{
  "abstract": "N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic relief valve for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on/off switch. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results suggest that ASPNAT can serve as an auxiliary matrix-aspartate sink when the AAT node is product-limited.",
  "abstract_shown": true,
  "affiliations": [
    "Biophysics Graduate Program, The Ohio State University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "N. Puthillathu"
    },
    {
      "name": "J. R. Moffett"
    },
    {
      "name": "B. S. Slusher"
    },
    {
      "name": "A. M. A. Namboodiri"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5jrz1j3nzmsyy.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.29.735215",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.06.29.735215v2.full",
  "id": "5jrz1j3nzmsyy",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.06.29.735215v2",
  "language": null,
  "licence": "CC0-1.0",
  "licence_label": "CC0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/publicdomain/zero/1.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "1303|Amino Acid Enzymes and Metabolism"
    ]
  ],
  "openalex": "W7167275515",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.06.29.735215v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5jrz1j3nzmsyy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:30Z",
      "native_id": "10.64898/2026.06.29.735215",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.06.29.735215v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase",
  "title_text": "N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:30Z",
  "url": "https://research.draconitic.com/paper/5jrz1j3nzmsyy",
  "venue": "bioRxiv",
  "versions": []
}