Regulation of longevity by depolarization-induced activation of PLC-β–IP ₃ R signaling in neurons

Abstract

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.

Regulation of Aging and Longevity by Ion Channels and Transporters

“…Advanced age is also associated with increased neuronal activity in C. elegans , and pharmacological attenuation of excitability and its consequences using the Cl − channel agonist, ivermectin, or the L-type voltage-gated Ca 2+ channel (VGCC) blocker, nimodipine, extended worm lifespan [ 10 ] ( Figure 1 B). Roles for excitability in the regulation of neuronal viability and organismal lifespan are also observed in Drosophila [ 11 , 12 , 13 , 14 , 15 ] ( Figure 1 B). Deletion of the fly K + channel genes, ether a go-go ( eag ) and shaker ( Sh )—expected to augment neuronal excitability—led to severe loss of motor coordination, sleep deficits, and shorter lifespan [ 11 , 15 ].…”

“…Deletion of the fly K + channel genes, ether a go-go ( eag ) and shaker ( Sh )—expected to augment neuronal excitability—led to severe loss of motor coordination, sleep deficits, and shorter lifespan [ 11 , 15 ]. Diminished Na + /K + ATPase activity, which leads to a loss of the resting membrane potential and severe neuronal hyperexcitability, also caused shorter lifespan in flies [ 11 , 12 , 16 ].…”

“…In Drosophila , itpr overexpression in glutamatergic neurons is sufficient to shorten animal lifespan [ 12 ]. Knockdown of itpr mitigates the effects of neurodegeneration-causing transgenes on fly lifespan and locomotion [ 12 , 58 ].…”

“…In Drosophila , itpr overexpression in glutamatergic neurons is sufficient to shorten animal lifespan [ 12 ]. Knockdown of itpr mitigates the effects of neurodegeneration-causing transgenes on fly lifespan and locomotion [ 12 , 58 ]. Together, these findings point to a necessary and sufficient role for neuronal IP 3 R activity in the regulation of fly lifespan.…”

“…Together, these findings point to a necessary and sufficient role for neuronal IP 3 R activity in the regulation of fly lifespan. Several lines of evidence suggest that elevated IP 3 R activity was a consequence of chronic depolarization of fly neurons expressing neurodegeneration-causing transgenes [ 12 ]. First, expression of ALS and tauopathy-related transgenes in fly glutamatergic neurons led to concomitant loss of membrane potential and elevated IP 3 R-mediated ER Ca 2+ release.…”