Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion

Sanjay Kumar, Christopher C. Pan, Nirav Shah, Sarah E. Wheeler, Kari R. Hoyt, Nadine Hempel, Karthikeyan Mythreye, Nam Y. Lee

Research output: Contribution to journalArticle

16 Citations (Scopus)

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. Kumar et al. demonstrate a nontranscriptional role for Smad2 in regulating mitochondrial function. Inactive cytoplasmic Smad2 promotes MFN2-induced mitochondrial fusion by recruiting RIN1 that acts as a GEF for MFN2-GTPase activation.

Original languageEnglish (US)
Pages (from-to)520-531
Number of pages12
JournalMolecular cell
Volume62
Issue number4
DOIs
StatePublished - May 19 2016
Externally publishedYes

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Mitochondrial Dynamics
GTP Phosphohydrolases
Transforming Growth Factors
Guanosine Triphosphate
Superoxides
Neurodegenerative Diseases
Carcinogenesis
Adenosine Triphosphate
Apoptosis
Genes
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kumar, S., Pan, C. C., Shah, N., Wheeler, S. E., Hoyt, K. R., Hempel, N., ... Lee, N. Y. (2016). Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Molecular cell, 62(4), 520-531. https://doi.org/10.1016/j.molcel.2016.04.010

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.

In: Molecular cell, Vol. 62, No. 4, 19.05.2016, p. 520-531.

Research output: Contribution to journalArticle

Kumar, S, Pan, CC, Shah, N, Wheeler, SE, Hoyt, KR, Hempel, N, Mythreye, K & Lee, NY 2016, 'Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion', Molecular cell, vol. 62, no. 4, pp. 520-531. https://doi.org/10.1016/j.molcel.2016.04.010
Kumar S, Pan CC, Shah N, Wheeler SE, Hoyt KR, Hempel N et al. Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. Molecular cell. 2016 May 19;62(4):520-531. https://doi.org/10.1016/j.molcel.2016.04.010
Kumar, Sanjay ; Pan, Christopher C. ; Shah, Nirav ; Wheeler, Sarah E. ; Hoyt, Kari R. ; Hempel, Nadine ; Mythreye, Karthikeyan ; Lee, Nam Y. / Activation of Mitofusin2 by Smad2-RIN1 Complex during Mitochondrial Fusion. In: Molecular cell. 2016 ; Vol. 62, No. 4. pp. 520-531.
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