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

Citrin is a liver-specific mitochondrial aspartate-glutamate carrier encoded by . Citrin deficiency caused by mutation results in carbohydrate toxicity, citrullinemia type II, and fatty liver diseases, the mechanisms of some of which remain unknown. Citrin shows a functional homolog in yeast aspartate-glutamate carrier (Agc1p) and Δ yeasts are used as a model organism of citrin deficiency. Here, we found that Δ yeasts decreased fat utilization, impaired NADH balance in peroxisomes, and decreased chronological lifespan. The activation of -mediated NAD regeneration in peroxisomes by over-expression or activation of the malate-oxaloacetate NADH peroxisomal shuttle, by increasing flux in this NADH shuttle and over-expression of , resulted in lifespan extension of Δ yeasts. In addition, over-expression of restored longevity of Δ yeasts as well as wild-type cells. The effect of -mediated longevity required the presence of the -mediated NADH peroxisomal shuttle, which was independent of the presence of the peroxisomal malate-oxaloacetate NADH shuttle and -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.