Mitochondrial dysfunction of renal tubular epithelial cells in chronic kidney disease-associated fibrosis: from organelle homeostasis to multicellular remodeling.

Chronic kidney disease (CKD) is a major global health burden, and renal fibrosis is a common pathological correlate of progressive loss of kidney function. Renal tubular epithelial cells (RTECs), particularly proximal tubular epithelial cells (PTECs), contain abundant mitochondria and depend on oxidative metabolism to support solute transport. This metabolic specialization renders them vulnerable to hypoxia, lipotoxicity, uremic toxins, aging, inflammation, and hemodynamic stress. Persistent mitochondrial injury can suppress fatty acid oxidation and oxidative phosphorylation, deplete nicotinamide adenine dinucleotide, increase mitochondrial reactive oxygen species, destabilize mitochondrial DNA, and disrupt biogenesis, dynamics, mitochondria-associated membrane signaling, and mitophagy. These abnormalities promote maladaptive repair, senescence, inflammatory cell death, and paracrine signaling to fibroblasts, macrophages, endothelial cells, and pericytes. Evidence is organized within a tubule-to-niche framework that distinguishes causal perturbation from temporal or transcriptomic association, model-specific findings from cross-model convergence, and experimental efficacy from clinical translation. Single-cell, spatial, and organoid studies are considered alongside evidence from human biopsy specimens and biomarkers. Mitochondrial dysfunction is thus treated as a context-dependent contributor to, and amplifier of, CKD-associated fibrotic remodeling rather than a universal initiating event. Although strategies targeting bioenergetics, redox balance, mitochondrial quality control, and tubular delivery are promising, translation is constrained by disease heterogeneity, intervention timing, target specificity, pharmacokinetics, and the scarcity of validated human antifibrotic endpoints.