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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. Editor's summary: The elongated morphology of neurons means that mitochondria must be trafficked over long distances to support energy-intensive processes in multiple subcellular compartments. Izquierdo-Villalba et al. found that mitochondrial trafficking in neurons required the interaction of the G protein Gαq with the mitochondrial protein Alex3. Gαq enhanced the binding of Alex3 to mitochondrial trafficking proteins that mediate anterograde traffic. Expression of a constitutively active form of Gαq in neurons from mice with a CNS-specific deficiency in Alex3 revealed that Gαq was necessary for the role of Alex3 in mitochondrial trafficking and distribution and dendritic arborization. These results raise the intriguing possibility that the activity of Gαq-coupled receptors can affect mitochondrial trafficking in neurons through the Gαq/Alex3 complex. —Wei Wong [ABSTRACT FROM AUTHOR]