GCN5L1 Aggravates Postherpetic Neuralgia Through Regulating Microglial Mitochondrial Fission–Fusion Homeostasis

Abstract

Postherpetic neuralgia (PHN) is a debilitating chronic pain condition following varicella-zoster virus (VZV) reactivation, characterised by persistent neuroinflammation. However, the intracellular mechanisms that drive microglial activation and sustained pain sensitisation remain poorly understood. Due to mice having no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well-established PHN mice model. Here, we identified GCN5L1, a mitochondrial acetylation modulator, as a critical regulator of microglial mitochondrial dynamics and a key contributor to PHN pathogenesis. We found that GCN5L1 was markedly upregulated in the spinal dorsal horn after PHN, particularly located in microglia. Microglial Gcn5l1 deficiency attenuated HSV-1-induced neuroinflammatory responses and alleviated mechanical allodynia, whereas Gcn5l1 overexpression exacerbated neuroinflammatory responses both in vivo and in vitro. Mechanistically, GCN5L1 promoted mitochondrial fission and impaired oxidative metabolism by enhancing DRP1 acetylation, without altering the expression of canonical fission–fusion regulators. Restoration of mitochondrial fission using MFI8 intrathecally reversed the anti-inflammatory and analgesic effects of Gcn5l1 deficiency, confirming that GCN5L1 mediated pain sensitisation through mitochondrial fission–fusion in PHN. Finally, inhibiting GCN5L1 by AAV-shGCN5L1 intrathecally suppressed neuroinflammation and mechanical allodynia in PHN mice. These findings uncovered that GCN5L1 aggravated neuroinflammation and PHN through regulating microglial mitochondrial fission–fusion homeostasis, offering new insights and potential feasibility in clinical translation for PHN management.