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Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion

Kumar, Sanjay, Pan, Christopher C., Shah, Nirav, Wheeler, Sarah E., Hoyt, Kari R., Hempel, Nadine, Mythreye, Karthikeyan, Lee, Nam Y.
Molecular cell 2016 v.62 no.4 pp. 520-531
adenosine triphosphate, apoptosis, carcinogenesis, genes, guanosine triphosphate, mitochondria, neoplasms, neurodegenerative diseases, transcription (genetics), transforming growth factor beta
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.