Mitochondrial physiology and beyond: Mechanistic insights into kaempferol actions

Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse in vitro and in vivo models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.