The Caenorhabditis elegans mitochondrial mutants (Mit) live longer and are more robust and active then wild-type animals or animals with severely affected mitochondrial respiratory chain (MRC) functionality. These observations suggest that mild suppression of MRC proteins extends longevity not simply by reducing animal metabolic rate but rather by an active induction of compensatory, protective pathways. Utilizing different biochemical and genetic approaches, our work is exploiting C. elegans to uncover stress response pathways required in the Mit mutants to optimize mitochondrial functions, protect from cellular damage accumulation and ultimately live longer. Our recent findings show that the C. elegans ortholog of the human tumor suppressor
p53,
cep-1, uniquely modulates lifespan and stress response of different Mit mutants, including
isp-1 and
frh-1. Frh-1 is a nuclear encoded mitochondrial protein involved in Fe-S cluster proteins biogenesis. Isp-1 encodes the Rieske-iron-sulfur subunit of complex III of the MRC and the
qm150 allele contains a missense point mutation that reduces protein function.
isp-1(
qm150) is one of the only available mitochondrial genetic mutant and similar to mild suppression of
isp-1 and of other mitochondrial proteins by RNAi knock-down, is slow growing and lives longer thus being a good representative for this class of longevity mutants. We crossed the
isp-1(
qm150) mutant with a GFP reporter strain where the GFP was cloned under the promoter of the antioxidant gene
gst-4 and observed that, similar to
frh-1 RNAi, the
gst-4 is induced in response to
isp-1 suppression and its induction is regulated by
cep-1/p53. Maintenance of genome integrity and fidelity is essential for the proper function and survival of all organisms. We therefore utilized the
isp-1(
qm150);Pgst4::GFP strain to screen a library of 300 RNAi clones, derived from the Arhinger whole genome RNAi library, against DNA repair and replication, chromatin organization and remodeling, cell cycle and checkpoint control genes. We identified few genes (e.g.
ung-1,
xpf-1,
brd-1) specifically affecting viability, development, fertility and
gst-4 induction of the
isp-1 mutant relative to wild type worms. We are currently assessing their ability to modulate Mit mutants longevity.