Sirtuin 3-dependent mitochondrial dynamic improvements protect against acute kidney injury

Marina Morigi, Luca Perico, Cinzia Rota, Lorena Longaretti, Sara Conti, Daniela Rottoli, Rubina Novelli, Giuseppe Remuzzi, Ariela Benigni

Research output: Contribution to journalArticlepeer-review


Acute kidney injury (AKI) is a public health concern with an annual mortality rate that exceeds those of breast and prostate cancer, heart failure, and diabetes combined. Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the pathways that mediate these events are poorly defined. Here, using a murine cisplatin-induced AKI model, we determined that both oxidative stress and mitochondrial damage are associated with reduced levels of renal sirtuin 3 (SIRT3). Treatment with the AMPK agonist AICAR or the antioxidant agent acetyl-L-carnitine (ALCAR) restored SIRT3 expression and activity, improved renal function, and decreased tubular injury in WT animals, but had no effect in Sirt3-/- mice. Moreover, Sirt3-deficient mice given cisplatin experienced more severe AKI than WT animals and died, and neither AICAR nor ALCAR treatment prevented death in Sirt3-/- AKI mice. In cultured human tubular cells, cisplatin reduced SIRT3, resulting in mitochondrial fragmentation, while restoration of SIRT3 with AICAR and ALCAR improved cisplatin-induced mitochondrial dysfunction. Together, our results indicate that SIRT3 is protective against AKI and suggest that enhancing SIRT3 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury.

Original languageEnglish
Pages (from-to)715-726
Number of pages12
JournalJournal of Clinical Investigation
Issue number2
Publication statusPublished - Feb 2 2015

ASJC Scopus subject areas

  • Medicine(all)


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