Editors' ChoiceCell Biology

Delivering STAT3 into Mitochondria

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Sci. Signal.  26 Feb 2013:
Vol. 6, Issue 264, pp. ec50
DOI: 10.1126/scisignal.2004095

Like other members of the STAT (signal transducer and activator of transcription) family, the nuclear translocation and activity of STAT3 is regulated by phosphorylation in response to various cytokine and growth factor signaling pathways. STAT3 also functions independently of its transcriptional regulatory activity in mitochondria, where it stimulates the electron transport chain complexes I and II. Tammineni et al. report that the complex I subunit GRIM-19 (gene associated with retinoid interferon induced cell mortality 19) mediates the import of STAT3 into mitochondria and its recruitment into complex I, which is located in the inner mitochondrial membrane. STAT3 was present in mitoplasts (mitochondria from which the outer membrane has been removed) from purified rat heart mitochondria, and both STAT3 and GRIM-19 associated with a large inner membrane complex in fractionated mitochondrial extracts. In vitro translated, radiolabeled STAT3 was imported into purified mitochondria that had intact membrane potential; disrupting membrane potential prohibited STAT3 import into mitochondria. Addition of GRIM-19 along with STAT3 to purified mitochondria stimulated STAT3 import compared with addition of STAT3 alone, but GRIM-19 did not stimulate import of other mitochondrial-localized proteins or of a cytoplasmic protein, indicating that GRIM-19 specifically recruits STAT3 into mitochondria. Immunoblotting of mitochondrial fractions after import of radiolabeled STAT3 indicated that STAT3 was associated with both the inner membrane and matrix when it was imported in the absence of exogenously added GRIM-19, but associated primarily with the inner membrane when STAT3 and GRIM-19 together were added to the purified mitochondria. Whereas STAT3 imported alone was weakly associated with complex I and susceptible to protease treatment, STAT3 imported with GRIM-19 associated with complex I in a protease-resistant fashion. Mitochondrial activity of STAT3 requires phosphorylation of Ser727, and experiments with truncated and mutant forms of STAT3 indicated that phosphorylation of Ser727 was required for optimal mitochondrial import of STAT3 and its integration into complex I. STAT3 contains no mitochondrial targeting sequence; thus, its efficient import into mitochondria and integration into complex I relies on the complex I component GRIM-19.

P. Tammineni, C. Anugula, F. Mohammed, M. Anjaneyulu, A. C. Larner, N. B. V. Sepuri, The import of the transcription factor STAT3 into mitochondria depends on GRIM-19, a component of the electron transport chain. J. Biol. Chem. 288, 4723–4732 (2013). [Abstract] [Full Text]