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.