Article: A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival

Authors: Izquierdo-Villalba-Ismael, Mirra-Serena, Manso-Yasmina, Parcerisas-Antoni, Rubio-Javier, Del Valle-Jaume, J.Gil-Francisco, Ulloa-Fausto, Herrero-Lorenzo-Marina, Verdaguer-Ester, Benincá-Cristiane, D.Castro-Torres-Rubén, Rebollo-Elena, Marfany-Gemma, Auladell-Carme, Navarro-Xavier, Enríquez-Jose A., López de Munain-Adolfo, Soriano-Eduardo, Aragay-Anna,

Link: https://www.science.org/doi/10.1126/scisignal.abq1007

Abstract:

Mitochondrial 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.