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This study demonstrates that neurons respond to mitochondrial dysfunction by upregulating glycolysis rather than simply restoring NAD+/NADH balance. Researchers found that different mitochondrial stresses in Drosophila neurons trigger increased expression of glycolytic genes, including lactate dehydrogenase (LDH), and that this metabolic reprogramming is essential for neuronal survival. Artificially raising NAD+/NADH ratios with bacterial NADH oxidase did not rescue neurons and actually worsened dysfunction, indicating that LDH's protective role involves broader metabolic changes beyond redox balance.
Why it matters
These findings challenge the prevailing assumption that restoring NAD+/NADH balance is the primary mechanism for neuroprotection during mitochondrial disease. Understanding that neurons require comprehensive glycolytic compensation could redirect therapeutic strategies for mitochondrial disorders and neurodegenerative diseases away from simple NAD+ supplementation toward supporting broader metabolic flexibility.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Neurons engage compensatory pathways that promote survival when confronted with mitochondrial dysfunction. Indeed, we recently showed that Drosophila neurons upregulate Ldh transcription to help survive the loss of the key mitochondrial fusion gene Opa1. Here, we further characterize this metabolic flexibility and show that it reflects a more general increase in glycolytic activity. A distinct mitochondrial perturbation, TFAM overexpression, similarly induces glycolytic gene expression including Ldh and also elevates lactate levels. LDH is also required to maintain neuronal function under TFAM overexpression. Notably, raising NAD+/NADH ratio by expressing the bacterial NADH oxidase LbNOX does not substitute for LDH function. On the contrary, it further compromises neuronal function in Opa1-deficient and TFAM-overexpressing neurons. Moreover, mitochondria-targeted LbNOX expression alone induces mitochondrial dysfunction and the compensatory glycolytic response. Together, these findings indicate that LDH-mediated rescue does not reflect an increase in NAD+/NADH ratio but is part of a broader neuroprotective metabolic reprogramming which enables neurons to withstand diverse forms of mitochondrial impairment.