Microbiota and Diapause-Induced Neuroprotection Share a Dependency on Calcium But Differ in Their Effects on Mitochondrial Morphology

Abstract

The balance between the degeneration and regeneration of damaged neurons depends on intrinsic and environmental variables. In nematodes, neuronal degeneration can be reversed by intestinal GABA and lactate-producing bacteria, or by hibernation driven by food deprivation. However, it is not known whether these neuroprotective interventions share common pathways to drive regenerative outcomes. Using a well-established neuronal degeneration model in the touch circuit of the bacterivore nematodeCaenorhabditis elegans,we investigate the mechanistic commonalities between neuroprotection offered by the gut microbiota and hunger-induced diapause. Using transcriptomics approaches coupled to reverse genetics, we identify genes that are necessary for neuroprotection conferred by the microbiota. Some of these genes establish links between the microbiota and calcium homeostasis, diapause entry, and neuronal function and development. We find that extracellular calcium as well as mitochondrial MCU-1 and reticular SCA-1 calcium transporters are needed for neuroprotection by bacteria and by diapause entry. While the benefits exerted by neuroprotective bacteria requires mitochondrial function, the diet itself does not affect mitochondrial size. In contrast, diapause increases both the number and length of mitochondria. These results suggest that metabolically-induced neuronal protection may occur via multiple mechanisms.Significance statementCalcium signaling and mitochondrial function have recently been suggested to promote axonal growth following neuronal damage, but the underlying mechanisms and physiological significance are unclear. Combining transcriptomics, genetics and cell biological approaches in a simple animal model of axonal degeneration and regeneration, we demonstrate that neuronal repair conferred by two different metabolic processes occurs in diverse ways, requiring differential changes in mitochondrial function and calcium homeostasis. Furthermore, this work shows that neuroprotection can be additive, providing a new conceptual framework for developing therapeutic interventions in neurodegenerative conditions that leverage the intersection of metabolism, microbiota and mitochondrial function.