Slc25a4, also known as the adenine nucleotide translocase 1 (ANT1), is a key mitochondrial carrier protein. It imports ADP into the mitochondrial matrix and exports ATP, which are crucial steps in oxidative phosphorylation [3]. It is also involved in maintaining a balanced mitochondrial nucleotide pool and is associated with mitochondrial DNA (mtDNA) maintenance pathways [2].

Mutations in Slc25a4 can lead to a broad phenotypic spectrum. Patients may present with encephalo-myo-cardiomyopathy, along with additional symptoms such as scoliosis, cataract, depression, headache, hydrocephalus, or arterial hypertension. These mutations can result in mtDNA depletion or multiple mtDNA deletions, with mtDNA depletion presenting a more severe phenotype, including respiratory insufficiency and more widespread cerebral disease [1]. In two reported patients with autosomal recessive Slc25a4 gene mutations, they showed exercise intolerance, hyperlactatemia, and hypertrophic cardiomyopathy [6]. A study on myocardial infarction (MI) found that Slc25a4 was identified as a biomarker of a cardiomyocyte subcluster associated with mitochondrial malfunction and apoptosis, and its down-regulation improved mitochondrial function and reduced cell apoptosis [4]. In osteosarcoma, SLC25A4 expression was significantly reduced, and overexpressing it in OS cells suppressed proliferation, migration, invasion, and enhanced apoptosis [5].

In summary, Slc25a4 is essential for mitochondrial energy metabolism and mtDNA maintenance. Findings from studies on patients with Slc25a4 mutations and in disease models like MI and osteosarcoma show its significance in various disease conditions, highlighting its potential as a therapeutic target. [1,4,5,6]

References:

1. Finsterer, Josef, Zarrouk-Mahjoub, Sinda. 2018. Phenotypic spectrum of SLC25A4 mutations. In Biomedical reports, 9, 119-122. doi:10.3892/br.2018.1115. https://pubmed.ncbi.nlm.nih.gov/30013777/

2. El-Hattab, Ayman W, Craigen, William J, Scaglia, Fernando. 2017. Mitochondrial DNA maintenance defects. In Biochimica et biophysica acta. Molecular basis of disease, 1863, 1539-1555. doi:10.1016/j.bbadis.2017.02.017. https://pubmed.ncbi.nlm.nih.gov/28215579/

3. Cimadamore-Werthein, Camila, Jaiquel Baron, Stephany, King, Martin S, Springett, Roger, Kunji, Edmund Rs. 2023. Human mitochondrial ADP/ATP carrier SLC25A4 operates with a ping-pong kinetic mechanism. In EMBO reports, 24, e57127. doi:10.15252/embr.202357127. https://pubmed.ncbi.nlm.nih.gov/37278158/

4. Zhou, Ting, Pan, Jing, Xu, Kai, Song, Haixu, Han, Yaling. 2024. Single-cell transcriptomics in MI identify Slc25a4 as a new modulator of mitochondrial malfunction and apoptosis-associated cardiomyocyte subcluster. In Scientific reports, 14, 9274. doi:10.1038/s41598-024-59975-8. https://pubmed.ncbi.nlm.nih.gov/38654053/

5. Zhang, Ying, Wang, Yinghui, Zhang, Wenyan, Li, Ka, Zhang, Aijun. 2024. Comprehensive transcriptomic analysis identifies SLC25A4 as a key predictor of prognosis in osteosarcoma. In Frontiers in genetics, 15, 1410145. doi:10.3389/fgene.2024.1410145. https://pubmed.ncbi.nlm.nih.gov/38957810/

6. Tosserams, Anouk, Papadopoulos, Constantinos, Jardel, Claude, Hogrel, Jean-Yves, Laforêt, Pascal. 2017. Two new cases of mitochondrial myopathy with exercise intolerance, hyperlactatemia and cardiomyopathy, caused by recessive SLC25A4 mutations. In Mitochondrion, 39, 26-29. doi:10.1016/j.mito.2017.08.009. https://pubmed.ncbi.nlm.nih.gov/28823815/