Natural products targeting mitochondrial homeostasis: a four-dimensional framework integrating dynamics, mitophagy, pharmacokinetics, and translational safety

Background Dysregulated mitochondrial dynamics, including fission, fusion, biogenesis, and mitophagy, underlie the pathogenesis of many diseases. Natural products have the potential for multi-target therapy, but insufficient understanding of their mechanisms of action and pharmacokinetic limitations hinder their clinical translation. Objective This review proposes a regulatory framework covering the four dimensions of biogenesis, morphology, quality control, and defense, aiming to systematically clarify how natural products regulate mitochondrial function and critically evaluate their translational potential. The framework emphasizes that inter-organelle contact platforms, such as mitochondria–endoplasmic reticulum contact sites (MERCs) and mitochondrial–lysosomal contact sites (MLCs), are key sites through which natural products exert regulatory effects. Methods Major scientific databases, including PubMed, Web of Science, and Scopus, were searched, and evidence on mechanisms, pharmacokinetics, and toxicology from preclinical and clinical studies was comprehensively reviewed. Results Natural products can selectively regulate key mitochondrial pathways and regulatory nodes, including the AMPK/SIRT1/PGC-1α axis involved in mitochondrial biogenesis, the DRP1 axis involved in mitochondrial fission, and the PINK1/Parkin pathway involved in mitophagy. Representative metabolites include resveratrol, curcumin, and Coptis chinensis -derived alkaloids. A key finding of this review is that the intestinal microbiota plays an important role in converting low-bioavailability precursors, such as tannins, into systemically active metabolites, such as urolithin A (UA), thus inducing mitophagy. Although these metabolites usually show strong activity in vitro , their low oral bioavailability and rapid metabolism lead to significant pharmacokinetic/pharmacodynamic (PK/PD) mismatch, which remains a major obstacle to their clinical translation. Conclusion Natural products are powerful multidimensional regulators of mitochondrial homeostasis. In order to fully realize their therapeutic potential, strategies must be adopted to overcome PK/PD mismatch, including the development of targeted delivery systems, in-depth analysis of microbiome–metabolite interactions, and the integration of artificial intelligence and CRISPR-based technological innovation to support precision therapy.