Temporal Dynamics of Kidney Mitochondrial Dysfunction in Type 2 Diabetes: Analysis of the Goto-Kakizaki Model

Abstract Type 2 diabetes mellitus (T2DM) is a major cause of diabetic kidney disease (DKD), a complication driven by chronic hyperglycemia, oxidative stress, and inflammation. Mitochondrial dysfunction has been recognized as a central feature of DKD, but the temporal relationship between mitochondrial alterations, mitophagy, and inflammatory responses remains unclear. Using the non-obese Goto-Kakizaki (GK) rat, a spontaneous model of T2DM, we examined renal mitochondrial changes at 21, 60, and 120 days. Histology revealed a trend toward increased glycation product deposition, more evident at 60 days. Cytochrome C and OPA-1 expression indicated early mitochondrial adaptation through enhanced respiratory activity and hyperfusion, while reduced PGC1-α and PINK suggested impaired biogenesis and mitophagy. By 120 days, PGC1-α and PINK increased, likely reflecting delayed, insufficient compensation, coinciding with mitochondrial depolarization. Cytokine analysis revealed a biphasic inflammatory profile: IL-18 and CXCL1 were sharply elevated at 21 days, IL-1β remained stable, and IL-10 was elevated at 21 and 60 days, indicating early pro-inflammatory activation followed by anti-inflammatory modulation. These findings suggest that renal mitochondrial dysfunction in GK rats evolves from an adaptive state to late-stage failure, with inflammation occurring as transient peaks rather than a persistent process. The period between 21 and 60 days emerges as a critical therapeutic window in which strategies to preserve mitochondrial quality control and modulate inflammasome-related responses may be most effective. Competing Interest Statement The authors have declared no competing interest.