A new non-canonical pathway of Gα(q) protein regulating mitochondrial dynamics and bioenergetics.
Contrary to previous assumptions, G proteins do not permanently reside on the plasma membrane, but are constantly monitoring the cytoplasmic surfaces of the plasma membrane and endomembranes. Here, we report that the Gαq and Gα11 proteins locate at the mitochondria and play a role in a complex signaling pathway that regulates mitochondrial dynamics. Our results provide evidence for the presence of the heteromeric G protein (Gαq/11βγ) at the outer mitochondrial membrane and for Gαq at the inner membrane. Both localizations are necessary to maintain the proper equilibrium between fusion and fission; which is achieved by altering the activity of mitofusin proteins, Drp1, OPA1 and the membrane potential at both the outer and inner mitochondrial membranes. As a result of the absence of Gαq/11, there is a decrease in mitochondrial fusion rates and a decrease in overall respiratory capacity, ATP production and OXPHOS-dependent growth. These findings demonstrate that the presence of Gαq proteins at the mitochondria serves as a physiological function: stabilizing elongated mitochondria and regulating energy production in Drp1 and Opa1 dependent mechanisms. This thereby links organelle dynamics and physiology.
Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona 08028, Spain; Department of Cardiovascular Development and Repair, Spanish Cardiovascular Research Center (CNIC), Madrid 28029, Spain.
Cristiane
C
Benincá
Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
Jesús
J
Planagumà
Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona 08028, Spain.
Adriana
A
de Freitas Shuck
Department of Cardiovascular Development and Repair, Spanish Cardiovascular Research Center (CNIC), Madrid 28029, Spain.
Rebeca
R
Acín-Perez
Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain; CIBERDEM, Barcelona 08028, Spain.
Juan Pablo
JP
Muñoz
Department of Genetics, Federal University of Paraná (UFPR), Curitiba PO Box 19071, Brazil.
Marina Mateus
MM
de Almeida
Department of Pharmacology, University of California (UCSD), San Diego, CA 92093-0636, USA.
Joan H
JH
Brown
Department of Pharmacology, University of California (UCSD), San Diego, CA 92093-0636, USA.
Anne N
AN
Murphy
Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain; Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona 08028, Spain; CIBERDEM, Barcelona 08028, Spain.
Antonio
A
Zorzano
Department of Cardiovascular Development and Repair, Spanish Cardiovascular Research Center (CNIC), Madrid 28029, Spain.
Jose Antonio
JA
Enríquez
Molecular Biology Institute of Barcelona (IBMB), Spanish National Research Council (CSIC), Barcelona 08028, Spain; Department of Biomedicine, University of Bergen, 5009 Bergen, Norway. Electronic address: aarbmc@ibmb.csic.es.
Anna M
AM
Aragay
D000818:Animals; D002460:Cell Line; D034281:Dynamins / Q000378:metabolism; D004734:Energy Metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism; D041681:NIH 3T3 Cells; D010085:Oxidative Phosphorylation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
D021122:Protein Subunits; D034741:RNA, Small Interfering; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C486391:Dnm1l protein, mouse; D034281:Dynamins
Drp; Fission; Fusion; Gq; Heterotrimeric G proteins; Mitochondria