Critical role of mitochondrial dysfunction and impaired mitophagy in diabetic nephropathy

J Cell Physiol. 2019 Nov;234(11):19223-19236. doi: 10.1002/jcp.28712. Epub 2019 Apr 29.

Abstract

Mitochondrial dynamics play a critical role in deciding the fate of a cell under normal and diseased condition. Recent surge of studies indicate their regulatory role in meeting energy demands in renal cells making them critical entities in the progression of diabetic nephropathy. Diabetes is remarkably associated with abnormal fuel metabolism, a basis for free radical generation, which if left unchecked may devastate the mitochondria structurally and functionally. Impaired mitochondrial function and their aberrant accumulation have been known to be involved in the manifestation of diabetic nephropathy, indicating perturbed balance of mitochondrial dynamics, and mitochondrial turnover. Mitochondrial dynamics emphasize the critical role of mitochondrial fission proteins such as mitochondrial fission 1, dynamin-related protein 1 and mitochondrial fission factor and fusion proteins including mitofusin-1, mitofusin-2 and optic atrophy 1. Clearance of dysfunctional mitochondria is aided by translocation of autophagy machinery to the impaired mitochondria and subsequent activation of mitophagy regulating proteins PTEN-induced putative kinase 1 and Parkin, for which mitochondrial fission is a prior event. In this review, we discuss recent progression in our understanding of the molecular mechanisms targeting reactive oxygen species mediated alterations in mitochondrial energetics, mitophagy related disorders, impaired glucose transport, tubular atrophy, and renal cell death. The molecular cross talks linking autophagy and renoprotection through an intervention of 5'-AMP-activated protein kinase, mammalian target of rapamycin, and SIRT1 factors are also highlighted here, as in-depth exploration of these pathways may help in deriving therapeutic strategies for managing diabetes provoked end-stage renal disease.

Keywords: diabetic nephropathy; free radicals; mitochondrial dysfunction; mitophagy; renal dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis / genetics
  • Autophagy / genetics*
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / pathology
  • Dynamins / genetics
  • GTP Phosphohydrolases / genetics
  • Humans
  • Membrane Proteins / genetics
  • Mitochondria / genetics*
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Proteins / genetics
  • Mitophagy / genetics*

Substances

  • Membrane Proteins
  • Mff protein, human
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • OPA1 protein, human
  • Mfn1 protein, human
  • DNM1L protein, human
  • Dynamins