Kidney Week

Abstract: SA-OR36

Mitochondrial Complex I Assembly Factor NDUFAF1 Regulates Tubulointerstitial Fibrosis in Diabetic Kidney Disease via a Tricarboxylic Acid Cycle Metabolite

Session Information

• Diabetic Kidney Disease - Basic: Discovery to Translational Science
  October 26, 2024 | Location: Room 7, Convention Center
  Abstract Time: 05:50 PM - 06:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Mise, Koki, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Koki Mise, MD, PhD

• Long, Jianyin, Nephrology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Jianyin Long, PhD

• Wada, Jun, Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Jun Wada, MD, PhD

• Chang, Benny B., Nephrology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Benny B. Chang, PhD

• Danesh, Farhad R., Nephrology Section, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Farhad R. Danesh, MD, FASN

Background

The mitochondrial electron transport chain (ETC) is a highly adaptive process that is crucial for meeting the metabolic demands of the cell. Dysregulation of the ETC has been associated with various clinical pathologies. We have recently highlighted the central role of NDUFS4, a subunit of Complex I, as a regulator of cristae remodeling and mitochondrial function in kidney podocytes (Mise K. et al. Nat Commun 2024 4;15:1965). However, the mechanism of ETC remodeling in the tubules of diabetic kidney disease (DKD) remains elusive.

Methods

We examined ETC remodeling in kidney tubules of two established mouse models of DKD, and generated DKD mice with proximal tubule-specific overexpression of Ndufaf1 (NADH: Ubiquinone Oxidoreductase Complex Assembly Factor 1, Ins2^Akita/+;Ndufaf1^PTCTg), an assembly factor of mitochondrial complex I, as a model to investigate the role of ETC integrity in diabetic tubules.

Results

We found that the rotenon-sensitive complex I enzymatic activity and the density of mitochondrial cristae were significantly reduced in proximal tubules of diabetic kidneys. Mitochondrial proteomic analysis revealed that several complex I assembly factors, including NDUFAF1, were significantly decreased in the tubular mitochondria of DKD mice. Importantly, the generation of diabetic mice with conditional overexpression of Ndufaf1 in proximal tubules (Ins2^Akita/+;Ndufaf1^PTCTg) exhibited reduced urinary KIM-1 and decreased collagen I and fibronectin along with improved cristae morphology. Primary proximal tubules from these mice exhibited increased ATP production and complex I enzymatic activity along with reduced mitochondrial ROS as compared to diabetic Ins2^Akita/+ mice. Mechanistically, we found that α-KG, a causal factor of renal fibrosis and enhanced TFG-β secretion, was significantly increased in the mitochondria from established models of DKD, whereas the levels of α-KG were normalized in Ins2^Akita/+;Ndufaf1^PTCTg mice.

Conclusion

This study discovered an unexpected role of Ndufaf1 as a powerful regulator of ETC in kidney fibrosis. These findings provide important insights into the mitochondrial mechanisms underlying the development of DKD and highlight the potential therapeutic targeting of the ETC assembly factor, NDUFAF1, for the management of this devastating condition.

Funding

• NIDDK Support