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Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion

Author:
Kumar, Sanjay, Pan, Christopher C., Shah, Nirav, Wheeler, Sarah E., Hoyt, Kari R., Hempel, Nadine, Mythreye, Karthikeyan, Lee, Nam Y.
Source:
Molecular cell 2016 v.62 no.4 pp. 520-531
ISSN:
1097-2765
Subject:
adenosine triphosphate, apoptosis, carcinogenesis, genes, guanosine triphosphate, mitochondria, neoplasms, neurodegenerative diseases, transcription (genetics), transforming growth factor beta
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.
Agid:
5302778