Abstract: TH-PO0306
Dynein-Mediated Spatial Energy Rearrangement Drives Metabolic Maladaptation in Diabetic Podocytes
Session Information
- Glomerular Diseases: Cell Biology
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Rooney, Faith F., University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Williquett, Jillian, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Allamargot, Chantal, University of Iowa, Iowa City, Iowa, United States
- Sun, Hua, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
Background
Cytoplasmic dynein is the major motor protein driving retrograde transport in podocytes. We previously demonstrated that dynein mistrafficks slit diagram proteins under diabetic stress, disrupting podocyte filtration. However, whether dynein broadly regulates cellular processes underlying metabolic adaptation during diabetic podocytopathy remains unknown.
Methods
To define the role of dynein in diabetic metabolic remodeling, we established a comparative dynein interactome of podocytes grown under hyperglycemic (HG) versus normoglycemic (NG) conditions using co-immunoprecipitation and quantitative proteomics. HG-induced dynein associations with mitochondrial tracking, fission, and bioenergetics, as well as glycolysis and the pentose phosphate pathway (PPP) were identified and validated. Dynein-dependent alterations in mitochondrial trafficking, fragmentation, ultrastructure, and metabolism were analyzed using live-cell imaging, transmission electron microscopy, and Seahorse metabolic assays. Förster resonance energy transfer (FRET) imaging was performed to visualize dynein-mediated recruitment of mitochondrial fission machinery and glucose metabolic enzymes.
Results
Hyperglycemia remodeled the dynein interactome toward a metabolic stress-associated state enriched with mitochondrial and glycolytic regulators. Under HG conditions, dynein-recruited mitochondria via Myo19 and promoted their migration proximally to the nucleus. FRET imaging showed increased dynein-mediated fission by recruiting Dnm2 and Drp1. These changes impaired mitochondrial respiratory flexibility during sustained hyperglycemia. Concurrently, dynein recruited glycolytic and PPP-associated enzymes, supporting a compensatory shift toward mitochondria-independent energy production. Dynein-dependent perinuclear accumulation of fragmented mitochondria was validated in diabetic mouse podocytes and reversed by genetic inactivation of dynein.
Conclusion
Dynein reprograms spatial energy by positioning fragmented mitochondria towards the perinuclear area, where glycolytic and PPP compensation is promoted. Although this response may initially support adaptation to glucotoxic stress, persistent dynein-driven depletion of peripheral energy causes podocyte structural and functional failure. These findings identify dynein as a central regulator linking intracellular trafficking to metabolic maladaptation in diabetic kidney disease.
Funding
- NIDDK Support