Mitochondria-mediated Hormetic Response in fission yeast Theventhiran Mahandaran1 and Fuyuki Ishikawa1 1Laboratory of Cell Cycle Regulation, Graduate School of Biostudies, Kyoto University
Hormesis is a biological response whereby a low dose stress induces beneficial effects but a higher dose is detrimental. Mitohormesis is a specific form of hormesis where mild mitochondrial stress benefits an organism. In Saccharomyces cerevisiae, it is known that mitohormesis leads to increased lifespan and stress resistance. Here, we explored mitohormetic responses in the fission yeast Schizosaccharomyces pombe (S. pombe). Although it has been shown that mutations or deletions of nuclear genes encoding mitochondrial proteins induce hormetic responses, it is not known if direct mitochondrial DNA (mtDNA) damage leads to similar responses. We, therefore, set out to investigate if mtDNA damage induces hormetic responses in fission yeast by several criteria. An S. pombe strain that inducibly expresses MTS-EcoRI (EcoRI conjugated to a mitochondrial targeting sequence) and a vector integrant control strain were constructed. We found that MTS-EcoRI expression reduced mtDNA copy number. MTS-EcoRI-induced cells also showed a longer chronological lifespan compared to the control cells without MTS-EcoRI expression. Under caloric restriction (CR) however, both control and MTS-EcoRI cells showed extended lifespans. Moreover, the lifespan extension due to CR and mtDNA damage was not additive. mRNA quantification using qRT-PCR hints at Sty1 Mitogen-activated Protein Kinase (MAPK) pathway's involvement in mitochondria-mediated lifespan extension. Furthermore, MTS-EcoRI cells displayed heat stress tolerance after exposure to lethal heat stress. Both control and MTS-EcoRI cells had comparable intracellular superoxide levels in stationary phase, excluding the possibility that superoxide production is responsible for the phenotypes in MTS-EcoRI cells. Taken together, mtDNA damage increases lifespan and heat stress tolerance in S. pombe. Similar lifespan extension in CR, mtDNA damage, along with the qPCR result suggests the possibility of pathway overlap between CR and mtDNA damage. Future study will uncover the exact signal(s) involved in mito-nuclear communication and pathways that lead to hormetic responses upon mtDNA damage.