DOI: 10.1126/scisignal.abq1007 ISSN: 1945-0877

A mammalian-specific Alex3/Gα q protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival

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

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 Gα q inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLCβ pathway. Mitoproteome analysis revealed that Gα q 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 Gα q 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/Gα q mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.

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