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Mol Cell. 2016 May 19;62(4):520-31. doi: 10.1016/j.molcel.2016.04.010. Epub 2016 May 12.

Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion.

Author information

1
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
2
Department of Pharmacology, Penn State University, Hershey, PA 17033, USA.
3
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
4
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: lee.5064@osu.edu.

Abstract

Smads are nuclear-shuttling transcriptional mediators of transforming growth factor-β (TGF-β) signaling. Although their essential nuclear roles in gene regulation during development and carcinogenesis are well established, whether they have important cytoplasmic functions remains unclear. Here we report that Smad2 is a critical determinant of mitochondrial dynamics. We identified mitofusin2 (MFN2) and Rab and Ras Interactor 1 (RIN1) as new Smad2 binding partners required for mitochondrial fusion. Unlike TGF-β-induced Smad2/3 transcriptional responses underlying mitochondrial fragmentation and apoptosis, inactive cytoplasmic Smad2 rapidly promotes mitochondrial fusion by recruiting RIN1 into a complex with MFN2. We demonstrate that Smad2 is a key scaffold, allowing RIN1 to act as a GTP exchange factor for MFN2-GTPase activation to promote mitochondrial ATP synthesis and suppress superoxide production. These results reveal functional implications between Smads and mitochondrial dysfunction in cancer and metabolic and neurodegenerative disorders.

PMID:
27184078
PMCID:
PMC4877164
DOI:
10.1016/j.molcel.2016.04.010
[Indexed for MEDLINE]
Free PMC Article

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