The Role of Natural Products in Ameliorating Mitochondrial Dysfunction in Diabetic Kidney Disease and the Underlying Mechanisms.

Abstract

Diabetic Kidney Disease (DKD), a prevalent microvascular complication of diabetes mellitus, represents the leading cause of end-stage renal disease worldwide. Its pathogenesis is multifactorial, involving metabolic disturbances, oxidative stress, inflammatory responses, and notably, mitochondrial dysfunction. Mitochondria, as the primary energy-producing organelles, undergo morphological and functional impairment under hyperglycemic conditions, including excessive reactive oxygen species generation, aberrant dynamics (fusion/fission imbalance), defective mitophagy, reduced biogenesis, and activation of mitochondria-mediated apoptosis. These interconnected abnormalities contribute to glomerular and tubular injury, ultimately promoting renal fibrosis and functional decline. Emerging evidence highlights the therapeutic potential of natural products-such as flavonoids, polyphenols, alkaloids, and saponins-in restoring mitochondrial homeostasis through multitarget mechanisms. These compounds activate the Nrf2/ARE and AMPK/SIRT1/PGC- 1α pathways to enhance antioxidant defense and promote mitochondrial biogenesis; regulate Drp1/Mfn1/2/OPA1 to restore mitochondrial dynamics; induce PINK1/Parkin- or BNIP3-mediated mitophagy to clear dysfunctional mitochondria; and modulate Bcl-2/Bax/caspase signaling to suppress apoptosis. Despite robust preclinical efficacy, clinical translation is hindered by poor bioavailability, batch-to-batch variability, lack of standardized formulations, and limited high-quality trials with mitochondrial-specific endpoints. Advances in kidney-targeted nanodelivery systems and AIdriven compound screening offer promising strategies to overcome these barriers. This review synthesizes current knowledge on the mechanisms by which natural products alleviate mitochondrial dysfunction in DKD, evaluates translational challenges, and proposes future directions for developing these compounds into adjunctive therapies.