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

• Published in: Free radical biology & medicine Vol. 74; pp. 129 - 144
• Main Authors: Ribeiro, Márcio, Rosenstock, Tatiana R., Oliveira, Ana M., Oliveira, Catarina R., Rego, A. Cristina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014
• Subjects: Akt; 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; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - metabolism; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Insulin/IGF-1 signaling; Mice; Mice, Inbred Strains; Mice, Knockout; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Nerve Tissue Proteins - genetics; Neurons - drug effects; Neurons - metabolism; Nrf2; Nuclear Proteins - genetics; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - metabolism; Oxidative stress; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinases - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Striatal cells; DHE; Oxidative stress; HKII; MT-COII; Reactive oxygen species; mtDNA; PI-3K; mHtt; H2DCFDA; HO-1; CDK; IRS; Drp1; IGF1R; CBP; GCLc; Mitochondria; CREB; TMRM; Nrf2; mTOR; Tfam; GSH; GSSG; NQO1; Tom20; Huntington disease; IR; SOD; IGF-1; PGC-1α; Akt; SDHA; GPx; Striatal cells; GCL; Hsp60; ARE; Insulin/IGF-1 signaling; ROS; NDUFS3; HD; Tom40; Erk
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.06.023

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. [Display omitted] •Insulin/IGF-1 precludes mHtt-induced mitochondrial ROS formation and SOD activity.•Insulin/IGF-1 protection in HD cells is independent of Nrf2 transcription activity.•Insulin/IGF-1 enhances mitochondrial function via PI3K/Akt pathway in HD cells.•Insulin/IGF-1 increases p-Akt, Tfam, and MT-COII in mitochondria of HD cells.