title: Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion.
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.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Pan
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nirav
authors.initials: N
authors.lastname: Shah
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kari R
authors.initials: KR
authors.lastname: Hoyt
authors.affiliation: Department of Pharmacology, Penn State University, Hershey, PA 17033, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hempel
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Mythreye
authors.affiliation: Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: lee.5064@osu.edu.
authors.forename: Nam Y
authors.initials: NY
authors.lastname: Lee
mesh_terms: D000072283:A549 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004734:Energy Metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D063154:Mitochondrial Dynamics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C092117:RIN1 protein, human; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D013481:Superoxides; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human