Global determination of reaction rates and lipid turnover kinetics in Mus musculus

Chen, Qishan; Li, Hu; Tian, He; Lam, Sin Man; Liao, Yuan; Zhang, Ziyin; Dong, Manyuan; Chen, Shaoru; Yao, Yuxiao; Meng, Jiemiao; Zhang, Yong; Zheng, Lemin; Meng, Zhuo-Xian; Han, Weiping; Shui, Guanghou; Zhu, Dahai; Fu, Suneng

doi:10.1016/j.cmet.2023.03.007

Cited by 5 publications

(2 citation statements)

References 42 publications

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“…The high microglial expression of the LDHB gene, which is preferentially expressed by cells converting lactate into pyruvate, led us to hypothesize that microglia might efficiently metabolize lactate. A growing body of literature now established lactate as a key metabolite, which not only can be a primary source of carbon for the TCA cycle 51 , 52 , but it also contributes to determining the cellular NADH/NAD + ratio sustaining redox buffering 53 , 54 .…”

Section: Discussionmentioning

confidence: 99%

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Monsorno,

Ginggen,

Ivanov

et al. 2023

Nat Commun

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Microglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced AMPA/GABA ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in mouse brain development and adult behavior.

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Section: Discussionmentioning

confidence: 99%

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Monsorno,

Ginggen,

Ivanov

et al. 2023

Nat Commun

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show abstract

“…The supernatant was then removed to another clean, 1.5 mL centrifuge tube and dried with a Speed-Vac (Fischer Scientific, USA). The extracts were redissolved with 2% acetonitrile in water and analyzed by HPLC-mass spectrometry [ 17 ]. Each group included 4 samples.…”

Section: Methodsmentioning

confidence: 99%

Schizophrenia-Like Behaviors Arising from Dysregulated Proline Metabolism Are Associated with Altered Neuronal Morphology and Function in Mice with Hippocampal PRODH Deficiency

Yao,

Jin,

Liao

et al. 2023

Aging and disease

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Despite decades of research being conducted to understand what physiological deficits in the brain are an underlying basis of psychiatric diseases like schizophrenia, it has remained difficult to establish a direct causal relationship between neuronal dysfunction and specific behavioral phenotypes. Moreover, it remains unclear how metabolic processes, including amino acid metabolism, affect neuronal function and consequently modulate animal behaviors. PRODH, which catalyzes the first step of proline degradation, has been reported as a susceptibility gene for schizophrenia. It has consistently been shown that PRODH knockout mice exhibit schizophrenia-like behaviors. However, whether the loss of PRODH directly impacts neuronal function or whether such neuronal deficits are linked to schizophrenia-like behaviors has not yet been examined. Herein, we first ascertained that dysregulated proline metabolism in humans is associated with schizophrenia. We then found that PRODH was highly expressed in the oreins layer of the mouse dorsal hippocampus. By using AAV-mediated shRNA, we depleted PRODH expression in the mouse dorsal hippocampus and subsequently observed hyperactivity and impairments in the social behaviors, learning, and memory of these mice. Furthermore, the loss of PRODH led to altered neuronal morphology and function both in vivo and in vitro . Our study demonstrates that schizophrenia-like behaviors may arise from dysregulated proline metabolism due to the loss of PRODH and are associated with altered neuronal morphology and function in mice.

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Amino acid is a major carbon source for hepatic lipogenesis

Liao,

Chen,

Liu

et al. 2024

Cell Metabolism

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Global determination of reaction rates and lipid turnover kinetics in Mus musculus

Cited by 5 publications

References 42 publications

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Schizophrenia-Like Behaviors Arising from Dysregulated Proline Metabolism Are Associated with Altered Neuronal Morphology and Function in Mice with Hippocampal PRODH Deficiency

Amino acid is a major carbon source for hepatic lipogenesis

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