In C. elegans, two mutations that affect mitochondrial electron transport chain subunits (isp-1(qm150) and nuo-6(qm200)) result in increased production of mitochondrial reactive oxygen species (mtROS). Animals carrying these mutations have a significantly increased lifespan relative to the wild type. It has also been shown that treatment with pro-oxidants such as paraquat (PQ) can significantly increase wild type lifespan but is not additive to the lifespan of the two mitochondrial mutants. Furthermore, treatment with antioxidants such as N-acetyl-cysteine (NAC) and Vitamin C can decrease the longevity of these mutants. Using gene arrays, we determined a large overlap of differentially expressed transcripts between isp-1, nuo-6 and paraquat treatment. These and other results suggest that increased levels of mtROS act as a signal to extend lifespan in C. elegans.
We were interested in determining the mechanism by which mtROS signalling is sensed and transduced in order to elicit these changes in gene expression. Many processes have been found to require components of the intrinsic apoptotic pathway to perform tasks that do not result in apoptosis, such as cell cycle regulation, neuronal regeneration and mitochondrial fission/fusion. In mammalian studies, components of the intrinsic apoptotic pathway have also been found to be sensitive to ROS, prompting us to test the involvement of this pathway with respect to mtROS-mediated longevity.
We found that components of the core intrinsic apoptotic pathway (CED-9, CED-4 and CED-3) are required for the longevity of isp-1 and nuo-6 mutants, as well as for lifespan extension induced by paraquat treatment. In addition, loss of the intrinsic pathway reversed a large portion of the gene expression changes observed in isp-1 and nuo-6 mutants. We found that to induce an effect on longevity the pathway is not stimulated by EGL-1 as for apoptosis, but by CED-13, an alternative BH3-only protein. We observed no effect on developmental apoptosis in isp-1 and nuo-6 mutants or by treatment with paraquat. We conclude that activation of the pathway by mtROS signaling does not affect apoptosis, but instead acts as a defense mechanism to protect against consequences of mitochondrial dysfunction by inducing gene expression changes that promotes survival and modulates stress sensitivity.
We are currently using CRISPR/Cas9 to study the molecular mechanisms that allow for a dual role of the pathway: apoptosis and longevity. .
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