期刊
ANTIOXIDANTS
卷 11, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/antiox11081487
关键词
KGDHc; alpha-ketoglutarate dehydrogenase complex; OGDHc; oxoglutarate dehydrogenase complex; ischemia-reperfusion; antioxidant systems; DLD; DLST; mitochondria; reactive oxygen species; reverse electron transfer; RET; ROS; cellular respiration; transgenic animal; succinate; alpha-glycerophosphate
资金
- Hungarian Brain Research Program 2 (Semmelweis University) [2017-1.2.1-NKP2017-00002]
- STIA-OTKA-2021 grant (from the Semmelweis University) [TKP2021-EGA-25]
- Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-EGA funding scheme [TKP2021-EGA-25]
- [EFOP-3.6.3-VEKOP-16-2017-00009]
The present study investigates the role of KGDHc and its subunits in the bioenergetics and ROS homeostasis of brain mitochondria. The study reveals that the functioning of KGDHc is associated with decreased oxygen consumption and H2O2 production, as well as attenuated ROS production related to ischemia-reperfusion injury.
alpha-ketoglutarate dehydrogenase complex (KGDHc), or 2-oxoglutarate dehydrogenase complex (OGDHc) is a rate-limiting enzyme in the tricarboxylic acid cycle, that has been identified in neurodegenerative diseases such as in Alzheimer's disease. The aim of the present study was to establish the role of the KGDHc and its subunits in the bioenergetics and reactive oxygen species (ROS) homeostasis of brain mitochondria. To study the bioenergetic profile of KGDHc, genetically modified mouse strains were used having a heterozygous knock out (KO) either in the dihydrolipoyl succinyltransferase (DLST+/-) or in the dihydrolipoyl dehydrogenase (DLD+/-) subunit. Mitochondrial oxygen consumption, hydrogen peroxide (H2O2) production, and expression of antioxidant enzymes were measured in isolated mouse brain mitochondria. Here, we demonstrate that the ADP-stimulated respiration of mitochondria was partially arrested in the transgenic animals when utilizing alpha-ketoglutarate (alpha-KG or 2-OG) as a fuel substrate. Succinate and alpha-glycerophosphate (alpha-GP), however, did not show this effect. The H2O2 production in mitochondria energized with alpha-KG was decreased after inhibiting the adenine nucleotide translocase and Complex I (CI) in the transgenic strains compared to the controls. Similarly, the reverse electron transfer (RET)-evoked H2O2 formation supported by succinate or alpha-GP were inhibited in mitochondria isolated from the transgenic animals. The decrease of RET-evoked ROS production by DLST+/- or DLD+/- KO-s puts the emphasis of the KGDHc in the pathomechanism of ischemia-reperfusion evoked oxidative stress. Supporting this notion, expression of the antioxidant enzyme glutathione peroxidase was also decreased in the KGDHc transgenic animals suggesting the attenuation of ROS-producing characteristics of KGDHc. These findings confirm the contribution of the KGDHc to the mitochondrial ROS production and in the pathomechanism of ischemia-reperfusion injury.
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