Control of histone demethylation by nuclear-localized α-ketoglutarate dehydrogenase

Huang, Fei; Luo, Xiao; Ou, Yang; Gao, Zhaoxu; Tang, Qiming; Chu, Zhulang; Zhu, Xin‐Guang; He, Yuehui

doi:10.1126/science.adf8822

Cited by 14 publications

(6 citation statements)

References 76 publications

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“…The distribution of metabolites is highly heterogeneous within cells (Li et al, 2023 ). Metabolic enzymes have been demonstrated to alter metabolite levels and efficiently modulate the activity of their interacting proteins (Huang et al, 2023 ; Wang et al, 2019 ). To identify potential targets of SUCLG1, we assayed the interaction between SUCLG1 and regulators of mtDNA replication and transcription.…”

Section: Resultsmentioning

confidence: 99%

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

Yan,

Xie,

Sun

et al. 2024

EMBO J

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Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

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Section: Resultsmentioning

confidence: 99%

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

Yan,

Xie,

Sun

et al. 2024

EMBO J

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“…LSD1 catalyzes the demethylation of mono- or dimethylated H3K4 and H3K9, whereas LSDs act as receptors in the mitochondrial ETC ( 161 ). JMJD-mediated demethylation of histones requires α-ketoglutarate ( 162 ), a substrate produced mainly by the tricarboxylic acid (TCA) cycle in the mitochondrial matrix. Current research has found that low methylation of DNMT1/DNMT3a/DNMT3b/DNMT3L promotes oocyte aging ( 17 ).…”

Section: Mitochondrial Dysfunction Leads To Ovarian Agingmentioning

confidence: 99%

Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

Ju,

Zhao,

et al. 2024

Front. Endocrinol.

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Mitochondria plays an essential role in regulating cellular metabolic homeostasis, proliferation/differentiation, and cell death. Mitochondrial dysfunction is implicated in many age-related pathologies. Evidence supports that the dysfunction of mitochondria and the decline of mitochondrial DNA copy number negatively affect ovarian aging. However, the mechanism of ovarian aging is still unclear. Treatment methods, including antioxidant applications, mitochondrial transplantation, emerging biomaterials, and advanced technologies, are being used to improve mitochondrial function and restore oocyte quality. This article reviews key evidence and research updates on mitochondrial damage in the pathogenesis of ovarian aging, emphasizing that mitochondrial damage may accelerate and lead to cellular senescence and ovarian aging, as well as exploring potential methods for using mitochondrial mechanisms to slow down aging and improve oocyte quality.

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“…On the other hand, in oligodendrocytes and their precursors, hGDH1 is expressed in the cell nucleus [46,47]. While this nuclear localization may appear aberrant, α-ketoglutarate dehydrogenase, another metabolic enzyme of the TCA cycle linked to GDH function, can also localize to the cell nucleus, where it generates α-ketoglutarate needed for gene regulation via histone modification [74]. Whether hGDH1 serves a similar function in dividing glial cells needs to be further understood.…”

Section: Studies On Human Central Nervous Tissuementioning

confidence: 99%

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition

Plaitakis,

Sidiropoulou,

Kotzamani

et al. 2024

IJMS

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Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations’ origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia–neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron–glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.

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Control of histone demethylation by nuclear-localized α-ketoglutarate dehydrogenase

Cited by 14 publications

References 76 publications

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression

Mechanisms of mitochondrial dysfunction in ovarian aging and potential interventions

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition

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