Affiliation:
1. Department of Cancer Biology Dana‐Farber Cancer Institute Boston MA USA
2. Department of Cell Biology Harvard Medical School Boston MA USA
Abstract
AbstractMitochondrial 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 is 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.
Funder
National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
Genetics,Molecular Biology,Biochemistry
Cited by
1 articles.
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