<i>Slc25a36</i> modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level

Xin, Yanli; Wang, Yanliang; Liu, Zhong; Shi, Bingbo; Liu, Hui; Han, Jianyong

doi:10.1042/bcj20190057

Cited by 14 publications

(20 citation statements)

References 92 publications

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“…Physiologically, SLC25A36 has the major activity [ 3 ]. Consistent with our patient’s chronical obstipation and general developmental delay, Xin et al [ 11 ] described a high expression of SLC25A36 in the large intestine and the brain. SLC25A36 is supposedly not expressed in the liver [ 11 ], but nevertheless, our patient presented with hyperammonemia.…”

Section: Discussionsupporting

confidence: 90%

“…Due to the impaired glutathione pathway in mESC [ 11 ], administering 500 mg of vitamin C per day was started to prevent oxidative stress. It was tolerated by the patient without any side effects.…”

Section: Resultsmentioning

confidence: 99%

“…They share a homologous sequence with 61% amino acid identity [ 10 ]. Especially, SLC25A36 plays an important role in maintaining mitochondrial biogenesis [ 11 ]. Human diseases related to SLC25A36 are not yet known.…”

Section: Introductionmentioning

confidence: 99%

“…Human diseases related to SLC25A36 are not yet known. SLC25A36 depletions in mouse embryonic stem cells (mESC) have been associated with mtDNA depletion as well as mitochondrial dysfunction [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Uridine Treatment of the First Known Case of SLC25A36 Deficiency

Jasper

Scarcia

Rust

et al. 2021

IJMS

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SLC25A36 is a pyrimidine nucleotide carrier playing an important role in maintaining mitochondrial biogenesis. Deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction. In human beings, diseases triggered by SLC25A36 mutations have not been described yet. We report the first known case of SLC25A36 deficiency in a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. Whole exome analysis identified the homozygous mutation c.803dupT, p.Ser269llefs*35 in the SLC25A36 gene. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with oral uridine led to an improvement of thyroid function and obstipation, increase of growth and developmental progress. Our findings suggest an important role of SLC25A36 in hormonal regulations and oral uridine as a safe and effective treatment.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Uridine Treatment of the First Known Case of SLC25A36 Deficiency

Jasper

Scarcia

Rust

et al. 2021

IJMS

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“…Interestingly, SLC25A36 appeared to be overexpressed in some cases of cervical cancers [ 64 ]. SLC25A36 was also highly expressed in naive mouse embryonic stem cells (mESCs), in which its suppression was proved to impair glutathione metabolism, to deplete mtDNA content and to affect mitochondrial morphology, leading to mitochondrial dysfunction and promoting mESC differentiation [ 217 ]. In Saccharomyces cerevisiae , the Rim2 gene encodes a mitochondrial pyrimidine nucleotide antiporter known as Rim2p, able to exchange pyrimidine deoxynucleoside tri- and di-phosphates and, to a lesser extent, pyrimidine deoxynucleoside monophosphates; its deletion was found to cause mtDNA depletion, as well as yeast cells’ inability to grow on non-fermentable carbon sources [ 209 ].…”

Section: Drosophila Melanogaster Vs Human Mitomentioning

confidence: 99%

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Curcio

Lunetti

Zara

et al. 2020

IJMS

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Mitochondrial carriers are a family of structurally related proteins responsible for the exchange of metabolites, cofactors and nucleotides between the cytoplasm and mitochondrial matrix. The in silico analysis of the Drosophila melanogaster genome has highlighted the presence of 48 genes encoding putative mitochondrial carriers, but only 20 have been functionally characterized. Despite most Drosophila mitochondrial carrier genes having human homologs and sharing with them 50% or higher sequence identity, D. melanogaster genes display peculiar differences from their human counterparts: (1) in the fruit fly, many genes encode more transcript isoforms or are duplicated, resulting in the presence of numerous subfamilies in the genome; (2) the expression of the energy-producing genes in D. melanogaster is coordinated from a motif known as Nuclear Respiratory Gene (NRG), a palindromic 8-bp sequence; (3) fruit-fly duplicated genes encoding mitochondrial carriers show a testis-biased expression pattern, probably in order to keep a duplicate copy in the genome. Here, we review the main features, biological activities and role in the metabolism of the D. melanogaster mitochondrial carriers characterized to date, highlighting similarities and differences with their human counterparts. Such knowledge is very important for obtaining an integrated view of mitochondrial function in D. melanogaster metabolism.

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Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation

Safran

Proskorovski‐Ohayon

Eskin‐Schwartz

et al. 2023

J of Inher Metab Disea

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Hyperinsulinism/hyperammonemia (HI/HA) syndrome has been known to be caused by dominant gain‐of‐function mutations in GLUD1, encoding the mitochondrial enzyme glutamate dehydrogenase. Pathogenic GLUD1 mutations enhance enzymatic activity by reducing its sensitivity to allosteric inhibition by GTP. Two recent independent studies showed that a similar HI/HA phenotype can be caused by biallelic mutations in SLC25A36, encoding pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane: one study reported a single case caused by a homozygous truncating mutation in SLC25A36 resulting in lack of expression of SLC25A36 in patients' fibroblasts. A second study described two siblings with a splice site mutation in SLC25A36, causing reduction of mitochondrial GTP content, putatively leading to hyperactivation of glutamate dehydrogenase. In an independent study, through combined linkage analysis and exome sequencing, we demonstrate in four individuals of two Bedouin Israeli related families the same disease‐causing SLC25A36 (NM_018155.3) c.284 + 3A > T homozygous splice‐site mutation found in the two siblings. We demonstrate that the mutation, while causing skipping of exon 3, does not abrogate expression of mRNA and protein of the mutant SLC25A36 in patients' blood and fibroblasts. Affected individuals had hyperinsulinism, hyperammonemia, borderline low birth weight, tonic–clonic seizures commencing around 6 months of age, yet normal intellect and no significant other morbidities. Chronic constipation, hypothyroidism, and developmental delay previously described in a single patient were not found. We thus verify that biallelic SLC25A36 mutations indeed cause HI/HA syndrome and clearly delineate the disease phenotype.

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Slc25a36 modulates pluripotency of mouse embryonic stem cells by regulating mitochondrial function and glutathione level

Cited by 14 publications

References 92 publications

Uridine Treatment of the First Known Case of SLC25A36 Deficiency

Uridine Treatment of the First Known Case of SLC25A36 Deficiency

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation

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