2026-07-16 ブラウン大学
＜関連情報＞
- https://www.brown.edu/news/2026-07-16/cell-metabolism-development
- https://www.science.org/doi/10.1126/science.adx8675
転写バイオセンサーにより、クロマチンへのα-ケトグルタル酸シグナル伝達のメカニズムが明らかになった A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin
Alex C. Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, […] , and Samuel K. McBrayer
Science Published:16 Jul 2026
DOI:https://doi.org/10.1126/science.adx8675
Mechanisms governing αKG-dependent chromatin demethylation. [Figure by Melissa Logies]
Abstract
The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
ミトコンドリア酵素GPT2の変異は、代謝機能障害および発達的かつ進行性の特徴を伴う神経疾患を引き起こす Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features
Qing Ouyang, Tojo Nakayama, Ozan Baytas, +25 , and Eric M. Morrow
Proceedings of the National Academy of Sciences Published:September 6, 2016
DOI:https://doi.org/10.1073/pnas.1609221113
Abstract
Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.
