Acute kidney injury (AKI) has been associated with not only higher in-hospital mortality but also the subsequent development of chronic kidney disease (CKD). Recent evidence has suggested the involvement of mitochondrial dysfunction and impaired dynamics in the pathogenesis of AKI. Estrogen-related receptor alpha (ERR alpha) is an orphan nuclear receptor that acts as a transcription factor to regulate the transcription of genes required for mitochondrial biogenesis and oxidative phosphorylation. In the present study, we examined the effects of ERR alpha deficiency on the progression of AKI induced by cisplatin. Male C57BL/6J wild-type and ERR alpha(-/-) mice received a single intraperitoneal injection of 20 mg/kg cisplatin. Seventy-two hours after the injection, kidney function and morphology were evaluated. ERR alpha expression was observed in renal tubules, and cisplatin inhibited its translocation into nuclei. ERR alpha deficiency exacerbated cisplatin-induced renal dysfunction and tubular injury, as well as oxidative stress and apoptosis. ERR alpha(-/-) mice kidneys revealed lower mitochondrial DNA content and swollen mitochondria with reduced cristae. In addition, these mice had lower expression of the mitochondrial fusion protein mitofusin-2. The cisplatin-induced decrease in mitochondrial DNA and altered mitochondrial structure were more severe in ERR alpha(-/-) mice. In cultured mouse proximal tubular epithelial cells, the ERR alpha, inverse agonist XCT-790 significantly inhibited mitofusin-2 expression and induced mitochondrial fragmentation. Taken together, our findings suggest the involvement of ERR alpha in the progression of cisplatin-induced AKI probably through impaired mitochondrial dynamics. (C) 2018 Elsevier Inc. All rights reserved.