The hallmarks of mitochondrial dysfunction in chronic kidney disease

Abstract

Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases since they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease (CKD) with special emphasis on its role in the development of diabetic nephropathy (DN). We will examine the current understanding on the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure is intimately linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and lncRNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases.

1,25-Dihydroxyvitamin D3 Attenuates Angiotensin II-Induced Renal Injury by Inhibiting Mitochondrial Dysfunction and Autophagy

“…Previous studies have suggested that MtD is mainly observed in acute kidney injury and CKD [28,29]. Our previous study demonstrated that NLRP3 deficiency may attenuate renal fibrosis by improving MtD in a mouse unilateral ureteral obstruction model for CKD [22].…”

Oxidative stress in chronic kidney disease

“…The most elaborated is undoubtedly the role of OS in diabetic nephropathy. In this specific context, increased OS has been shown to be due to multiple mechanisms including mitochondrial dysfunction, increased NOX activity, eNOS uncoupling, and deficiencies in antioxidant defense mechanisms, both enzymatic and nonenzymatic, for which we refer to extensive reviews by several groups [54,56].…”

“…In CKD, increased mitochondrial ROS generation and mitochondrial dysfunction are frequently reported. Especially in diabetic nephropathy, mitochondrial dysfunction has been well explored with findings on both morphological as well as functional disturbances in the renal mitochondria [56]. But also in nondiabetic CKD patients, disturbed regulatory MiRNAs such as MiR21 have been reported in CKD patients and an impaired complex IVactivity has been reported [57,59].…”

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

“…Movement of foot processes in response to environmental changes requires the redistribution of actin filaments which is dependent upon phosphorylation-mediated signalling. Mitochondrial dysfunction with insufficient ATP production may contribute to the development of DN [52][53][54]. Mitochondria and glycolysis maintain energy homeostasis in podocytes [41,51], with glycolysis responsible for the intracellular ATP distribution in the cortical area of podocytes [41].…”