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. 2009 Feb 6;323(5915):793-7.
doi: 10.1126/science.1164551. Epub 2009 Jan 8.

Function of mitochondrial Stat3 in cellular respiration

Joanna Wegrzyn  1 , Ramesh Potla, Yong-Joon Chwae, Naresh B V Sepuri, Qifang Zhang, Thomas Koeck, Marta Derecka, Karol Szczepanek, Magdalena Szelag, Agnieszka Gornicka, Akira Moh, Shadi Moghaddas, Qun Chen, Santha Bobbili, Joanna Cichy, Jozef Dulak, Darren P Baker, Alan Wolfman, Dennis Stuehr, Medhat O Hassan, Xin-Yuan Fu, Narayan Avadhani, Jennifer I Drake, Paul Fawcett, Edward J Lesnefsky, Andrew C Larner
Affiliations

Function of mitochondrial Stat3 in cellular respiration

Joanna Wegrzyn et al. Science. .

Abstract

Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria of cultured cells and primary tissues, including the liver and heart. In Stat3(-/-) cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.

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Figures

Fig. 1
Fig. 1
Stat3 in the mitochondria from mouse heart and liver. (A) Whole cell (WCE), cytoplasmic (Cyto), and mitochondrial (Mito) extracts were separated by SDS-PAGE. The blots were probed with antisera against Stat3, α-tubulin, calreticulin, and GRIM-19. (B) Increasing amounts of heart and liver mitochondria probed for Stat3, tubulin, and cytochrome c. (C) mStat3 is proteinase K–resistant. Mitochondria were incubated with (lanes 2 and 3) or without (lane 1) proteinase K (PK). To disrupt mitochondrial integrity, triton X-100 was added in the digestion buffer (lane 3). Samples were probed for Stat3, porin, Bcl-2, and GRIM-19. (D) mStat3 is serine phosphorylated. Purified mitochondria, as well as cytosolic and whole cell extracts were prepared from WT mice hearts. The immunoblots were probed for either total Stat3 or serine phosphorylated Stat3, as well as voltage-dependent anion channel (VDAC) and α-tubulin as controls for mitochondrial purity. A fluorescent conjugated secondary antibody was used to develop the blots allowing the relative amount of total and serine phosphorylated Stat3 to be measured. The ratio of total Stat3 to serine phosphorylated Stat3 in whole cell extracts was 2.5, in cytosolic extracts was 2.3, and in mitochondria extracts was 0.3.
Fig. 2
Fig. 2
Stat3 in complex I immunoprecipitates (IP). Antibody to complex I (CxI) or a nonspecific isotype-matched IgG were incubated with liver mitochondrial extracts. Immunoprecipitates were resolved on SDS-PAGE and probed for Stat3, GRIM-19, NDUFA9, Cx II Fp subunit, Cx III core protein 2, Cx IV subunit I, and Cx V α subunit.
Fig. 3
Fig. 3
Depressed mitochondrial respiration in Stat3−/− pro-B cells. (A) Mitochondrial oxidase activity in WT and Stat3−/− cells: NADH oxidase (left) and DHQ oxidase (right). Oxygen consumption is expressed as nanogram atom of oxygen per minute per milligram of mitochondrial protein (nAtom O/min/mg) and is presented as mean ± SD. (B) ETC activities of complexes I, II, III, and IV. Activities are expressed as milliunits (nanomoles per minute) per milligram of mitochondrial protein and were normalized to citrate synthase activity. Results are presented as mean ± SD. Error bars indicate SD; asterisks indicate P < 0.05.
Fig. 4
Fig. 4
Decreased rates of O2 consumption in Stat3−/− heart mitochondria. Mitochondria isolated from littermates of WT (left) and Stat3−/− (right) hearts were incubated in an oxygen sensor chamber, and O2 consumption (y axis) as a function of incubation time (x axis) was recorded. In the upper panels, the mitochondria were incubated with pyruvate/malate (complex I substrates), and they were incubated with succinate (complex II substrate) in the lower panels. Different concentrations of ADP were added to the mitochondria to measure state 3 respiration (0.2 mM ADP) or state 3 Vmax rates of respiration (2 mM ADP). State 4 rates of respiration were calculated when 0.2mM ADP was depleted from the reaction.
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