Nitration of Drp1 provokes mitophagy activation mediating neuronal injury in experimental autoimmune encephalomyelitis

Free Radic Biol Med. 2019 Nov 1:143:70-83. doi: 10.1016/j.freeradbiomed.2019.07.037. Epub 2019 Aug 1.

Abstract

Active autophagy/mitophagy could mediate neurodegeneration and motor disabilities in multiple sclerosis (MS). Mitochondrial recruitment of dynamin-related protein 1 (Drp1) is a crucial step to initiate mitophagy. Peroxynitrite (ONOO-) could be a player in MS pathology but the mechanisms remain unknown. We used animal model of experimental autoimmune encephalomyelitis (EAE) and tested whether ONOO- mediates Drp1 assembly in mitochondria for mitophagy and aggravates MS pathology. We found that autophagy/mitophagy activation was coincidently increased with axonal damage, apoptosis and disease progression in active EAE mice, which were remarkably attenuated by mitochondrial division/mitophagy inhibitor Mdivi-1. Importantly, increased ONOO- production was companied with Drp1 mitochondrial recruitment, PINK1/Parkin-mediated mitophagy, axonal degeneration and neuronal cell death, which were reversed by peroxynitrite decomposition catalyst (PDC). Furthermore, ONOO- production induced Drp1 nitration, promoted Drp1 assembly and mitochondrial recruitment for mitophagy activation, contributing to the EAE pathology. Together, we conclude that ONOO- serves as a key mediator in Drp1 nitration modification and assembly for facilitating mitophagy activation. Targeting ONOO--mediated Drp1 assembly and mitochondrial recruitment could be an important therapeutic strategy for multiple sclerosis treatment.

Keywords: Dynamin-related protein 1; Mitophagy; Multiple sclerosis; Neuronal damages; Nitration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Axons / metabolism
  • Chromatography, Liquid
  • Disease Models, Animal
  • Dynamins / metabolism*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism*
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Dynamics / drug effects
  • Mitophagy*
  • Multiple Sclerosis / therapy
  • Neurons / metabolism*
  • Nitrogen / metabolism
  • Peroxynitrous Acid / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Stochastic Processes
  • Tandem Mass Spectrometry

Substances

  • Peroxynitrous Acid
  • Dnm1l protein, mouse
  • Dnm1l protein, rat
  • Dynamins
  • Nitrogen