Perturbations in mitochondrial dynamics by p66Shc lead to renal tubular oxidative injury in human diabetic nephropathy

Clinical Science
Ming ZhanYashpal S Kanwar

Abstract

Renal tubular injury is increasingly being recognized as an early characteristic of diabetic nephropathy (DN). Mitochondrial dynamic alterations and redox protein p66Shc-mediated oxidative stress are both critical for ensuing diabetic tubular cell injury and apoptosis; whether these two processes are interlinked remains unclear. In the present study, we observed changes in mitochondrial morphology and expression of associated proteins in tubules of patients with DN. We demonstrated mitochondrial fragmentation as an important pathogenic feature of tubular cell injury that is linked to oxidative stress and p66Shc up-regulation. In renal proximal tubular cells, alterations in mitochondrial dynamics and expression of fission-fusion proteins were observed under high glucose (HG) ambience, along with p66Shc Ser36 phosphorylation. Gene ablation of p66Shc alleviated HG-induced mitochondrial fragmentation, down-regulated Fis1 and reduced p66Shc-Fis1 binding, increased Mfn1 expression, and disrupted interactions between Mfn1 and proapoptotic Bak. Overexpression of p66Shc exacerbated these changes, whereas overexpression of dominant-negative p66Shc Ser36 mutant had a marginal effect under HG, indicating that p66Shc phosphorylation as a pr...Continue Reading

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Citations

Feb 5, 2019·Evidence-based Complementary and Alternative Medicine : ECAM·Xinhui LiuShunmin Li
Apr 16, 2020·International Journal of Molecular Sciences·Lucas Opazo-RíosJesús Egido
Aug 17, 2020·Ageing Research Reviews·Hilal Ahmad MirFirdous A Khanday
Apr 13, 2021·Frontiers in Endocrinology·Ugochukwu Kelvin IhenachoR Blake Hill
Jun 3, 2021·Antioxidants·Kiyoung Kim, Eun-Young Lee
Jun 3, 2021·Biomolecules·Liang-Jun Yan
Aug 1, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Wenwen LiuTian Lan
Aug 24, 2021·Frontiers in Cell and Developmental Biology·Wenni DaiLiyu He
Jan 3, 2020·Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association·Miaoyuan ZhangLin Zhou

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