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

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.

Citation

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. A mammalian-specific Alex3/Gαq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival. Science signaling. 2024 Feb 06;17(822):eabq1007

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PMID: 38320000

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