LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain
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 patter...
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MDPI AG
2022-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/2/261 |
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| author | Jun Sung Park Kamran Saeed Myeung Hoon Jo Min Woo Kim Hyeon Jin Lee Chan-Bae Park Gwang Lee Myeong Ok Kim |
| author_facet | Jun Sung Park Kamran Saeed Myeung Hoon Jo Min Woo Kim Hyeon Jin Lee Chan-Bae Park Gwang Lee Myeong Ok Kim |
| author_sort | Jun Sung Park |
| collection | DOAJ |
| 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 (<i>Ldhb</i><sup>−/−)</sup> mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (<i>Ldhb</i><sup>−/−</sup>) mice were generated by the ablation of the <i>Ldhb</i> gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The <i>Ldhb</i><sup>−/−</sup> 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. <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> mice. |
| first_indexed | 2024-03-09T22:45:22Z |
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| spelling | doaj.art-4aca47cdc35241ca9e1f3dee70e48f192023-11-23T18:30:56ZengMDPI AGAntioxidants2076-39212022-01-0111226110.3390/antiox11020261LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse BrainJun Sung Park0Kamran Saeed1Myeung Hoon Jo2Min Woo Kim3Hyeon Jin Lee4Chan-Bae Park5Gwang Lee6Myeong Ok Kim7Division of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaDivision of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaDivision of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaDivision of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaDivision of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaDepartment of Otolaryngology, Ajou University School of Medicine, Suwon 16499, KoreaDepartment of Physiology, Ajou University School of Medicine, Suwon 16499, KoreaDivision of Life Science and Applied Life Science (BK21 FOUR), College of Natural Sciences, Gyeongsang National University, Jinju 52828, KoreaAge-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 (<i>Ldhb</i><sup>−/−)</sup> mice to test the hypothesis that LDHB deficiency plays an important role in oxidative stress-mediated neuroinflammation and neurodegeneration. LDHB knockout (<i>Ldhb</i><sup>−/−</sup>) mice were generated by the ablation of the <i>Ldhb</i> gene using the Cre/loxP-recombination system in the C57BL/6 genetic background. The <i>Ldhb</i><sup>−/−</sup> 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. <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> 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 <i>Ldhb</i><sup>−/−</sup> mice.https://www.mdpi.com/2076-3921/11/2/261Lactate dehydrogenase-Bmitochondrial dysfunctionoxidative stressinflammationp-AMPK/Sirt1/PGC-1alpha signalingosmotin |
| spellingShingle | Jun Sung Park Kamran Saeed Myeung Hoon Jo Min Woo Kim Hyeon Jin Lee Chan-Bae Park Gwang Lee Myeong Ok Kim LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain Antioxidants Lactate dehydrogenase-B mitochondrial dysfunction oxidative stress inflammation p-AMPK/Sirt1/PGC-1alpha signaling osmotin |
| title | LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain |
| title_full | LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain |
| title_fullStr | LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain |
| title_full_unstemmed | LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain |
| title_short | LDHB Deficiency Promotes Mitochondrial Dysfunction Mediated Oxidative Stress and Neurodegeneration in Adult Mouse Brain |
| title_sort | ldhb deficiency promotes mitochondrial dysfunction mediated oxidative stress and neurodegeneration in adult mouse brain |
| topic | Lactate dehydrogenase-B mitochondrial dysfunction oxidative stress inflammation p-AMPK/Sirt1/PGC-1alpha signaling osmotin |
| url | https://www.mdpi.com/2076-3921/11/2/261 |
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