Chronic mitochondrial fragmentation elicits a neuroprotective Warburg-like effect in Drosophila neurons

Mitochondrial fission and fusion are dynamic and important cellular processes, but the roles of these two very different mitochondrial forms - predominantly spherical and tubular - are not well-characterized in neurons of animals and especially in aging neurons. This is important because neurons are long-lived and mitochondrial dynamics is associated with neurodegenerative diseases. We used here an efficient cell type-specific CRISPR approach to knockout key fission-fusion genes and disrupt mitochondrial dynamics within the inessential clock neurons of Drosophila. Surprisingly, fusion is much more important than fission for maintaining long-term neuronal function. Neurons survive chronic mitochondrial fragmentation due to loss of fusion by triggering a cancer-like transcriptomic response. This Warburg effect includes ATF4-mediated upregulation of the aerobic glycolysis gene Lactate dehydrogenase (Ldh), and LDH is essential to prevent neurodegeneration of neurons deficient in the fusion gene Opa1. These results and others provide insights into the intersection of neuronal metabolism, aging and neurodegeneration.