Metabolite Regulation of Mitochondrial Quality Control and Regulated Cell Death

Background: 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). Scope of Review: 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. Major Conclusions: 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.