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β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.

ABSTRACT: Low-grade inflammation is a critical pathological factor contributing to the development of metabolic disorders. β-carotene oxygenase 2 (BCO2) was initially identified as an enzyme catalyzing carotenoids in the inner mitochondrial membrane. Mutations in BCO2 are associated with inflammation and metabolic disorders in humans, yet the underlying mechanisms remain unknown. Here, we used loss-of-function approaches in mice and cell culture models to investigate the role of BCO2 in inflammation and metabolic dysfunction. We demonstrated decreases in BCO2 mRNA and protein levels and suppression of mitochondrial respiratory complex I proteins and mitochondrial superoxide dismutase levels in the liver of type 2 diabetic human subjects. Deficiency of BCO2 caused disruption of assembly of the mitochondrial respiratory supercomplexes, such as supercomplex III₂+IV in mice, and overproduction of superoxide radicals in primary mouse embryonic fibroblasts. Further, deficiency of BCO2 increased protein carbonylation and populations of natural killer cells and M1 macrophages, and decreased populations of T cells, including CD4⁺ and/or CD8⁺ in the bone marrow and white adipose tissues. Elevation of plasma inflammatory cytokines and adipose tissue hypertrophy and inflammation were also characterized in BCO2 deficient mice. Moreover, BCO2 deficient mice were more susceptible to high-fat diet-induced obesity and hyperglycemia. Double knockout of BCO2 and leptin receptor genes caused a significantly greater elevation of the fasting blood glucose level in mice at 4 weeks of age, compared to the age- and sex-matched leptin receptor knockout. Finally, administration of Mito-TEMPO, a mitochondrial specific antioxidant attenuated systemic low-grade inflammation induced by BCO2 deficiency. Collectively, these findings suggest that BCO2 is essential for mitochondrial respiration and metabolic homeostasis in mammals. Loss or decreased expression of BCO2 leads to mitochondrial oxidative stress, low-grade inflammation, and the subsequent development of metabolic disorders.

SUBMITTER: Wu L

PROVIDER: S-EPMC7946548 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.

Wu Lei L Lu Peiran P Guo Xin X Song Kun K Lyu Yi Y Bothwell James J Wu Jinglong J Hawkins Olivia O Clarke Stephen L SL Lucas Edralin A EA Smith Brenda J BJ Chowanadisai Winyoo W Hartson Steve D SD Ritchey Jerry W JW Wang Weiqun W Medeiros Denis M DM Li Shitao S Lin Dingbo D

Free radical biology & medicine 20210113

Low-grade inflammation is a critical pathological factor contributing to the development of metabolic disorders. β-carotene oxygenase 2 (BCO2) was initially identified as an enzyme catalyzing carotenoids in the inner mitochondrial membrane. Mutations in BCO2 are associated with inflammation and metabolic disorders in humans, yet the underlying mechanisms remain unknown. Here, we used loss-of-function approaches in mice and cell culture models to investigate the role of BCO2 in inflammation and m ...[more]

PMID: 33453359

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Project description:Purpose: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial encephalomyopathy subtype, is caused by mutations of thymidine phosphorylase (TYMP). As a metabolic enzyme localized in the cytoplasm, the biological processes disturbed by TYMP functional defect are supposed to be not limited in the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic biological alterations and associated homeostatic regulation caused by TYMP deficiency. Methods: Clinical evaluation and genetic analysis were performed on three patients from two independent families carrying heterozygous TYMP variants. Molecular dynamic (MD) simulation and nucleosides detection were used to investigate the pathogenicity of the variants. Plasma from patients with MNGIE and m.A3243G MELAS and healthy volunteers were analyzed by targeted and untargeted metabolomics to characterize the metabolic profiles of MNGIE. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from these three groups of subjects. Results: Three novel TYMP pathogenic variants were identified in our MNGIE patients. Total 72 plasma metabolites were identified as specific alterations of MNGIE patients through comparing the differentially changed metabolites in MNGIE patients and m.A3243G MELAS patients. Beside pyrimidine metabolism, MNGIE patients showed significant changes in multiple metabolisms, such as bile acids metabolism, caffeine metabolism and steroid hormone metabolism. Despite comparable mitochondrial dysfunction existing in fibroblasts from patients with TYMP deficiency and ones with m.A3243G mutation, a distinct downregulated cholesterol metabolism and fatty acids (FAs) metabolism were revealed in the fibroblasts from MNGIE patients via multiple analysis of metabolites levels, metabolic enzymes expression, mitochondrial substrates dependency and transcription factors expression. Conclusions: Our findings revealed a more expansive metabolic disturbance may be caused by TYMP deficiency beyond mitochondrial disfunction, extending a comprehensive understanding of the biochemical outcome of TYMP deficiency.

Project description:Age-related decline in mitochondrial function and oxidative stress plays a critical role in neurodegeneration. Lactate dehydrogenase-B (LDHB) is a glycolytic enzyme that catalyzes the conversion of lactate, an important brain energy substrate, into pyruvate. It has been reported that the LDHB pattern changes in the brain during ageing. Yet very little is known about the effect of LDHB deficiency on brain pathology. Here, we have used Ldhb knockout (Ldhb-/-) mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (Ldhb-/-) mice were generated by the ablation of the Ldhb gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The Ldhb-/- mice were treated with either osmotin (15 μg/g of the body; intraperitoneally) or vehicle twice a week for 5-weeks. After behavior assessments, the mice were sacrificed, and the cortical and hippocampal brain regions were analyzed through biochemical and morphological analysis. Ldhb-/- mice displayed enhanced reactive oxygen species (ROS) and lipid peroxidation (LPO) production, and they revealed depleted stores of cellular ATP, GSH:GSSG enzyme ratio, and downregulated expression of Nrf2 and HO-1 proteins, when compared to WT littermates. Importantly, the Ldhb-/- mice showed upregulated expression of apoptosis mediators (Bax, Cytochrome C, and caspase-3), and revealed impaired p-AMPK/SIRT1/PGC-1alpha signaling. Moreover, LDHB deficiency-induced gliosis increased the production of inflammatory mediators (TNF-α, Nf-ĸB, and NOS2), and revealed cognitive deficits. Treatment with osmotin, an adipoR1 natural agonist, significantly increased cellular ATP production by increasing mitochondrial function and attenuated oxidative stress, neuroinflammation, and neuronal apoptosis, probably, by upregulating p-AMPK/SIRT1/PGC-1alpha signaling in Ldhb-/- mice. In brief, LDHB deficiency may lead to brain oxidative stress-mediated progression of neurodegeneration via regulating p-AMPK/SIRT1/PGC-1alpha signaling, while osmotin could improve mitochondrial functions, abrogate oxidative stress and alleviate neuroinflammation and neurodegeneration in adult Ldhb-/- mice.

Dataset Information

β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.

Publications

β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.

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