Targeted inhibition of mitochondrial ROS maintains TFAM and mitochondrial DNA homeostasis in acute kidney injury

Background Acute kidney injury (AKI) is a serious worldwide health issue with high mortality and morbidity, and oxidative stress / mitochondrial dysfunction have been recognized as key features of AKI. Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondria DNA (mtDNA) transcription and replication, which maintains the cellular mitochondrial redox and energy homeostasis in various physiological conditions, but its alteration in AKI is not complete clear. In this study, we aim to investigate the effect of mitochondrial ROS (mtROS) on TFAM signaling and mtDNA damage in AKI. Methods In vitro, human proximal tubule epithelial cell lines (HK‐2) were incubated under hypoxia/reoxygenation (H/R) condition, and cellular mtROS were specifically eliminated by mitochondria‐targeted antioxidant Mito‐Tempo (MT). The changes of intracellular ROS, TFAM, mitochondrial biogenesis, mtDNA copy number, cell apoptosis and inflammation in HK2 cells were analyzed. In vivo, AKI mice were induced by renal ischemia/reperfusion (I/R) injury and treated with MT, and the changes of renal function, tubular injury, inflammation, mitochondrial function, mtROS, ATP production, and mtDNA level were measured. Results In vitro, H/R condition induced mtROS with declined TFAM and mtDNA injury, as well as increased inflammation and apoptosis in HK2 cells. By contrast, targeted inhibition of mtROS restored TFAM, mtDNA copy number and mitochondrial biogenesis (PGC1α), and reduced proinflammatory cytokines (IL‐1β/TNF‐α) and pro‐apoptotic factors (FAS) expression in HK2 cells. However, the cytoprotective role of mtROS inhibition on mtDNA and mitochondrial biogenesis was diminished in HK2 cells when knockdown of TFAM by siRNA, In vivo, targeted inhibition of mtROS also reduced the levels of serum BUN/CREA, necrotic tubules number, tubular apoptosis and renal inflammation in AKI mice. Moreover, targeted inhibition of mtROS rescued the TFAM and mtDNA damage with improved mitochondrial morphology, ATP production and mtDNA copy number in kidney of AKI mice. Conclusion This study highlights that TFAM plays an essential role in maintaining mitochondrial redox homeostasis, and mtROS induce renal dysfunction via disturbing TFAM and mtDNA, thus targeted inhibition of mtROS is a promising therapy for AKI. Support or Funding Information This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .