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G12 is targeted to the mitochondria and affects mitochondrial morphology and motility

Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA

¹ Correspondence: Department of Pharmacology (MC 868), University of Illinois at Chicago, 909 S. Wolcott Ave., Chicago, IL 60612, USA. E-mail: tvy{at}uic.edu

G12 constitutes, along with G13, one of the four families of subunits of heterotrimeric G proteins. We found that the N terminus of G12, but not those of other G subunits, contains a predicted mitochondrial targeting sequence. Using confocal microscopy and cell fractionation, we demonstrated that up to 40% of endogenous G12 in human umbilical vein endothelial cells colocalize with mitochondrial markers. N-terminal sequence of G12 fused to GFP efficiently targeted the fusion protein to mitochondria. G12 with mutated mitochondrial targeting sequence was still located in mitochondria, suggesting the existence of additional mechanisms for mitochondrial localization. Lysophosphatidic acid, one of the known stimuli transduced by G12/13, inhibited mitochondrial motility, while depletion of endogenous G12 increased mitochondrial motility. G12Q229L variants uncoupled from RhoGEFs (but not fully functional activated G12Q229L) induced transformation of the mitochondrial network into punctate mitochondria and resulted in a loss of mitochondrial membrane potential. All examined G12Q229L variants reduced phosphorylation of Bcl-2 at Ser-70, while only mutants unable to bind RhoGEFs also decreased cellular levels of Bcl-2. These G12 mutants were also more efficient Hsp90 interactors. These findings are the first demonstration of a heterotrimeric G protein subunit specifically targeted to mitochondria and involved in the control of mitochondrial morphology and dynamics.—Andreeva, A. V., Kutuzov, M. A., Voyno-Yasenetskaya, T. A. G12 is targeted to the mitochondria and affects mitochondrial morphology and motility.

Key Words: heterotrimeric G proteins • Bcl-2 • Hsp90 • mitochondrial fission • organelle motility