Citrin is a liver-specific mitochondrial aspartate–glutamate carrier 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 functional homolog in yeast
            
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            Citrin is a liver-specific mitochondrial aspartate–glutamate carrier 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 functional homolog in yeast aspartate-glutamate carrier (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 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.
            
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