Next Article in Journal
Acknowledgement to Reviewers of Diseases in 2019
Previous Article in Journal
“I Actually Don’t Know What HIV Is”: A Mixed Methods Analysis of College Students’ HIV Literacy
Open AccessArticle

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

1
Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
2
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
3
Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
*
Author to whom correspondence should be addressed.
Diseases 2020, 8(1), 2; https://doi.org/10.3390/diseases8010002
Received: 25 November 2019 / Revised: 23 December 2019 / Accepted: 7 January 2020 / Published: 9 January 2020
(This article belongs to the Section Rare Syndrome)
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. View Full-Text
Keywords: citrin deficiency; mitochondrial aspartate–glutamate carrier; peroxisomes; NAD+ regeneration; Saccharomyces cerevisiae citrin deficiency; mitochondrial aspartate–glutamate carrier; peroxisomes; NAD+ regeneration; Saccharomyces cerevisiae
Show Figures

Figure 1

MDPI and ACS Style

Chalermwat, C.; Thosapornvichai, T.; Jensen, L.T.; Wattanasirichaigoon, D. Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency. Diseases 2020, 8, 2.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop