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

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Citation

Sanjay Kumar, Christopher C Pan, Nirav Shah, Sarah E Wheeler, Kari R Hoyt, Nadine Hempel, Karthikeyan Mythreye, Nam Y Lee. Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Molecular cell. 2016 May 19;62(4):520-31

PMID: 27184078

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