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Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival

ABSTRACT: Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations are redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

SUBMITTER: Dr. Conor, Terrance Ronayne

PROVIDER: S-SCDT-10_15252-EMBR_202357228 | biostudies-other |

REPOSITORIES: biostudies-other

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Tetracyclines promote survival and fitness in mitochondrial disease models.

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2016-05-31 | E-GEOD-68006 | biostudies-arrayexpress

Oxidative quality control regulates response to ER stress through translation control

Project description:The transcriptomic response after 3 hours of DTT treatment shows there is not a drastic difference in most genes between WT and skn7∆, yap1∆ . Vma13∆, sse2∆ were also used as part of the study.

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A Role for Macro-ER-Phagy in ER Quality Control.

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