A mammalian-specific Alex3/Gq protein complex regulates mitochondrial trafficking, dendritic complexity, and neuronal survival
SCIENCE SIGNALING(2024)
摘要
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 G alpha(q) inhibited mitochondrial trafficking in neurons through a mechanism that was independent of the canonical downstream PLC beta pathway. Mitoproteome analysis revealed that G alpha(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 G alpha(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/G alpha(q) mitochondrial complex, which enables control of mitochondrial trafficking and neuronal death by GPCRs.
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