Ca²⁺ channels couple spiking to mitochondrial metabolism in substantia nigra dopaminergic neurons.

ABSTRACT: How do neurons match generation of adenosine triphosphate by mitochondria to the bioenergetic demands of regenerative activity? Although the subject of speculation, this coupling is still poorly understood, particularly in neurons that are tonically active. To help fill this gap, pacemaking substantia nigra dopaminergic neurons were studied using a combination of optical, electrophysiological, and molecular approaches. In these neurons, spike-activated calcium (Ca²⁺) entry through Ca_v1 channels triggered Ca²⁺ release from the endoplasmic reticulum, which stimulated mitochondrial oxidative phosphorylation through two complementary Ca²⁺-dependent mechanisms: one mediated by the mitochondrial uniporter and another by the malate-aspartate shuttle. Disrupting either mechanism impaired the ability of dopaminergic neurons to sustain spike activity. While this feedforward control helps dopaminergic neurons meet the bioenergetic demands associated with sustained spiking, it is also responsible for their elevated oxidant stress and possibly to their decline with aging and disease.

SUBMITTER: Zampese E 

PROVIDER: S-EPMC9524841 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature