Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance
Aims: Ischemia-reperfusion injuries (IRI)-caused acute kidney injuries (IRI-AKI) is characterised by elevated amounts of reactive oxygen species (ROS), mitochondrial disorder, and inflammation, however the potential link of these features remains unclear. Within this study, we aimed to research the particular role of mitochondrial ROS (mtROS) in initiating mitochondrial DNA (mtDNA) damage and inflammation during IRI-AKI. Methods: The alterations in kidney function, mitochondrial function, and inflammation in IRI-AKI rodents without or with mtROS inhibition were examined in vivo. The outcome of mtROS on TFAM (mitochondrial transcription factor A), Lon protease, mtDNA, mitochondrial respiration, and cytokine release was examined in kidney tubular cells in vitro. The results of TFAM knockdown on mtDNA, mitochondrial function, and cytokine release were also examined in vitro. Finally, alterations in TFAM and mtDNA nucleoids were measured in kidney samples from IRI-AKI rodents and patients. Results: Decreasing mtROS levels attenuated kidney disorder, mitochondrial damage, and inflammation in IRI-AKI rodents. Decreasing mtROS levels also reversed the reduction in TFAM levels and mtDNA copy number occurring in HK2 cells under oxidative stress. mtROS reduced the abundance of mitochondrial TFAM in HK2 cells by suppressing its transcription and promoting Lon-mediated TFAM degradation. Silencing of TFAM abolished the Mito-Tempo (MT)-caused save of Mito-TEMPO mitochondrial function and cytokine release in HK2 cells under oxidative stress. Lack of TFAM and mtDNA damage put together in kidneys from IRI-AKI rodents and AKI patients. Conclusion: mtROS can promote kidney injuries by suppressing TFAM-mediated mtDNA maintenance, leading to decreased mitochondrial energy metabolic process and elevated cytokine release. TFAM defects can be a promising target for kidney repair after IRI-AKI.