A metabolic cell death program downstream of SARM1 couples NAD plus depletion to BAX activation and APAF1 degradation

• 成果类型: Article
• 署名作者: Pan, Weilong; Guo, Dejia; Liu, Daiyuan; Wang, Xiaodong
• 署名单位: Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; National Institute of Biological Sciences, Beijing
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2522444122
• 发表日期: 2025-12-16
• 页码: e2522444122
• 关键词: apoptosis; sarm1; NAD plus; bax; APAF1; cytochrome-c; triggers; deletion; crispr/cas9; SEPARATION; pathways; switch; genes; akt

摘要

SARM1 is a neuronal Nicotinamide adenine dinucleotide (NAD+) hydrolase that drives axonal degeneration and neuronal death by depleting NAD+, yet how NAD+ loss triggers axon loss and cell death has remained unclear. Here, we define a nonapoptotic death program downstream of endogenous SARM1 activation and NAD+ loss using a genetically tractable nonneuronal eHAP cell model. Upon NAD+ depletion, BAX is activated but caspase activation is suppressed due to APAF1 degradation via the E3 ligase HERC4, effectively uncoupling mitochondrial outer membrane permeabilization from apoptosome formation. Mechanistically, NAD+ depletion inhibits mTOR/AKT signaling, destabilizing MCL1 and relieving BAX from repression. We further identified Neurofibromatosis type II, NF2, as a regulator that promotes SARM1 transcription through the Hippo-YAP/TAZ pathway. The SARM1-dependent BAX activation and the role of NF2 in axon degradation were validated in neuronal models of axon degeneration. Together, these findings reveal how SARM1-driven metabolic collapse rewires cell death execution, positioning BAX, MCL1, APAF1, NF2, and HERC4 as core effectors in a nonapoptotic degenerative pathway linking metabolic stress to neurodegeneration