Arizona Health Sciences

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

TitleActivation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion.
Publication TypeJournal Article
Year of Publication2016
AuthorsKumar S, Pan CC, Shah N, Wheeler SE, Hoyt KR, Hempel N, Mythreye K, Lee NY
JournalMol Cell
Volume62
Issue4
Pagination520-31
Date Published2016 May 19
ISSN1097-4164
KeywordsA549 Cells, Adenosine Triphosphate, Animals, Cercopithecus aethiops, COS Cells, Energy Metabolism, GTP Phosphohydrolases, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, Signal Transduction, Smad2 Protein, Superoxides, Transfection
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.

DOI10.1016/j.molcel.2016.04.010
Alternate JournalMol. Cell
PubMed ID27184078
PubMed Central IDPMC4877164
Grant ListP20 GM109091 / GM / NIGMS NIH HHS / United States
R01 CA178443 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.