Abstract
Mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase (IDH2) plays a key role in the intermediary metabolism and energy production via catalysing oxidative decarboxylation of isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle. Despite studies reporting potential interlinks between IDH2 and various diseases, there is lack of effort to comprehensively characterize signature(s) of IDH2 knockout (IDH2 KO) mice. A total of 6583 transcripts were identified from both wild-type (WT) and IDH2 KO mice liver tissues. Afterwards, 167 differentially expressed genes in the IDH2 KO group were short-listed compared to the WT group based on our criteria. The online bioinformatic analyses indicated that lipid metabolism is the most significantly influenced metabolic process in IDH2 KO mice. Moreover, the TR/RXR activation pathway was predicted as the top canonical pathway significantly affected by IDH2 KO. The key transcripts found in the bioinformatic analyses were validated by qPCR analysis, corresponding to the transcriptomics results. Further, an additional qPCR analysis confirmed that IDH2 KO caused a decrease in hepatic de novo lipogenesis via the activation of the fatty acid β-oxidation process. Our unbiased transcriptomics approach and validation experiments suggested that IDH2 might play a key role in homeostasis of lipid metabolism.
Highlights
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate into α-ketoglutarate [1] and are classified into two subclasses based on a type of cofactors utilized in the reaction
Regarding NADPH production, IDH2 plays a critical role in mitochondrial homeostasis since glucose 6-phosphate dehydrogenase, another key enzyme participating the pentose phosphate pathway to produce NADPH, is lacking in mitochondria [1]
In non-cancer studies, the mechanistic contributions of IDH2 are fairly clear as to reactive oxygen species (ROS) homeostasis which might be related to NADPH production and glutathione regeneration
Summary
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate into α-ketoglutarate [1] and are classified into two subclasses based on a type of cofactors utilized in the reaction. Either nicotinamide adenine dinucleotide (NAD+ ) or NADP+ is utilized as a cofactor to form NADH (reduced form of NAD+ ) or NADPH (reduced form of NADP+ ), respectively [2]. There are three isoforms of IDHs depending upon their localization: Cytosolic NADP+ -dependent. IDH1 and IDH2 produce NADPH, which is a molecule required for the regeneration of glutathione [4], and for the utilization of anabolic pathways, such as fatty acid elongation processes [5]. Regarding NADPH production, IDH2 plays a critical role in mitochondrial homeostasis since glucose 6-phosphate dehydrogenase, another key enzyme participating the pentose phosphate pathway to produce NADPH, is lacking in mitochondria [1]. In non-cancer studies, the mechanistic contributions of IDH2 are fairly clear as to ROS homeostasis which might be related to NADPH production and glutathione regeneration.
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