ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: TH-PO034

SIRT5 Alleviates Ischemia-Induced Mitochondrial Dysfunction in Human Proximal Tubular Epithelial Cells

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Haschler, Timo Nicolas, University College London, London, United Kingdom
  • Horsley, Harry, University College London, London, United Kingdom
  • Balys, Monika, Great Ormond Street Hospital for Children, London, United Kingdom
  • Anderson, Glenn William, Great Ormond Street Hospital for Children, London, United Kingdom
  • Taanman, Jan-Willem, UCL Queen Square Institute of Neurology, London, United Kingdom
  • Unwin, Robert J., University College London Medical School, London, United Kingdom
  • Norman, Jill T., University College London, London, United Kingdom

Acute kidney injury (AKI) is a major global health concern with a high mortality and poorly effective therapies. The most common cause of AKI is renal hypoperfusion, leading to ischemia/reperfusion injury (IRI). Mitochondria are highly dynamic organelles required for energy production that undergo constant fission and fusion to meet metabolic requirements. Accumulating evidence has identified excessive mitochondrial fragmentation causing mitochondrial dysfunction as a central pathologic feature of IRI. Recently, the mitochondrial NAD+-dependent lysine-desuccinylase/demalonylase sirtuin 5 (SIRT5) has emerged as a key regulator of mitochondrial form and function, but its role in renal IRI is unknown.


Male C57Bl/6J mice underwent renal IRI or sham-surgery. Kidneys were screened for SIRT5 by immunohistochemistry. Human proximal tubular (PT) cells (HKC-8) were exposed to oxygen/nutrient-deprivation (OND; 1%O2+HBSS), an in vitro model developed to mimic renal ischemia in vivo, and analysed by qPCR and Western blot (WB). A SIRT5 RNA interference (RNAi) strategy combined with OND was applied, followed by assessment of mitochondrial form and function using confocal/ transmission electron microscopy, ATP assay, Seahorse, FACS and WB.


SIRT5 expression was increased in murine PTs after renal IRI and in HKC-8 cells exposed to OND. Knockdown of SIRT5 impaired glycolytic and mitochondrial ATP generation, reduced mitochondrial membrane potential and induced mitochondrial fragmentation. WB analysis of proteins involved in mitochondrial dynamics revealed that SIRT5 depletion disrupted the fission/fusion equilibrium by increasing pro-fission proteins (DRP1, DRP1-S616) and decreasing pro-fusion proteins (MFN1/2, OPA1), and that this effect was exacerbated by OND. Finally, combining the OND model with SIRT5 RNAi showed that SIRT5 reduced mitochondrial swelling and increased respiration (OXPHOS) to improve mitochondrial function in PT cells exposed to ischemia.


Our findings suggest SIRT5 is a central component of the endogenous stress response that alleviates ischemia-induced mitochondrial dysfunction in PTs and, therefore, may be a promising therapeutic target in AKI.


  • Commercial Support