Kidney Week

Abstract: FR-OR38

NDUFS4 Regulates Cristae Remodeling in Diabetic Kidney Disease

Session Information

• How Sweet It Is: Basics of Diabetic Kidney Disease
  November 03, 2023 | Location: Room 121, Pennsylvania Convention Center
  Abstract Time: 05:33 PM - 05:42 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Mise, Koki, The University of Houston MD Anderson Cancer Center, Houston, United States

Koki Mise, MD, PhD

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

Jianyin Long,

• Wada, Jun, Okayama University Graduate School of Medicine, Dentistry & Pharmaceutical Sciences, Okayama, Japan

Jun Wada,

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

Benny B. Chang,

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

Farhad R. Danesh,

Background

Despite considerable progress in understanding the role of mitochondrial remodeling in kidney cells, the exact role and nature of mitochondrial electron transport chain (ETC) in the diabetic environment remains elusive.

Methods

We examined ETC remodeling in podocytes of established mouse models of diabetic kidney disease (DKD), and generated diabetic mice with podocyte-specific overexpression of Ndufs4 (NADH: ubiquinone oxidoreductase iron-sulfur protein 4, Ins2^Akita/+;Ndufs4^podTg), an accessory subunit of mitochondrial complex I, as a model to investigate the role of ETC integrity in DKD. APEX2 proximity labeling and complexsome profiling were performed to seek the Ndufs4 interactome in the context of mitochondrial respiratory supercomplexes (RSCs).

Results

We found that diabetic mice with conditional overexpression of Ndufs4 in podocytes (Ins2^Akita/+;Ndufs4^podTg) showed reduced albuminuria coupled with marked improvement in cristae morphology and mitochondrial dynamics. Importantly, primary podocytes from these mice exhibited increased ATP production, oxygen consumption rates, and complex I activity along with significantly reduced mitochondrial ROS and mitochondrial fission as compared to diabetic Ins2^Akita/+ mice. Using cryo-electron tomography, we found that diabetes-induced cristae remodeling was significantly improved with the forced expression of NDUFS4. By coupling proximity labeling, streptavidin pulldown assays, complexsome profiling and super-resolution imaging approaches, we identified a possible interaction between STOML2, a 39 kDa cristae shaping protein, and NDUFS4 in the context of improved supercomplexes assembly as the main explanation for the NDUFS4-mediated improvement in the cristae morphology. We further validated this interaction and found that two regions of the β-pleated sheet structures in STOM domain of STOML2 were crucial for its binding to NDUFS4.

Conclusion

Our findings uncover an unexpected role of Ndufs4 as a powerful regulator of cristae remodeling and mitochondrial dynamics. We propose that impaired mitochondrial respiration is a key defining feature of mitochondrial dysfunction in the diabetic environment, and targeting Ndufs4 could be a promising approach for developing therapies to slow the progression of DKD.

Funding

• NIDDK Support