Journal article
mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1
Molecular cell, Vol.67(6), pp.922-935.e5
09/21/2017
DOI: 10.1016/j.molcel.2017.08.013
PMID: 28918902
Abstract
The mechanisms that link environmental and intracellular stimuli to mitochondrial functions, including fission/fusion, ATP production, metabolite biogenesis, and apoptosis, are not well understood. Here, we demonstrate that the nutrient-sensing mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates translation of mitochondrial fission process 1 (MTFP1) to control mitochondrial fission and apoptosis. Expression of MTFP1 is coupled to pro-fission phosphorylation and mitochondrial recruitment of the fission GTPase dynamin-related protein 1 (DRP1). Potent active-site mTOR inhibitors engender mitochondrial hyperfusion due to the diminished translation of MTFP1, which is mediated by translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Uncoupling MTFP1 levels from the mTORC1/4E-BP pathway upon mTOR inhibition blocks the hyperfusion response and leads to apoptosis by converting mTOR inhibitor action from cytostatic to cytotoxic. These data provide direct evidence for cell survival upon mTOR inhibition through mitochondrial hyperfusion employing MTFP1 as a critical effector of mTORC1 to govern cell fate decisions.
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•The mTORC1/4E-BPs/MTFP1/DRP1 axis controls mitochondrial dynamics•Active-site mTOR inhibitors induce mitochondrial hyperfusion and branching•mTORC1 regulates MTFP1 translation and mitochondrial recruitment of DRP1 via 4E-BPs•Uncoupling MTFP1 levels from the mTORC1 axis upon mTOR inhibition leads to apoptosis
Morita et al. show that mTORC1 signaling controls mitochondrial dynamics to govern cell fate decisions. mTORC1 inhibition by asTORi treatment leads to mitochondrial branching and hyperfusion through 4E-BP-dependent suppression of MTFP1 mRNA translation.
Details
- Title: Subtitle
- mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1
- Creators
- Masahiro Morita - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaJulien Prudent - Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, CanadaKaustuv Basu - Department of Anatomy and Cell Biology and Facility for Electron Microscopy Research, McGill University, Montreal, QC H3A 0C7, CanadaVanessa Goyon - Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, CanadaSakie Katsumura - Department of Molecular Medicine and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USALaura Hulea - Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, CanadaDana Pearl - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaNadeem Siddiqui - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaStefan Strack - Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USAShawn McGuirk - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaJulie St-Pierre - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaOla Larsson - Department of Oncology-Pathology, Karolinska Institutet, Stockholm 171 76, SwedenIvan Topisirovic - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, CanadaHojatollah Vali - Department of Anatomy and Cell Biology and Facility for Electron Microscopy Research, McGill University, Montreal, QC H3A 0C7, CanadaHeidi M McBride - Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, CanadaJohn J Bergeron - Department of Medicine, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, CanadaNahum Sonenberg - Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada
- Resource Type
- Journal article
- Publication Details
- Molecular cell, Vol.67(6), pp.922-935.e5
- DOI
- 10.1016/j.molcel.2017.08.013
- PMID
- 28918902
- NLM abbreviation
- Mol Cell
- ISSN
- 1097-2765
- eISSN
- 1097-4164
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/501100000024, name: Canadian Institutes of Health Research, award: CIHR MOP-7214, FDN-148423, MOP-5605, MOP-68833, MOP-115195, PJT-148603, MOP-106603; DOI: 10.13039/501100000015, name: Canadian Cancer Society Research Institute, award: CCSRI 16208; DOI: 10.13039/501100004376, name: Terry Fox Research Institute, award: TFF-116128, TFF-242122; DOI: 10.13039/501100000038, name: National Sciences and Engineering Research Council of Canada; DOI: 10.13039/100000011, name: Howard Hughes Medical Institute; DOI: 10.13039/501100000024, name: CIHR; name: Fonds de Recherche du Québec- Santé (FRQ-S); DOI: 10.13039/501100000156, name: FRSQ; DOI: 10.13039/100007476, name: Canadian Diabetes Association; DOI: 10.13039/501100000024, name: CIHR, award: MFE-140925; name: CIHR Vanier Canada Graduate, award: VGS-338305; DOI: 10.13039/501100004359, name: Swedish Research Council; DOI: 10.13039/501100002794, name: Swedish Cancer Society; name: Wallenberg Academy Fellow
- Language
- English
- Date published
- 09/21/2017
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984040228202771
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