Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected conditions, and CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches are needed. Mitochondrial dysfunction and oxidative stress have emerged as drivers of kidney injury in acute and chronic settings, promoting the AKI-to-CKD transition. In this work, we review the role of mitochondrial dysfunction and oxidative stress in AKI and CKD progression and discuss novel therapeutic approaches. Specifically, evidence for mitochondrial dysfunction in diverse models of AKI (nephrotoxicity, cytokine storm, and ischemia-reperfusion injury) and CKD (diabetic kidney disease, glomerulopathies) is discussed; the clinical implications of novel information on the key role of mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), and carnitine palmitoyl-transferase 1A (CPT1A) in kidney disease are addressed; the current status of the clinical development of therapeutic approaches targeting mitochondria are updated; and barriers to the clinical development of mitochondria-targeted interventions are discussed, including the lack of clinical diagnostic tests that allow us to categorize the baseline renal mitochondrial dysfunction/mitochondrial oxidative stress and to monitor its response to therapeutic intervention. Finally, key milestones for further research are proposed.

Astragaloside IV alleviates 1-deoxysphinganine-induced mitochondrial dysfunction during the progression of chronic kidney disease through p62-Nrf2 antioxidant pathway

“…Oxidative stress caused by excessive ROS production and the occurrence as well as progression of CKD have been reported in several prior studies (Fontecha-Barriuso et al, 2022;Rahman et al, 2022). Oxidative stress can induce substantial chronic inflammation often observed in the process of renal injury and fibrosis, ultimately leading to the renal dysfunction.…”

Expression Profiles of Kidney Mitochondrial Proteome during the Progression of the Unilateral Ureteral Obstruction: Focus on Energy Metabolism Adaptions

“…Based on the above, we consider our work’s perspective is useful in identification of proteins from the renal mitochondrial protein profiles which could be potential biomarkers of ON or therapeutic targets. In line with the latter, experimental results have shown that OXPHOS [ 53 , 54 , 55 ], inhibition of glycolysis [ 19 , 20 ], or enhancing FA metabolism [ 50 , 56 , 57 , 58 , 59 ] are potential therapeutic strategies related to the mitochondrial function that might decrease renal damage in the UUO.…”

Ultrasmall and highly biocompatible carbon dots derived from natural plant with amelioration against acute kidney injury

“…Oxidative stress takes on a critical significance to the development of AKI. Since myoglobin produced by rhabdomyolysis enters the kidney, considerable ROS is metabolized to produce lipid peroxidation, thus increasing oxidative damage and inducing inflammatory responses [ 61 , 62 ]. MDA and SOD are important indicators of the level of oxidative stress, representing the degree of lipidation of oxygen radicals and the activity of antioxidant enzymes, respectively [ 63 , 64 ].…”