Reprogramming mitochondrial homeostasis in renal ischemia-reperfusion injury

Acute kidney injury (AKI) caused by renal ischemia-reperfusion injury (RIRI) is primarily a mitochondrial disorder characterized by disrupted dynamics, impaired biogenesis, and defective quality control. Excessive DRP1-mediated fission, suppression of the AMPK-SIRT-PGC-1α axis, and failure of the PINK1-Parkin mitophagy system converge to drive tubular dysfunction and ferroptosis. Here, we integrate recent insights into a "mitochondrial reprogramming" framework encompassing three axes-dynamic remodeling, metabolic renewal, and proteostatic reinforcement. Therapeutic strategies targeting these axes, such as DRP1 inhibition, AMPK-SIRT-PGC-1α activation, and reinforcement of mitophagy and MAM integrity by agents like melatonin, puerarin, or Schisandrin B, have shown promise in restoring mitochondrial resilience. Furthermore, mitochondrial biomarkers and imaging tools (mtDNA, mitochondrial peptides, [¹⁸F]BCPP-EF PET) may enable phenotype-guided interventions. This review outlines the "RIRI-Mitochondria-AKI-CKD continuum," emphasizing that mitochondrial maladaptation bridges acute injury and chronic fibrosis, highlighting mitochondria as precision therapeutic targets in AKI.