Izquierdo-Villalba, IsmaelMirra, SerenaManso, YasminaParcerisas, AntoniRubio, JavierDel Valle, JaumeGil-Bea, Francisco JUlloa, FaustoHerrero-Lorenzo, MarinaVerdaguer, EsterBenincá, CristianeCastro-Torres, Rubén DRebollo, ElenaMarfany, GemmaAuladell, CarmeNavarro, XavierEnriquez, Jose AntonioLópez de Munain, AdolfoSoriano, EduardoAragay, Anna M2024-07-092024-07-092024-02-06Sci Signal. 2024 Feb 6;17(822):eabq1007.http://hdl.handle.net/20.500.12105/20363Mitochondrial dynamics and trafficking are essential to provide the energy required for neurotransmission and neural activity. We investigated how G protein-coupled receptors (GPCRs) and G proteins control mitochondrial dynamics and trafficking. The activation of Gαq inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gαq interacted with the Eutherian-specific mitochondrial protein armadillo repeat-containing X-linked protein 3 (Alex3) and the Miro1/Trak2 complex, which acts as an adaptor for motor proteins involved in mitochondrial trafficking along dendrites and axons. By generating a CNS-specific Alex3 knockout mouse line, we demonstrated that Alex3 was required for the effects of Gαq on mitochondrial trafficking and dendritic growth in neurons. Alex3-deficient mice had altered amounts of ER stress response proteins, increased neuronal death, motor neuron loss, and severe motor deficits. These data revealed a mammalian-specific Alex3/Gαq mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.engVoRhttp://creativecommons.org/licenses/by/4.0/AxonsNeuronsAnimalsMiceMammalsMitochondrial ProteinsAtribución 4.0 Internacional3832000017822eabq100710.1126/scisignal.abq10071937-9145Science signalingopen access