Defective mitophagy activity in experimental diabetic nephropathy

Elif Ekinci, Gavin C Higgins, Tuong Vi B Nguyen, Sally A. Penfold, Vicki Thallas-Bonke, Brooke E. Harcourt, Portia M Robb, Georg Ramm, George Jerums, Alison Skene, R. J. MacIsaac, David A. Power, KE White, RW Bilous, Mark E. Cooper, Josephine M. Forbes, Melinda T. Coughlan

    Research output: Contribution to journalMeeting Abstract


    Aim: Here, we aimed to determine if there was an impairment in mitophagy and changes in mitochondrial dynamics in the kidney in Diabetic Nephropathy (DN).

    Background: DN is the major cause of end stage renal disease in the Western world. Defects in mitochondrial bioenergetics are evident in DN and are thought to initiate renal impairment. Accumulation of fragmented mitochondria are found in the renal cortex in experimental diabetes, suggesting that in tandem with a shift in dynamics, mitochondrial clearance mechanisms may be impaired. The process of mitophagy is the selective targeting of damaged or dysfunctional mitochondria to autophagosomes for degradation through the autophagy pathway.

    Markers of mitophagy and mitochondrial bioenergetics and dynamics were followed in the renal cortex from rodents rendered diabetic with the beta cell toxin streptozotocin (STZ).

    Results: Bioenergetics was impaired in isolated mitochondria from diabetic mice, with a decline in ATP content, increased reactive oxygen species and depolarisation of the inner mitochondrial membrane. Increased recruitment of Drp‐1 to mitochondria was observed in diabetes, indicating a shift towards fission. Electron microscopy imaging revealed mitochondrial fragmentation in the proximal tubule epithelial cells (PTECs). Mitophagy impairment was seen with decreased autophagic flux (decline in LC3‐II) in renal cortical cell lysates, coupled with a decline in Parkin translocation to mitochondria. Importantly, these data correlate with findings from renal biopsies of patients with DN that show striking changes in morphology of mitochondria residing within PTECs manifesting an increase of fragmented mitochondria, indicative of a shift towards fission.

     These data demonstrate that in chronic hyperglycaemia, mitochondria undergo fission, however, there is a defect in mitophagy, leading to reduced mitochondrial turnover and accumulation of dysfunctional mitochondria.

    Original languageEnglish
    Article number162
    Pages (from-to)60-61
    Number of pages2
    Issue numberS4
    Publication statusPublished - 2014


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