Natural polysaccharides as modulators of mitochondrial homeostasis: structural determinants, pharmacological mechanisms, and translational challenges

Abstract

Mitochondrial dysfunction is a convergent pathological feature of neurodegenerative, metabolic, cardiovascular, hepatic, and cancer-related disorders, making mitochondrial homeostasis an important therapeutic target. Natural polysaccharides (NPs) are structurally diverse macromolecules that have emerged as promising multifunctional modulators of mitochondrial homeostasis. This review summarizes the structural basis and mechanistic actions underlying the mitochondrial regulatory effects of NPs. Key structural features, including molecular weight, monosaccharide composition, glycosidic linkages, branching patterns, and chemical modifications, largely determine the mitochondria-regulating potential of NPs. Mechanistically, NPs regulate mitochondrial homeostasis by restoring bioenergetic function, reducing oxidative stress, maintaining mitochondrial quality control, and modulating mitochondria-dependent apoptosis. These effects support disease-context-specific therapeutic benefits, as NPs generally preserve mitochondrial homeostasis in non-malignant diseases while potentially inducing mitochondrial stress and cell death in cancer. This review also highlights key translational barriers to NP-based mitochondrial therapy, underscoring the need for standardized structural characterization, mechanism-oriented mitochondrial assays, and disease-specific evaluation.