Functional analysis of CEP-1/P53 targeted genes in mitochondrial mutant of Caenorhabditis elegans

Mitochondrial originated signaling alters expression of nuclear genes to modify cellular function and metabolism. It was demonstrated using Caenorhabditiselegans as a model that CEP-1, worm homologue of mammalian p53, senses mitochondrial status and adjusts physiological outcomes accordingly. To study how cellular homeostasis is readjusted upon mitochondrial ETC dysfunction physiologically, the mitochondrial mutant isp-1(qm150), with a defective complex-III protein, was used. CEP-1 target genes, fat-2 and acs-2, were studied. In C. elegans, fat-2characterized as having delta-12 fatty acid dehydrogenase activity, is involved in the first step in PUFA production and acs- 2, encoding anacyl-CoA synthetase, catalyzes fatty acid conversion to acyl-CoA for further beta oxidation. RNAi knock down of fat-2 gene shows that it is critical in development, reproduction as well as lifespan of C. elegans, both in wild-type (WT) and isp-1 mutant, whereas, acs-2 affects lifespan without impairing reproduction and development. Considering the important role of mitochondria in fat metabolism, total body fat accumulation was compared in WT with the mutant. Compared to WT, isp-1 mutant showed increased body fat in CEP-1 dependent manner and fat-2 and acs - 2RNAi knockdown in isp-1 mutant affected body fat in contradictory manner. Our study suggests that dysfunctional mitochondria in isp-1 mutant causes CEP-1 dependent transcriptional changes in both fatty acid biosynthesis and oxidation genes that lead to metabolic restructuring to maintain cellular homeostasis.