Fig. 7: Proposed mechanism of altered mitochondrial homeostasis caused by S.
ven metabolite-induced toxicity. This experimental model illustrates our current understanding of the effect of S. ven metabolite on mitochondrial homeostatic mechanisms in the development of neurodegeneration. metabolite-induced ROS gradually impairs mitochondria through mitochondrial complex I damage, energy deprivation, and eventually, the loss of ΔΨm. As ΔΨm is decreased, C. elegans PINK-1 and PDR-1 would be mobilized to the OMM, which would then recruit the OMM fission factor, DRP-1, to the OMM to degrade the damaged organelle, resulting in mitochondrial fragmentation. Moreover, proteolytic cleavage of EAT-3 by the decline in ΔΨm and increased DRP-1 could lead to neuron cell death. In our genetic studies, the reduction of eat-3 (RNAi) attenuated neurotoxicity induced by metabolite or in the pink-1 mutant background, demonstrating that eat-3 depletion (RNAi) might counteract cell death and have a role as an antiapoptotic factor when the cell death pathway is activated by DRP-1. Moreover, we observed a genetic interaction between drp-1 and egl-1, a component of the cell death pathway as well as increased mRNA expression of ced-9 in the presence of metabolite. Another DRP-1-related response observed involves C. elegans AAK-2 (AMPK), which is a candidate signaling molecule and known regulator of mitochondrial biogenesis. The AMPK pathway converges with the gene expression of mitochondrial fission and fusion genes, such as drp-1 and eat-3, representing a prospective mechanism of response to S. ven exposure.
