Pharmacological regulation of mitochondrial fitness and intercellular transfer mechanisms in mesenchymal stem cells for diabetic kidney disease therapy

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by progressive renal dysfunction, wherein mitochondrial dysfunction plays a central role. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic platform, partly owing to their ability to transfer functional mitochondria to injured cells and restore cellular bioenergetics. However, mitochondrial transfer efficiency remains limited under pathological conditions, restricting its therapeutic potential. Recent evidence indicates that multi-component pharmacological agents can modulate mitochondrial homeostasis and cellular metabolism. In this review, we propose a mechanism-oriented framework in which pharmacological modulation enhances MSC-mediated mitochondrial transfer through coordinated regulation at three levels: i) mitochondrial fitness in donor MSCs, ii) intercellular transfer pathways, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and gap junctions, and iii) recipient microenvironment remodeling. Notably, this process can be interpreted using multiple measurable biological and bioenergetic parameters, including mitochondrial deoxyribonucleic acid (mtDNA) content, respiratory function, and redox status. From an analytical perspective, mitochondrial transfer can be assessed through quantifiable endpoints across the donor, transfer, and recipient stages, enabling a more systematic understanding of its therapeutic efficacy. This review integrates pharmacological modulation with measurable indicators of mitochondrial function and intercellular transfer to provide a framework for evaluating and optimizing mitochondrial transfer-based therapies for DKD.