This study investigates the role of NDUFS4, an accessory subunit of mitochondrial complex I, in diabetic kidney disease (DKD). The research reveals that NDUFS4 regulates cristae remodeling and mitochondrial function in kidney podocytes, which are critical for maintaining mitochondrial respiration and preventing DKD progression. Using a podocyte-specific Ndufs4 transgenic mouse model, the study shows that overexpression of Ndufs4 improves cristae morphology, mitochondrial dynamics, and reduces albuminuria in diabetic mice. The findings suggest that NDUFS4 is essential for maintaining cristae integrity and mitochondrial function in podocytes, and its deficiency contributes to the progression of DKD. The study also identifies STOML2 as a key protein that interacts with NDUFS4 to regulate cristae remodeling and RSC assembly. The results highlight the importance of NDUFS4 in maintaining mitochondrial function and suggest that targeting NDUFS4 could be a promising therapeutic approach for DKD. The study provides new insights into the molecular mechanisms underlying DKD and highlights the potential of NDUFS4 as a therapeutic target.This study investigates the role of NDUFS4, an accessory subunit of mitochondrial complex I, in diabetic kidney disease (DKD). The research reveals that NDUFS4 regulates cristae remodeling and mitochondrial function in kidney podocytes, which are critical for maintaining mitochondrial respiration and preventing DKD progression. Using a podocyte-specific Ndufs4 transgenic mouse model, the study shows that overexpression of Ndufs4 improves cristae morphology, mitochondrial dynamics, and reduces albuminuria in diabetic mice. The findings suggest that NDUFS4 is essential for maintaining cristae integrity and mitochondrial function in podocytes, and its deficiency contributes to the progression of DKD. The study also identifies STOML2 as a key protein that interacts with NDUFS4 to regulate cristae remodeling and RSC assembly. The results highlight the importance of NDUFS4 in maintaining mitochondrial function and suggest that targeting NDUFS4 could be a promising therapeutic approach for DKD. The study provides new insights into the molecular mechanisms underlying DKD and highlights the potential of NDUFS4 as a therapeutic target.