Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency

Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency

Blog Article

Citrin is a liver-specific mitochondrial aspartate−glutamate copyright encoded by SLC25A13.Citrin deficiency caused by SLC25A13 mutation results in carbohydrate toxicity, citrullinemia type II, and fatty liver diseases, the mechanisms of some of which remain unknown.Citrin shows a Pendant Light functional homolog in yeast aspartate-glutamate copyright (Agc1p) and agc1Δ yeasts are used as a model organism of citrin deficiency.Here, we found that agc1Δ yeasts decreased fat utilization, impaired NADH balance in peroxisomes, and decreased chronological lifespan.The activation of GPD1-mediated NAD+ regeneration in peroxisomes by GPD1 over-expression or activation of the malate−oxaloacetate NADH peroxisomal shuttle, by increasing flux in this NADH shuttle and over-expression of MDH3, resulted in lifespan extension of agc1Δ yeasts.

In addition, over-expression of PEX34 restored longevity of agc1Δ yeasts as well as wild-type cells.The effect of PEX34-mediated longevity required the presence of the GPD1-mediated NADH peroxisomal shuttle, which was independent of the presence of Ornament the peroxisomal malate−oxaloacetate NADH shuttle and PEX34-induced peroxisome proliferation.These data confirm that impaired NAD+ regeneration in peroxisomes is a key defect in the yeast model of citrin deficiency, and enhancing peroxisome function or inducing NAD+ regeneration in peroxisomes is suggested for further study in patients’ hepatocytes.