mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1

Masahiro Morita; Julien Prudent; Kaustuv Basu; Vanessa Goyon; Sakie Katsumura; Laura Hulea; Dana Pearl; Nadeem Siddiqui; Stefan Strack; Shawn McGuirk; Julie St-Pierre; Ola Larsson; Ivan Topisirovic; Hojatollah Vali; Heidi M McBride; John J Bergeron; Nahum Sonenberg

doi:10.1016/j.molcel.2017.08.013

mTOR Controls Mitochondrial Dynamics and Cell Survival via MTFP1

Mol Cell. 2017 Sep 21;67(6):922-935.e5. doi: 10.1016/j.molcel.2017.08.013. Epub 2017 Sep 14.

Authors

Masahiro Morita¹, Julien Prudent², Kaustuv Basu³, Vanessa Goyon⁴, Sakie Katsumura⁵, Laura Hulea⁶, Dana Pearl⁷, Nadeem Siddiqui⁷, Stefan Strack⁸, Shawn McGuirk⁷, Julie St-Pierre⁷, Ola Larsson⁹, Ivan Topisirovic¹⁰, Hojatollah Vali³, Heidi M McBride¹¹, John J Bergeron¹², Nahum Sonenberg¹³

Affiliations

¹ Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada; 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, USA. Electronic address: [email protected].
² Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
³ Department of Anatomy and Cell Biology and Facility for Electron Microscopy Research, McGill University, Montreal, QC H3A 0C7, Canada.
⁴ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
⁵ 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, USA.
⁶ Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada.
⁷ Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada.
⁸ Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
⁹ Department of Oncology-Pathology, Karolinska Institutet, Stockholm 171 76, Sweden.
¹⁰ Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada; Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada; Department of Oncology, McGill University, Montreal, QC H3T 1E2, Canada.
¹¹ Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: [email protected].
¹² Department of Medicine, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada. Electronic address: [email protected].
¹³ Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, QC H3A1A3, Canada. Electronic address: [email protected].

PMID: 28918902
DOI: 10.1016/j.molcel.2017.08.013

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.

Keywords: 4E-BP; DRP1; mRNA translation; mTOR; mitochondrial fission.

Publication types

Video-Audio Media

MeSH terms

Adaptor Proteins, Signal Transducing
Apoptosis
CRISPR-Cas Systems
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Cycle Proteins
Cell Line, Tumor
Cell Survival
Dynamins / genetics
Dynamins / metabolism
Eukaryotic Initiation Factors / genetics
Eukaryotic Initiation Factors / metabolism
Humans
Mechanistic Target of Rapamycin Complex 1
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mitochondria / drug effects
Mitochondria / enzymology*
Mitochondria / ultrastructure
Mitochondrial Dynamics* / drug effects
Multiprotein Complexes / genetics
Multiprotein Complexes / metabolism
Phosphoproteins / genetics
Phosphoproteins / metabolism
Phosphorylation
Protein Kinase Inhibitors / pharmacology
RNA Interference
Signal Transduction
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Transfection

Substances

Adaptor Proteins, Signal Transducing
Carrier Proteins
Cell Cycle Proteins
Eif4ebp1 protein, mouse
Eif4ebp2 protein, mouse
Eukaryotic Initiation Factors
MTFP1 protein, mouse
Membrane Proteins
Multiprotein Complexes
Phosphoproteins
Protein Kinase Inhibitors
mTOR protein, mouse
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Dnm1l protein, mouse
Dynamins

Grants and funding

MC_UU_00015/7/MRC_/Medical Research Council/United Kingdom