Mitochondrial Dysfunction in Individuals with Diabetic Kidney Disease: A Systematic Review

Abstract

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in individuals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or individuals with diabetes but without kidney disease (DC), individuals with DKD (age ~55 years; diabetes duration ~15 years) had evidence of mitochondrial dysfunction. Individuals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include individuals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.

Promoting mitochondrial dynamics by inhibiting the PINK1–PRKN pathway to relieve diabetic nephropathy

“…In fact, increased renal mitochondrial fission and fragmentation have been shown in patients with diabetic nephropathy ( Flemming et al, 2022 ). Under hyperglycemic conditions, decreased fusion and increased fission have been linked to mitochondrial uncoupling, and the disrupted mitochondrial dynamics have been associated with accumulation of damaged mitochondria, unbalanced ATP levels, increased production of ROS, mitophagy and apoptosis ( Chen et al, 2019 ; Coughlan et al, 2016 ; Flemming et al, 2022 ; Kowluru and Mohammad, 2022 ; Zeng et al, 2019 ). This clinical picture is recapitulated in our flies when they are subjected to a high-sugar diet or a disrupted Pink1–Park pathway.…”

Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway

“…[ 80 ] Additionally, mitochondrial dysfunction is associated with the severity of DKD. [ 81 ] When mesangial cells are exposed to high glucose concentrations, an increase in intracellular mtDNA content, accumulation of ROS, and increased mitochondrial damage can be observed. [ 82 ] In mice with DKD, kidney podocytes experience mitochondrial dysfunction and damage, which results in the leakage of mtDNA into the cytosol through BAX-mediated macropores.…”

Regulation of autophagy by natural polyphenols in the treatment of diabetic kidney disease: therapeutic potential and mechanism

“…Mitophagy, which contributes to mitochondrial quality, is an important selective autophagy mechanism in DKD, as impaired mitochondrial function and abnormal mitochondrial accumulation are involved in DKD onset and progression ( 41 , 42 ). Mitophagy inhibition aggravates tubulointerstitial inflammation and premature tubular cell aging ( 43 , 44 ).…”