期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 74, 期 -, 页码 129-144出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2014.06.023
关键词
Huntington disease; Oxidative stress; Insulin/IGF-1 signaling; Nrf2; Mitochondria; Reactive oxygen species; Striatal cells; Akt
资金
- European community fund FEDER through Programa Operacional Tematico Factores de Competitividade - COMPETE
- European community fund FEDER through Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PEst-C/SAU/LA0001/2013-2014, PTDC/SAU-FCF/66421/2006, PTDC/SAU-FCF/108056/2008]
- [SFRH/BD/41285/2007]
- [SFRH/BPD/44246/2008]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-FCF/66421/2006, PTDC/SAU-FCF/108056/2008, SFRH/BPD/44246/2008] Funding Source: FCT
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. (C) 2014 Elsevier Inc. All rights reserved.
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