Tissue-wide metabolic buffering confers resilience to mosaic 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.