Table 2.

Disease-stratified mito epigenetic mechanisms.

Disease context	Temporal window and dominant cell stress	Mitochondrial state	Epigenetic or RNA pattern	Immune/fibrotic phenotype	Therapeutic implication
Ischemia/reperfusion AKI	Minutes to days; proximal tubules and endothelium	ATP depletion, membrane depolarization, Drp1-linked fragmentation, mtDNA release	Rapid stress-responsive chromatin changes; altered DNA methylation during repair	DAMP sensing, NLRP3/cGAS-STING activation, failed repair	Early mitochondrial stabilization and controlled mitophagy may be more relevant than late antifibrotic therapy (14, 16, 26, 37)
Diabetic kidney disease	Months to years; podocytes, tubules, mesangial and endothelial cells	Hyperglycemia-driven mtROS, impaired FAO, metabolic inflexibility	Metabolic memory; miR-21/miR-192/miR-34a; histone acetylation changes	Low-grade inflammation, albuminuria, matrix deposition	Therapy should pair metabolic control with targets that interrupt persistent epigenetic memory (20, 21, 25)
Progressive CKD/fibrosis	Chronic maladaptive repair; tubules, fibroblasts, immune cells	FAO failure, defective mitophagy, persistent ROS	HDAC activation, EZH2-mediated repression, profibrotic methylation	Myofibroblast activation, macrophage persistence, ECM accumulation	Cell-selective epigenetic or metabolic delivery is critical because systemic HDAC/DNMT blockade is risky (68, 71, 74, 75)
Aging kidney	Long-term senescence; tubules, endothelium, immune cells	mtDNA mutations, reduced biogenesis, NAD+ decline	Klotho methylation, senescence-associated chromatin changes	Sterile inflammation, reduced repair reserve, fibrosis susceptibility	NAD+ restoration and senolytic/immunometabolic strategies need renal safety validation (77, 78)
Polycystic kidney disease	Developmental and chronic cyst expansion; epithelial metabolic rewiring	Altered oxidative metabolism and mTOR-linked metabolic reprogramming	miRNA dysregulation and chromatin changes affecting proliferation	Cyst growth, inflammation, interstitial fibrosis	Metabolic-epigenetic interpretation is plausible but less mature than AKI/DKD evidence (79, 80)
IgA nephropathy	Chronic/relapsing; mesangial cells, podocytes, B/T cells	Altered mesangial respiration, mitochondrial dynamics and mtROS; MFN1-linked dysfunction	CD4+/B-cell DNA methylation changes; miRNA dysregulation including miR-23b	Mesangial proliferation, immune-complex inflammation, proteinuria, glomerulosclerosis	Mesangial mitochondrial stabilization combined with disease-specific immune/epigenetic modulation; clinical validation required
Lupus nephritis	Relapsing immune-complex nephritis; glomerular cells plus infiltrating T/B cells and myeloid cells	Context-dependent T-cell metabolic/mitochondrial remodeling; altered NAD+ metabolism	IFN-associated DNA hypomethylation; renal miRNA dysregulation	Immune-complex inflammation, IFN signaling, glomerular/tubular injury and fibrosis	Cell-state-specific immunometabolic and epigenetic targeting rather than generalized mitochondrial stimulation