Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms,...

Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators.