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Abstract: SA-PO160

Mitochondrial Morphology Regulates Proximal Tubule Cell Differentiation Status

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Elias, Bertha C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Acute Kidney Injury (AKI) frequently occurs in hospitalized patients and predisposes them to developing chronic kidney disease (CKD). Our lab and others have shown prolonged proximal tubule cell (PTC) dedifferentiation in the form of maladaptive repair contributes to this AKI-to-CKD transition. One of the most striking histological features of dedifferentiated PTCs is fragmentation of the mitochondria, which occurs through the mitochondrial fission pathway involving dynamin related protein 1 (Drp1). While it is known mitochondrial fragmentation reduces mitochondrial function, it is unclear if fragmentation contributes to PTC dedifferentiation.


Mitochondrial morphology in kidney tissue was monitored using super-resolution microscopy. Using primary PTCs and LLC-PK1 cells treated with aristolochic acid (AA), we developed an in vitro model of PTC dedifferentiation. Mitochondrial fragmentation was suppressed with specific inhibitors. In vivo, inducible Drp1 KO mice (Drp1ΔPT) were used to regulated mitochondrial fragmentation and compared to wild-type (WT) littermates age 8-12. Kidney injury was induced by aristolochic acid nephropathy, repeat low-dose cisplatin, and bilateral ischemic reperfusion injury models. Dedifferentiation markers were measured by immunofluorescence, protein expression and mRNA levels.


Using super-resolution imaging of kidney tissue, we found that dedifferentiated PTCs had greatly reduced mitochondrial volume and network length, indicating mitochondrial fragmentation. In vitro, AA treatment reproduced this phenotype by inducing mitochondrial fragmentation early after injury, which was followed by dedifferentiation at later time points. Pharmacological inhibition of mitochondrial fragmentation prevented PTC dedifferentiation. Similarly, knocking out Drp1 in vivo after kidney injury improved mitochondrial morphology and reduced markers of dedifferentiation in all three injury models tested. Improved mitochondrial morphology was associated with reduced kidney fibrosis in all three models.


Inhibition of mitochondrial fragmentation prevents proximal tubular cell dedifferentiation and reduces renal fibrosis. Interventions targeting mitochondrial health may lead to novel therapeutics to improve chronic kidney injury.