling and the integrated stress response (Reviewed in Eckl et al. 2021, Picard and Shirihai 2022, Lu et al. 2022, Liu and Birsoy 2023). The mitochondrial stress response participates in adapting cells to harsher environments and, hence, plays a role in tumor progression and metastasis (reviewed in Lee et al. 2022).
In unstressed mitochondria, DELE1 is constitutively imported into the mitochondrial matrix and degraded by the LONP1 ATP-dependent protease (Fessler et al. 2022, Sekine et al. 2023). Mitochondrial stress inhibits the complete transit of DELE1 into the matrix and activates the inner membrane protease OMA1 by self-cleavage (Fessler et al. 2022, Sekine et al. 2023, inferred from the mouse Oma1 homolog in Baker et al. 2014, Zhang et al. 2014). Activated OMA1 cleaves the N-terminal region of DELE1 on the outer face of the inner membrane as DELE1 is unable to fully cross the inner membrane (Fessler et al. 2020, Guo et al. 2020, Fessler et al. 2022). The resulting C-terminal fragment of DELE1 egresses from the intermembrane space to the cytosol where it oligomerizes to form an octamer (Yang et al. 2023) which binds and activates EIF2AK1, a constituent kinase of the integrated stress response that phosphorylates EIF2S1, the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2) (Fessler et al. 2020, Guo et al. 2020, Cheng et al. 2022). Phosphorylation of EIF2S1 inhibits general translation but increases translation of specific mRNAs that possess upstream open reading frames (reviewed in Wek 2018). Among these mRNAs are the transcription factors DDIT3 (CHOP), ATF4, and ATF5, which activate expression of chaperone genes among others.
Literature References
PubMed ID Title Journal Year
36323233 Mitochondrial signal transduction

Shirihai, OS, Picard, M

Cell Metab 2022
35388015 DELE1 tracks perturbed protein import and processing in human mitochondria

Fessler, E, Jae, LT, Krumwiede, L

Nat Commun 2022
36931256 Metabolic sensing and control in mitochondria

Birsoy, K, Liu, Y

Mol Cell 2023
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
34228161 Sensing, signaling and surviving mitochondrial stress

Ziegemann, O, Fessler, E, Jae, LT, Eckl, EM, Krumwiede, L

Cell Mol Life Sci 2021
24719224 Membrane depolarization activates the mitochondrial protease OMA1 by stimulating self-cleavage

Zhang, K, Li, H, Song, Z

EMBO Rep 2014
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
37550454 DELE1 oligomerization promotes integrated stress response activation

Chen, W, Guo, X, Yang, J, Kampmann, M, Lander, GC, Luke Wiseman, R, Baron, KR, Aviles, G, Song, AS, Schneemann, A, Pride, DE

Nat Struct Mol Biol 2023
24550258 Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics

Tatsuta, T, Lampe, PA, Stojanovski, D, Baker, MJ, Korwitz, A, Langer, T, Anand, R

EMBO J 2014
36611815 Mitochondrial Unfolded Protein Response and Integrated Stress Response as Promising Therapeutic Targets for Mitochondrial Diseases

Liu, Y, Cao, Y, Li, M, Zou, W, Wang, X, Liang, C, Zhang, Z, Lu, H, Liang, D, Ji, D

Cells 2022
29440070 Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress

Wek, RC

Cold Spring Harb Perspect Biol 2018
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
35269393 Role of Mitochondrial Stress Response in Cancer Progression

Park, DH, Chae, YC, Lee, YG

Cells 2022
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