Pavlović Nikola, Križanac Marinela, Kumrić Marko, Vukojević Katarina, Božić Joško
Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia.
Department of Paediatrics, University Hospital of Split, 21000 Split, Croatia.
Cells. 2025 May 28;14(11):794. doi: 10.3390/cells14110794.
Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia-reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as and . Epigenetic dysregulation also impacts mitochondrial-ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions-ranging from Drp1 inhibition to mitochondrial transplantation-hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies.
线粒体功能障碍是急性肾损伤（AKI）、慢性肾脏病（CKD）以及肾和尿路先天性异常（CAKUT）发病机制中的关键驱动因素。肾脏的线粒体密度仅次于心脏，依赖氧化磷酸化来满足溶质重吸收和滤过对ATP的高需求。线粒体动力学的破坏，如由Drp1介导的过度裂变，会加剧缺血再灌注损伤等AKI模型中的肾小管凋亡和炎症。在CKD中，持续的线粒体功能障碍会导致氧化应激、纤维化和代谢重编程，表观遗传机制（DNA甲基化、组蛋白修饰、非编码RNA）调控对线粒体稳态至关重要的基因，如 和 。表观遗传失调还会影响线粒体与内质网的相互作用，影响肾脏病理中的钙信号传导和自噬。线粒体自噬，即对受损线粒体的选择性清除，在肾脏疾病中起双重作用。虽然PINK1/Parkin介导的线粒体自噬通过防止线粒体碎片化和凋亡来预防顺铂诱导的AKI，但其失调会导致纤维化和CKD进展。例如，巨噬细胞特异性缺失MFN2等线粒体自噬调节因子会放大ROS产生和纤维化反应。相反，BNIP3/NIX依赖性线粒体自噬通过抑制NLRP3炎性小体激活来减轻造影剂诱导的AKI。在糖尿病肾病中，线粒体自噬受损与估算肾小球滤过率（eGFR）下降和间质纤维化相关，突出了其诊断和治疗潜力。新兴的治疗策略通过抗氧化剂（如MitoQ、SS-31）、线粒体自噬诱导剂（如COPT纳米颗粒）和线粒体移植来靶向线粒体功能障碍，线粒体移植通过恢复生物能量和调节炎症途径来减轻AKI。纳米技术增强的药物递送系统，如载有姜黄素的纳米颗粒，可改善肾脏靶向性并降低氧化应激。表观遗传干预措施，包括PPAR-α激动剂和KLF4调节剂，在逆转代谢重编程和纤维化方面显示出前景。这些进展强调线粒体是肾脏病理生理学的核心枢纽。从抑制Drp1到线粒体移植的定制干预措施具有减轻肾损伤和改善临床结果的变革潜力。此外，饮食干预和腺源体等新型调节剂正在成为调节线粒体功能和减轻肾脏疾病进展的有前景的策略。未来的研究应填补对线粒体自噬在CAKUT中的作用的理解空白，并优化用于精准治疗的靶向递送系统。
