Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), often occurring under conditions such as hypotension, sepsis, and surgical procedures. Despite extensive research, the complex pathophysiology of IRI-induced AKI remains poorly understood, and effective treatments are lacking. Mitochondria, crucial for energy metabolism, play a significant role in the early phases of IRI by producing reactive oxygen species (ROS), releasing cell death factors, and causing tubular epithelial cell (TEC) apoptosis. This review highlights recent advances in understanding mitochondrial pathology in ischemic AKI and discusses promising therapeutic approaches targeting mitochondrial dysfunction to prevent or treat human ischemic AKI. Key points include: 1. **Mitochondrial Pathology in IRI-AKI**: Mitochondrial damage in IRI-AKI mice is characterized by increased ROS levels, decreased ATP, and structural abnormalities such as swelling, fragmentation, and membrane integrity disruption. 2. **Therapeutic Targets**: - **Targeting Mitochondrial Energy Metabolism**: Modulating fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle can improve mitochondrial function and reduce ROS production. - **Targeting Mitophagy**: Activating mitophagy pathways, such as the PINK1-PRKN/PARK2 and BNIP3-mediated pathways, can eliminate damaged mitochondria and reduce ROS levels. - **Reducing ROS Levels**: Antioxidants like MitoQ and Bax inhibitor-1 (Bt1) can inhibit ROS production and protect mitochondria from oxidative damage. - **Targeting Mitochondrial Fusion and Fission**: Regulating key proteins involved in mitochondrial dynamics, such as Drp1 and Mfn2, can prevent mitochondrial fragmentation and improve kidney function. 3. **Biomarkers**: Urinary full-length ATP5b and elevated mtDNA levels are potential biomarkers for renal mitochondrial dysfunction in IRI-AKI. 4. **Future Directions**: Further research is needed to validate these targets and develop targeted therapies for AKI, with a focus on clinical trials to assess their efficacy and safety. This review underscores the importance of mitochondrial dysfunction in IRI-AKI and highlights the potential of mitochondrial-targeted therapies as a promising approach to improve kidney injury and disease.Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), often occurring under conditions such as hypotension, sepsis, and surgical procedures. Despite extensive research, the complex pathophysiology of IRI-induced AKI remains poorly understood, and effective treatments are lacking. Mitochondria, crucial for energy metabolism, play a significant role in the early phases of IRI by producing reactive oxygen species (ROS), releasing cell death factors, and causing tubular epithelial cell (TEC) apoptosis. This review highlights recent advances in understanding mitochondrial pathology in ischemic AKI and discusses promising therapeutic approaches targeting mitochondrial dysfunction to prevent or treat human ischemic AKI. Key points include: 1. **Mitochondrial Pathology in IRI-AKI**: Mitochondrial damage in IRI-AKI mice is characterized by increased ROS levels, decreased ATP, and structural abnormalities such as swelling, fragmentation, and membrane integrity disruption. 2. **Therapeutic Targets**: - **Targeting Mitochondrial Energy Metabolism**: Modulating fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle can improve mitochondrial function and reduce ROS production. - **Targeting Mitophagy**: Activating mitophagy pathways, such as the PINK1-PRKN/PARK2 and BNIP3-mediated pathways, can eliminate damaged mitochondria and reduce ROS levels. - **Reducing ROS Levels**: Antioxidants like MitoQ and Bax inhibitor-1 (Bt1) can inhibit ROS production and protect mitochondria from oxidative damage. - **Targeting Mitochondrial Fusion and Fission**: Regulating key proteins involved in mitochondrial dynamics, such as Drp1 and Mfn2, can prevent mitochondrial fragmentation and improve kidney function. 3. **Biomarkers**: Urinary full-length ATP5b and elevated mtDNA levels are potential biomarkers for renal mitochondrial dysfunction in IRI-AKI. 4. **Future Directions**: Further research is needed to validate these targets and develop targeted therapies for AKI, with a focus on clinical trials to assess their efficacy and safety. This review underscores the importance of mitochondrial dysfunction in IRI-AKI and highlights the potential of mitochondrial-targeted therapies as a promising approach to improve kidney injury and disease.