Ammonia Accumulation Drives Intervertebral Disc Degeneration by Triggering Ammonia‐Induced Cell Death Through Lysosome–Mitochondria Crosstalk

ABSTRACT

Intervertebral disc degeneration (IVDD) is a major cause of low back pain and is closely associated with metabolic imbalance within the disc microenvironment, yet the underlying mechanisms remain poorly understood. Here, we identify ammonia accumulation as a metabolically relevant stressor that promotes nucleus pulposus cell injury and death and characterise ammonia‐induced cell death (AICD) as a non‐canonical, metabolite‐driven pathological process in IVDD. Through a combination of clinical cohort‐based analyses of human samples, multi‐omics profiling, in vitro experiments, and in vivo models, we demonstrate that ammonia stress induces AICD characterised by coordinated disruption of organelle homeostasis. Mechanistically, ammonia accumulation initially impairs lysosomal integrity, which subsequently triggers mitochondrial dysfunction and oxidative stress, accompanied by a metabolic shift from oxidative phosphorylation towards glycolysis, ultimately leading to suppressed mitophagy and activation of cell death pathways. Notably, AICD exhibits crosstalk with multiple programmed cell death pathways, highlighting its integration within the broader cell death network. Importantly, modulation of ammonia levels or restoration of organelle homeostasis effectively alleviates NP cell injury and attenuates IVDD progression. Collectively, these findings support AICD as a previously underappreciated, metabolite‐driven process contributing to IVDD and highlight the ammonia metabolism–organelle axis as a potential target for future metabolism‐ and organelle‐directed therapeutic strategies.