Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis
Open Access
- 12 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 29 (2), 451-464
- https://doi.org/10.1038/s41418-021-00868-y
Abstract
Mitochondria support multiple cell functions, but an accumulation of dysfunctional or excessive mitochondria is detrimental to cells. We previously demonstrated that a defect in the autophagic removal of mitochondria, termed mitophagy, leads to the acceleration of apoptosis induced by herpesvirus productive infection. However, the exact molecular mechanisms underlying activation of mitophagy and regulation of apoptosis remain poorly understood despite the identification of various mitophagy-associated proteins. Here, we report that the mitochondrial translation elongation factor Tu, a mitophagy-associated protein encoded by the TUFM gene, locates in part on the outer membrane of mitochondria (OMM) where it acts as an inhibitor of altered mitochondria-induced apoptosis through its autophagic function. Inducible depletion of TUFM potentiated caspase-8-mediated apoptosis in virus-infected cells with accumulation of altered mitochondria. In addition, TUFM depletion promoted caspase-8 activation induced by treatment with TNF-related apoptosis-inducing ligand in cancer cells, potentially via dysregulation of mitochondrial dynamics and mitophagy. Importantly, we revealed the existence of and structural requirements for autophagy-competent TUFM on the OMM; the GxxxG motif within the N-terminal mitochondrial targeting sequences of TUFM was required for self-dimerization and mitophagy. Furthermore, we found that autophagy-competent TUFM was subject to ubiquitin-proteasome-mediated degradation but stabilized upon mitophagy or autophagy activation. Moreover, overexpression of autophagy-competent TUFM could inhibit caspase-8 activation. These studies extend our knowledge of mitophagy regulation of apoptosis and could provide a novel strategic basis for targeted therapy of cancer and viral diseases.Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R21CA136356, R01CA214131)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1TR003098)
This publication has 46 references indexed in Scilit:
- Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction?Mitochondrion, 2013
- Hepatitis C Virus Induces the Mitochondrial Translocation of Parkin and Subsequent MitophagyPLoS Pathogens, 2013
- The Mitochondrial Proteins NLRX1 and TUFM Form a Complex that Regulates Type I Interferon and AutophagyImmunity, 2012
- Human Herpesvirus 8 Interferon Regulatory Factor-Mediated BH3-Only Protein Inhibition via Bid BH3-B MimicryPLoS Pathogens, 2012
- The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteinsThe Journal of cell biology, 2011
- Bim Nuclear Translocation and Inactivation by Viral Interferon Regulatory FactorPLoS Pathogens, 2010
- Nix is a selective autophagy receptor for mitochondrial clearanceEMBO Reports, 2009
- Hypoxia‐inducedBNIP3expression and mitophagy:in vivocomparison of the rat and the hypoxia‐tolerant mole rat,Spalax ehrenbergiThe FASEB Journal, 2009
- Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane PermeabilizationDevelopmental Cell, 2008
- Determination of the Cleavage Site of the Presequence by Mitochondrial Processing Peptidase on the Substrate Binding Scaffold and the Multiple Subsites inside a Molecular CavityOnline Journal of Public Health Informatics, 2003