Gene of the month: FH

Zyla, Roman; Hodgson, Anjelica

doi:10.1136/jclinpath-2021-207830

“…Remarkably, the DEGs encoding a fumarate hydratase (FH) class I aerobic ( SPC_2263 ) and a succinate dehydrogenase catalytic subunit ( SPC_0731 ) were greatly downregulated (0.084-fold and 0.097-fold). The FH catalyzes the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle (TCA) [ 28 ]. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Antibacterial Components and Modes of the Methanol-Phase Extract from Commelina communis Linn

Liu

¹

,

Tang

²

,

Chen

³

2023

Plants

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Infectious diseases caused by pathogenic bacteria severely threaten human health. Traditional Chinese herbs are potential sources of new or alternative medicine. In this study, we analyzed for the first time antibacterial substances in the methanol-phase extract from a traditional Chinese herb—Commelina communis Linn—which showed an inhibition rate of 58.33% against 24 species of common pathogenic bacteria. The extract was further purified using preparative high-performance liquid chromatography (Prep-HPLC), which generated four single fragments (Fragments 1 to 4). The results revealed that Fragment 1 significantly increased bacterial cell surface hydrophobicity and membrane permeability and decreased membrane fluidity, showing disruptive effects on cell integrity of Gram-positive and Gram-negative bacteria, such as Bacillus cereus, Enterococcus faecalis, Staphylococcus aureus, and Salmonella enterica subsp., compared to the control groups (p < 0.05). In sum, 65 compounds with known functions in Fragment 1 were identified using liquid chromatography and mass spectrometry (LC-MS), of which quercetin-3-o-glucuronide was predominant (19.35%). Comparative transcriptomic analysis revealed multiple altered metabolic pathways mediated by Fragment 1, such as inhibited ABC transporters, ribosome, citrate cycle and oxidative phosphorylation, and upregulated nitrogen metabolism and purine metabolism, thereby resulting in the repressed bacterial growth and even death (p < 0.05). Overall, the results of this study demonstrate that Fragment 1 from C. communis Linn is a promising candidate against common pathogenic bacteria.

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“…Interestingly, fumarate was the only metabolite that exhibited an elevation in levels that inversely correlated with memory in aged dLdh transgenic flies. The excessive buildup of fumarate in humans with Fumarate hydratase (FH) deficiency, a rare genetic disease, results in brain atrophy, neurologic abnormalities, and intellectual impairment AGING [161,162]. Interestingly, cancer cells with an FH deficiency produce excess fumarate that, in turn, promotes increased ROS levels (Sullivan et al, Mol Cell -2013).…”

Section: Dldh Involvement In Long-term Memory Is Age and Cell-type De...mentioning

confidence: 99%

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

Frame

¹

,

Robinson

²

,

Mahmoudzadeh

³

et al. 2023

Aging

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The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

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“…Interestingly, fumarate was the only metabolite that exhibited an elevation in levels that inversely correlated with memory in aged dLdh transgenic flies. The excessive buildup of fumarate in humans with Fumarate hydratase (FH) deficiency, a rare genetic disease, results in brain atrophy, neurologic abnormalities, and intellectual impairment [151,152]. Interestingly, cancer cells with an FH deficiency produce excess fumarate that, in turn, promotes increased ROS levels (Sullivan et al, Mol Cell -2013).…”

Section: Dldh Involvement In Long-term Memory Is Age and Cell-type De...mentioning

confidence: 99%

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

Frame

¹

,

Robinson

²

,

Mahmoudzadeh

³

et al. 2022

Preprint

0

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The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression ofDrosophila melanogasterlactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.Author SummaryThe brain is composed of metabolically demanding cell types that must remain functional throughout life to maintain cognitive tasks like memory formation. How brain metabolism varies between cell-types across the lifespan is uncertain. It has been suggested that in vertebrate brains glia breakdown sugars to produce lactate and shuttle it to neurons to support long-term memory and survival. Yet, this phenomenon has not been directly tested in invertebrates. InDrosophila melanogasterflies, we genetically manipulated lactate dehydrogenase, a central enzyme in lactate metabolism, specifically within the adult brain. We discovered that shifting lactate metabolism to either higher or lower levels in neurons caused decreased survival and worse long-term memory with age. In contrast, we found increased glial lactate metabolism worsened survival, whereas decreased glial lactate metabolism impaired long-term memory in aged flies. Both increased glial or neuronal lactate metabolism led to increased accumulation of metabolites, such as 2-hydroxyglutarate, mitochondrial metabolites, and neutral lipids, in aged fly brains. These findings provide evidence for the first time in invertebrates that lactate and memory are connected and altered lactate metabolism in neurons and glia differentially impact survival and memory, but only in an age-dependent manner.Graphical Abstract

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Gene of the month: FH

Cited by 18 publications

References 48 publications

Antibacterial Components and Modes of the Methanol-Phase Extract from Commelina communis Linn

Antibacterial Components and Modes of the Methanol-Phase Extract from Commelina communis Linn

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

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