{
  "abstract": "Mitochondria and oxidative phosphorylation (OxPhos) are essential for cellular homeostasis. However, the phenotypes caused by mitochondrial dysfunction often display remarkable tissue-specificity. What determines the susceptibility of individual cells to metabolic or mitochondrial defects in a complex in vivo tissue context, remains largely unknown. We find that neural stem cells (NSCs) in the developing Drosophila brain can maintain normal proliferation despite severe cell-autonomous OxPhos-dysfunction, provided that sufficient neighbouring cells remain metabolically intact. This tissue-wide buffering progressively fails as the proportion of NSCs with OxPhos dysfunction increases, indicating that the phenotypic threshold for mitochondrial dysfunction is an emergent property of a tissue rather than only of individual cells or cell-types. Mechanistically, we find that OxPhos-deficient NSCs activate a stress-response associated with ATF4/crc-transcriptional activation. NSCs upregulate lactate dehydrogenase (LDH) expression to maintain glycolysis, but their proliferation remains limited by NAD+ regeneration rather than by ATP production. Non-cell-autonomous rescue of NSC-proliferation depends on LDH-dependent NAD+-production in a brain-wide glial network connected by gap junctions and the glutamate/aspartate-transporter Eaat1. These findings demonstrate that the phenotypic threshold for mitochondrial dysfunction is determined by tissue-wide spare metabolic capacity rather than only of individual cells or cell-types. Tissue heterogeneity thus provides resilience to metabolic dysfunction, evidencing key benefits of diversity, and suggesting new therapeutic strategies to enhance endogenous metabolic buffering.",
  "abstract_shown": true,
  "affiliations": [
    "University of Cambridge"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "S. Petridi"
    },
    {
      "name": "A. Dhawanjewar"
    },
    {
      "name": "D. Dubal"
    },
    {
      "name": "R. Chandrasegaram"
    },
    {
      "name": "H. Dickmänken"
    },
    {
      "name": "N. Bala-Muraly"
    },
    {
      "name": "B. A. Wilson"
    },
    {
      "name": "T. Eve"
    },
    {
      "name": "B. Marzullo"
    },
    {
      "name": "A. Hynes-Allen"
    },
    {
      "name": "S. A. Jones"
    },
    {
      "name": "M. S. King"
    },
    {
      "name": "R. Butler"
    },
    {
      "name": "M. Sciacovelli"
    },
    {
      "name": "E. R. S. Kunji"
    },
    {
      "name": "D. A. Tennant"
    },
    {
      "affs": [
        0
      ],
      "name": "J. van den Ameele"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/9btyyb6ftjvy0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.27.747448",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2.full",
  "id": "9btyyb6ftjvy0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "developmental biology"
    ],
    [
      "openalex",
      "1312|Mitochondrial Function and Pathology"
    ]
  ],
  "openalex": "W7204585742",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/9btyyb6ftjvy0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:31Z",
      "native_id": "10.64898/2026.08.27.747448",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:developmental biology",
      "subfield": "developmental-biology"
    }
  ],
  "title": "Tissue-wide metabolic buffering confers resilience to mitochondrial dysfunction",
  "title_text": "Tissue-wide metabolic buffering confers resilience to mitochondrial dysfunction",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:31Z",
  "url": "https://research.draconitic.com/paper/9btyyb6ftjvy0",
  "venue": "bioRxiv",
  "versions": []
}