Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction

J Alzheimers Dis. 2014;40(2):245-56. doi: 10.3233/JAD-132060.

Abstract

Mitochondria are essential cytoplasmic organelles, critical for cell survival and death. Recent mitochondrial research revealed that mitochondrial dynamics-the balance of fission and fusion in normal mitochondrial dynamics--is an important cellular mechanism in eukaryotic cell and is involved in the maintenance of mitochondrial morphology, structure, number, distribution, and function. Research into mitochondria and cell function has revealed that mitochondrial dynamics is impaired in a large number of aging and neurodegenerative diseases, and in several inherited mitochondrial diseases, and that this impairment involves excessive mitochondrial fission, resulting in mitochondrial structural changes and dysfunction, and cell damage. Attempts have been made to develop molecules to reduce mitochondrial fission while maintaining normal mitochondrial fusion and function in those diseases that involve excessive mitochondrial fission. This review article discusses mechanisms of mitochondrial fission in normal and diseased states of mammalian cells and discusses research aimed at developing therapies, such as Mdivi, Dynasore and P110, to prevent or to inhibit excessive mitochondrial fission.

Keywords: Alzheimer's disease; fission inhibitors; free radical production; mitochondrial dynamics; mitochondrial dysfunction; oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Hydrazones / therapeutic use
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / therapy*
  • Mitochondrial Dynamics / drug effects
  • Mitochondrial Dynamics / physiology*
  • Mitochondrial Proteins / antagonists & inhibitors
  • Mitochondrial Proteins / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / therapeutic use
  • Quinazolinones / therapeutic use

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Hydrazones
  • Mitochondrial Proteins
  • N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
  • Quinazolinones
  • 9-deoxy-delta-9-prostaglandin D2
  • Prostaglandin D2