Tissue-wide metabolic buffering confers resilience to mosaic mitochondrial dysfunction

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 tissue context, remains largely unknown. Using genetic models of mitochondrial mosaicism in Drosophila, we find that neural stem cells (NSCs) in the developing 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 metabolic 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 this proliferation defect depends on a brain-wide glial network connected by gap junctions, which supplies metabolic support to NSCs through LDH-dependent glial NAD+ production and transmembrane transporters, including the glutamate/aspartate transporter Eaat1. These findings demonstrate that vulnerability of an individual cell is determined not only by its mutation load but also by the spare metabolic capacity of the surrounding tissue. Tissue heterogeneity thus provides resilience to metabolic dysfunction, evidencing key benefits of diversity, and suggesting new therapeutic strategies to enhance endogenous metabolic buffering.