Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells

Free Radic Biol Med. 2014 Sep;74:129-44. doi: 10.1016/j.freeradbiomed.2014.06.023. Epub 2014 Jun 30.

Abstract

Oxidative stress and mitochondrial dysfunction have been described in Huntington's disease, a disorder caused by expression of mutant huntingtin (mHtt). IGF-1 was previously shown to protect HD cells, whereas insulin prevented neuronal oxidative stress. In this work we analyzed the role of insulin and IGF-1 in striatal cells derived from HD knock-in mice on mitochondrial production of reactive oxygen species (ROS) and related antioxidant and signaling pathways influencing mitochondrial function. Insulin and IGF-1 decreased mitochondrial ROS induced by mHtt and normalized mitochondrial SOD activity, without affecting intracellular glutathione levels. IGF-1 and insulin promoted Akt phosphorylation without changing the nuclear levels of phosphorylated Nrf2 or Nrf2/ARE activity. Insulin and IGF-1 treatment also decreased mitochondrial Drp1 phosphorylation, suggesting reduced mitochondrial fragmentation, and ameliorated mitochondrial function in HD cells in a PI-3K/Akt-dependent manner. This was accompanied by increased total and phosphorylated Akt, Tfam, and mitochondrial-encoded cytochrome c oxidase II, as well as Tom20 and Tom40 in mitochondria of insulin- and IGF-1-treated mutant striatal cells. Concomitantly, insulin/IGF-1-treated mutant cells showed reduced apoptotic features. Hence, insulin and IGF-1 improve mitochondrial function and reduce mitochondrial ROS caused by mHtt by activating the PI-3K/Akt signaling pathway, in a process independent of Nrf2 transcriptional activity, but involving enhanced mitochondrial levels of Akt and mitochondrial-encoded complex IV subunit.

Keywords: Akt; Huntington disease; Insulin/IGF-1 signaling; Mitochondria; Nrf2; Oxidative stress; Reactive oxygen species; Striatal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • Corpus Striatum / pathology*
  • DNA-Binding Proteins / metabolism
  • Dynamins / metabolism
  • High Mobility Group Proteins / metabolism
  • Humans
  • Huntingtin Protein
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Nerve Tissue Proteins / genetics
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nuclear Proteins / genetics
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • DNA-Binding Proteins
  • HTT protein, human
  • High Mobility Group Proteins
  • Htt protein, mouse
  • Huntingtin Protein
  • Insulin
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Reactive Oxygen Species
  • Tfam protein, mouse
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt
  • Dnm1l protein, mouse
  • Dynamins