Journal
MOLECULAR CELL
Volume 62, Issue 4, Pages 520-531Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.04.010
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Funding
- NIH [CA178443]
- Ohio State University College of Pharmacy, Davis Heart Lung Research Institute
- James Comprehensive Cancer Center
- Office Of The Director
- Office of Integrative Activities [1317771] Funding Source: National Science Foundation
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Smads are nuclear-shuttling transcriptional mediators of transforming growth factor-beta (TGF-beta) 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-beta-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.
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