Tissue-wide metabolic buffering confers resilience to mitochondrial dysfunction

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.

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BibTeX RIS

BibTeX

@misc{petridi2026tissuewide,
  title = {{Tissue-wide metabolic buffering confers resilience to mitochondrial dysfunction}},
  author = {S. Petridi and A. Dhawanjewar and D. Dubal and R. Chandrasegaram and H. Dickmänken and N. Bala-Muraly and B. A. Wilson and T. Eve and B. Marzullo and A. Hynes-Allen and S. A. Jones and M. S. King and R. Butler and M. Sciacovelli and E. R. S. Kunji and D. A. Tennant and J. van den Ameele},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.27.747448},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Tissue-wide metabolic buffering confers resilience to mitochondrial dysfunction
AU  - S. Petridi
AU  - A. Dhawanjewar
AU  - D. Dubal
AU  - R. Chandrasegaram
AU  - H. Dickmänken
AU  - N. Bala-Muraly
AU  - B. A. Wilson
AU  - T. Eve
AU  - B. Marzullo
AU  - A. Hynes-Allen
AU  - S. A. Jones
AU  - M. S. King
AU  - R. Butler
AU  - M. Sciacovelli
AU  - E. R. S. Kunji
AU  - D. A. Tennant
AU  - J. van den Ameele
PY  - 2026
DA  - 2026/08/27
PB  - bioRxiv
DO  - 10.64898/2026.08.27.747448
UR  - https://www.biorxiv.org/content/10.64898/2026.08.27.747448v2
AB  - 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.
ER  -

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