Exome sequencing identifies a disease variant of the mitochondrial ATP‐Mg/Pi carrier SLC25A25 in two families with kidney stones

Jabalameli, M. Reza; Fitzpatrick, Fiona; Colombo, Roberto; Howles, Sarah; Leggatt, Gary; Walker, Valerie; Wiberg, Akira; Kunji, Edmund R. S.; Ennis, Sarah

doi:10.1002/mgg3.1749

Cited by 6 publications

(5 citation statements)

References 54 publications

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“…Unsurprisingly, it was found that the mutant protein only had $20% of the wild-type protein's ATP transport activity. 103 Interestingly, just as in dominant ANT1 mutations, the dominant mutations in SLC25A24 and SLC25A25 described here all occur in the transmembrane α-helices. This may point to a particular vulnerability of these protein domains across the mitochondrial carriers.…”

Section: Calcium-dependent Adenine Nucleotide Transporters and Diseasementioning

confidence: 68%

“…The glutamine to histidine substitution in the protein was suggested to perturb a conserved polar interaction leading to structural instability in the mutant protein. Unsurprisingly, it was found that the mutant protein only had ~20% of the wild‐type protein's ATP transport activity 103 …”

Section: Calcium‐dependent Adenine Nucleotide Transporters and Diseasementioning

confidence: 99%

“…More generally, the clustering of clogging-associated adPEO mutations in the transmembrane α-helices of SLC25A4 suggests that the fidelity of these protein domains is essential to prevent clogging. Moreover, pathogenic mutations in SLC25A24 and SLC25A25 are also found in transmembrane α-helices [101][102][103] raising the possibility that protein import clogging contributes to these syndromes as well.…”

Section: Mitochondrial Protein Import Clogging As a Mechanism For Mposmentioning

confidence: 99%

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Adenine nucleotide carrier protein dysfunction in human disease

2023

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Adenine nucleotide translocase (ANT) is the prototypical member of the mitochondrial carrier protein family, primarily involved in ADP/ATP exchange across the inner mitochondrial membrane. Several carrier proteins evolutionarily related to ANT, including SLC25A24 and SLC25A25, are believed to promote the exchange of cytosolic ATP‐Mg2+ with phosphate in the mitochondrial matrix. They allow a net accumulation of adenine nucleotides inside mitochondria, which is essential for mitochondrial biogenesis and cell growth. In the last two decades, mutations in the heart/muscle isoform 1 of ANT (ANT1) and the ATP‐Mg2+ transporters have been found to cause a wide spectrum of human diseases by a recessive or dominant mechanism. Although loss‐of‐function recessive mutations cause a defect in oxidative phosphorylation and an increase in oxidative stress which drives the pathology, it is unclear how the dominant missense mutations in these proteins cause human diseases. In this review, we focus on how yeast was productively used as a model system for the understanding of these dominant diseases. We also describe the relationship between the structure and function of ANT and how this may relate to various pathologies. Particularly, mutations in Aac2, the yeast homolog of ANT, were recently found to clog the mitochondrial protein import pathway. This leads to mitochondrial precursor overaccumulation stress (mPOS), characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. We anticipate that in coming years, yeast will continue to serve as a useful model system for the mechanistic understanding of mitochondrial protein import clogging and related pathologies in humans.

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Section: Calcium-dependent Adenine Nucleotide Transporters and Diseasementioning

confidence: 68%

Section: Calcium‐dependent Adenine Nucleotide Transporters and Diseasementioning

confidence: 99%

Section: Mitochondrial Protein Import Clogging As a Mechanism For Mposmentioning

confidence: 99%

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Adenine nucleotide carrier protein dysfunction in human disease

2023

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“…All five patients had a heterozygous dominant mutation manifested as Gln349His substitution. The human wild-type APC3b isoform found in kidneys and the disease variant were expressed in yeast mitochondria, purified, analysed by thermal stability assays and reconstituted in liposomes to measure transport rates [109]. The transport activity of the Gln349His mutant was severely affected and calcium-regulated ATP transport was reduced to~20% of the wild-type.…”

Section: Human Diseases Associated With Atp-mg/p I Carriermentioning

confidence: 99%

“…The transport activity of the Gln349His mutant was severely affected and calcium-regulated ATP transport was reduced to~20% of the wild-type. It is supposed that APC3b Gln349His mutant may augment urine lithogenicity through impaired supply of ATP for solute transport processes in the kidney, and/or for purinergic signalling [109].…”

Section: Human Diseases Associated With Atp-mg/p I Carriermentioning

confidence: 99%

Learning from Yeast about Mitochondrial Carriers

et al. 2021

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Mitochondria are organelles that play an important role in both energetic and synthetic metabolism of eukaryotic cells. The flow of metabolites between the cytosol and mitochondrial matrix is controlled by a set of highly selective carrier proteins localised in the inner mitochondrial membrane. As defects in the transport of these molecules may affect cell metabolism, mutations in genes encoding for mitochondrial carriers are involved in numerous human diseases. Yeast Saccharomyces cerevisiae is a traditional model organism with unprecedented impact on our understanding of many fundamental processes in eukaryotic cells. As such, the yeast is also exceptionally well suited for investigation of mitochondrial carriers. This article reviews the advantages of using yeast to study mitochondrial carriers with the focus on addressing the involvement of these carriers in human diseases.

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