Apoptosis. 2026 Nov 03. pii: 256. [Epub ahead of print]31(11):
Parkinson's disease (PD) is the second‑most prevalent central‑nervous‑system neurodegenerative disorder, pathologically characterized by progressive midbrain dopaminergic neuron loss and α‑synuclein‑aggregated Lewy bodies. Impaired mitophagy‑autophagy‑lysosomal quality control is a well‑documented upstream feature of PD; however, its characterization as a core causal driver-and how, or whether, mitophagy insufficiency is converted into irreversible dopaminergic neuronal death-remains incompletely resolved and lacks direct human evidence. Mitoxyperilysis is a recently described non‑caspase‑dependent lytic regulated cell‑death pathway. It can be triggered by combined innate‑immune activation and cellular metabolic disturbance, featuring mitochondrial oxidative stress, stable mitochondria‑plasma‑membrane anchoring and focal lipid‑peroxidation‑driven membrane rupture under the primary regulatory influence of the mTORC2-RhoA-cytoskeleton axis, a regulatory role established primarily in non-PD innate-immune and metabolic stress models. Mitophagy deficiency cannot directly initiate mitoxyperilysis but increases neuronal susceptibility by enabling persistent accumulation of ROS‑generating damaged mitochondria. This review summarizes mitoxyperilysis's core features, regulatory cascades and detection approaches, focusing on its bidirectional crosstalk with the mitophagy‑autophagy‑lysosomal system. We discuss how PD‑associated genetic variants, α‑synuclein aggregation and neuroinflammation disrupt mitophagy‑lysosomal homeostasis and may predispose dopaminergic neurons to mitoxyperilysis‑related injury. We overview pre‑clinical therapeutic candidates and potential biomarkers, and consider plausible links to other neurodegenerative diseases, peripheral pathology and aging. Critical caveats are highlighted: most supporting data derive from cell and animal models, and unambiguous evidence for bona‑fide mitoxyperilysis in human PD tissues remains absent. We outline translational bottlenecks and future priorities centred on autophagy‑mitophagy‑mitoxyperilysis signalling crosstalk, offering proposed mechanistic perspectives that may connect mitophagy-lysosomal dysfunction to neuronal demise, a causal linkage that has not yet been directly demonstrated in human PD, together with conceptual considerations for PD drug discovery and early intervention.
Keywords: Mitochondrial dysfunction; Mitoxyperilysis; Oxidative stress; Parkinson''s disease; mTORC2