Metabolite Regulation of Mitochondrial Quality Control and Regulated Cell Death

Altered metabolism contributes to disease progression and variable treatment response, but metabolite abundance alone rarely determines whether stressed cells recover or undergo regulated cell death (RCD).

This review proposes mitochondrial quality control (MQC) as an intermediate gating layer that links metabolic signals to cell-fate execution through coordinated redox control, mitochondrial integrity, organelle turnover, and renewal. Four representative metabolites-β-hydroxybutyrate (β-BHB), lactate, succinate, and acetate-span complementary substrate-, receptor-, redox-, and acylation-dependent mechanisms and illustrate how distinct metabolic inputs converge on different MQC nodes.

This framework explains why the same metabolite may support adaptation in one tissue or exposure window yet lower the death threshold in another. It predicts that tissue-specific flux and functional MQC reserve will outperform bulk metabolite abundance in forecasting RCD responses, that disrupting and rescuing the dominant MQC node will, respectively, abolish and restore a metabolite-dependent death phenotype, and that MQC changes will precede modality-specific execution events.Translational Outlook:Clinically, this predominantly preclinical framework can now be tested through mechanism-enriched trials that integrate metabolite exposure, metabolic competence, mitochondrial target engagement, and RCD output, providing a practical route for causal validation in humans. Antioxid. Redox Signal. 00, 000-000.