Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion

Mol Cell. 2016 May 19;62(4):520-31. doi: 10.1016/j.molcel.2016.04.010. Epub 2016 May 12.


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.

MeSH terms

  • A549 Cells
  • Adenosine Triphosphate / metabolism
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Energy Metabolism
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mitochondria / enzymology*
  • Mitochondrial Dynamics*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • Signal Transduction
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Superoxides / metabolism
  • Transfection


  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • RIN1 protein, human
  • SMAD2 protein, human
  • Smad2 Protein
  • Superoxides
  • Adenosine Triphosphate
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, human