Mitochondrial activity tunes nociceptor resilience to excitotoxicity, 2025, Yuan et al.

[SNT Gatchaman]

Mitochondrial activity tunes nociceptor resilience to excitotoxicity
Lin Yuan; Navdeep S Chandel; David Julius

The capsaicin receptor, TRPV1, mediates the detection of noxious chemical and thermal stimuli by nociceptors, primary sensory neurons of the pain pathway. Overactivation of TRPV1 leads to cellular damage or death through calcium entry and excitotoxicity.

We have exploited this phenomenon to conduct a systematic analysis of excitotoxicity through a genome-wide CRISPRi screen, thereby revealing a comprehensive network of regulatory pathways.

We show that decreased expression of mitochondrial electron transport chain (ETC) components protects against capsaicin-induced toxicity and other challenges by mitigating both calcium imbalance and the generation of mitochondrial reactive oxygen species via distinct pathways. Moreover, we confirm the regulatory roles of the ETC in sensory neurons through gain-of-function and loss-of-function experiments. Interestingly, TRPV1+ sensory neurons maintain lower expression of ETC components and can better tolerate excitotoxicity and oxidative stress compared with other sensory neuron subtypes, implicating ETC tuning as an intrinsic cellular strategy that protects nociceptors against excitotoxicity.

HIGHLIGHTS
• A genome-wide screen identifies pathways regulating excitotoxicity

• Electron transport chain (ETC) is a major determinant of resilience to excitotoxicity

• Reducing oxidative stress and calcium entry underlie this protective mechanism

• Nociceptors have lower ETC expression and greater resilience to excitotoxicity

Web | PDF | Cell | Open Access

 

[SNT Gatchaman]

we find that TRPV1+ nociceptors from adult mice express ETC components at lower levels compared with other sensory neurons, conferring greater resilience to cell death due to calcium or ROS overload. Furthermore, we show that ETC suppression is protective against a broad range of excitotoxic insults. We therefore propose that tuning of aerobic respiration helps nociceptors mitigate risk associated with injury and other noxious events. These insights into cellular mechanisms controlling nociceptor excitotoxicity are relevant to understanding neuropathological consequences of diabetes, chemotherapy, and other conditions that disrupt normal, protective pain sensation.

Our comprehensive chemical genetic and pharmacologic dissections now support an unexpected aspect of mitochondrial function in which ETC tuning in sensory neurons fosters resilience.

Given its critical role in ATP production and NAD + regeneration, impairing ETC activity generally has negative consequences for cellular health, as we observed with both proliferating cell models and neurons. However, we show that maintaining low ETC activity can be beneficial in the face of excitotoxicity, revealing interesting parallels to other physiologically challenging scenarios.

We also uncovered an unexpected regulatory effect of the ETC on calcium overload. Specifically, we found that pyruvate addition can negate the effect of ETC regulation on calcium overload but not ROS, implying that these outcomes represent distinct modulatory pathways

As many ion channels, including Kv2.1, have been reported to cluster and/or localize to lipid rafts, this pathway may act broadly, beyond TRPV1, to regulate cell surface expression of signaling molecules that control excitability of primary afferent nociceptors.

Further analysis of endocytic and other pathways in relation to pyruvate and lactate metabolism may provide further insights into how and why dysregulated metabolic conditions, such as obesity or diabetes, are associated with chronic pain syndromes.