Abstract: TH-PO0300
Podocyte Mitochondrial Transcription Factor A (TFAM) Deficiency Worsens Kidney Outcomes in Diabetic Kidney Disease
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
- Fontanella, Antonio Miguel, University of Miami Miller School of Medicine, Miami, Florida, United States
- Njeim, Rachel, University of Miami Miller School of Medicine, Miami, Florida, United States
- Saadat, Saeida, University of Miami Miller School of Medicine, Miami, Florida, United States
- Molina David, Judith T., University of Miami Miller School of Medicine, Miami, Florida, United States
- Soler, Anthony Michael, Florida Atlantic University, Boca Raton, Florida, United States
- Allen, Katherine C., University of Miami Miller School of Medicine, Miami, Florida, United States
- Marsden, Evan R., University of Miami, Coral Gables, Florida, United States
- Burke, George William, University of Miami Miller School of Medicine, Miami, Florida, United States
- Merscher, Sandra, University of Miami Miller School of Medicine, Miami, Florida, United States
- Fornoni, Alessia, University of Miami Miller School of Medicine, Miami, Florida, United States
- Mitrofanova, Alla, University of Miami Miller School of Medicine, Miami, Florida, United States
Background
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States, yet therapies targeting kidney-intrinsic metabolic pathways remain limited. Emerging evidence links impaired mitophagy and activation of innate immune signaling to kidney injury in DKD. Our prior work demonstrated that experimental DKD is associated with sterile inflammation driven by activation of the stimulator of interferon genes (STING) pathway, leading to podocyte apoptosis and autophagic cell death. In tubular cells, STING activation can result from cytosolic mitochondrial DNA (mtDNA) released when mitochondrial transcription factor A (TFAM), a key regulator of mtDNA stability, is reduced. However, the role of TFAM in podocyte mitochondrial quality control remains poorly defined. We hypothesized that TFAM protects podocytes in DKD by limiting mtDNA-driven STING-dependent inflammation.
Methods
Human podocytes with TFAM knockdown were used to assess apoptosis and cytosolic mtDNA levels in vitro. In vivo, mice with podocyte-specific Tfam deletion were used to induce type 1 diabetes (40 mg/kg streptozotocin for 5 consecutive days). Similarly, type 2 diabetic db/db mice with constitutive TFAM overexpression were used to assess the protective effects of TFAM against DKD. Kidney injury was evaluated by albuminuria, histology, and serum analyses. Single-cell RNA sequencing was performed to define podocyte-specific transcriptional changes.
Results
TFAM expression was reduced in podocytes from both human DKD datasets and experimental models. TFAM deficiency increased cytosolic mtDNA in vitro (p<0.05) and in vivo (p<0.01), and accelerated DKD progression in vivo (p<0.05). Single-cell analyses revealed enhanced sterile inflammation and impaired metabolic pathways in TFAM-deficient podocytes. In contrast, TFAM overexpression improved renal outcomes in diabetic mice (p<0.01).
Conclusion
These findings identify TFAM as a critical regulator of podocyte mitochondrial quality control and suggest that restoring TFAM levels may slow DKD progression.
Funding
- NIDDK Support