Slc25a10-KO Mouse

Slc25a10, also known as the dicarboxylate carrier (DIC), is a member of the mitochondrial carrier family. It is located in the mitochondrial inner membrane and is involved in transporting malate and succinate out of the mitochondria in exchange for phosphate and sulfate [9]. It may also participate in glutathione transport to mitochondria, which is crucial for redox-homeostasis and mitochondrial function [2,3,10]. The gene is associated with pathways related to cell metabolism, apoptosis, and ferroptosis, and is of great biological importance in maintaining normal cellular functions.

In human osteosarcoma, high expression of Slc25a10 is associated with poor clinicopathological parameters. Knockdown of Slc25a10 significantly suppresses cell proliferation, increases apoptosis, and decreases mitosis, suggesting an oncogenic role, potentially mediated by CCNE1, P21, and P27 [1]. In H9c2 cardioblasts, inhibition of Slc25a10 aggravates ferroptosis, increases mitochondrial ROS, membrane depolarization, and GSH depletion, indicating its role in preventing ferroptosis [2]. In a child with severe epileptic encephalopathy and respiratory complex I deficiency, biallelic mutations in Slc25a10 led to reduction in RNA quantity, aberrant splicing, absence of the protein and its transporting function, demonstrating its importance in preventing this mitochondrial neurodegenerative disorder [3]. In ischemia/reperfusion rats and hypoxia-reoxygenation cardiomyocytes, suppressing Slc25a10 expression reverses the protective effects of mild therapeutic hypothermia on myocardial injury, suggesting its role in mitochondrial apoptosis during myocardial ischemia/reperfusion injury [4]. In colorectal cancer, overexpression of Slc25a10 can reverse the antitumor effects of PYCR1 silencing, indicating its role in promoting tumor growth and desensitizing cells to 5-fluorouracil [5]. In A549 cells, knockdown of Slc25a10 changes the growth properties to a less malignant phenotype, increases glutamine dependency, and sensitivity to oxidative stress, showing its role in regulating cancer cell growth [6]. In Hepa1-6 cells, knockout of Slc25a10 using CRISPR/Cas9 leads to disordered glucose homeostasis, increased oxidative stress, and damaged electron transport chains, revealing its role in cell metabolism regulation by the circadian protein CLOCK [7]. In cancer cells, genetic or pharmacological inhibition of Slc25a10 increases the cytotoxic effects of ionizing radiation, overcoming chronic-cycling hypoxia-induced radioresistance [8]. In lung cancer cells, metformin treatment downregulates Slc25a10 expression, affecting the supply of nutrients and the metabolic state of cancer cells [9]. In myocardial ferroptosis, absence of MPV17 leads to ubiquitination-dependent degradation of Slc25a10, impairing mitochondrial glutathione import, while overexpression of MPV17 can reduce ferroptosis by maintaining Slc25a10-mediated mitochondrial glutathione import [10].

In conclusion, Slc25a10 plays essential roles in multiple biological processes such as cell metabolism, apoptosis, and ferroptosis. Model-based research, including gene knockdown and knockout studies, has revealed its significance in various disease conditions, such as osteosarcoma, cardiomyocyte ferroptosis, intractable epileptic encephalopathy, myocardial ischemia/reperfusion injury, colorectal cancer, and cancer radioresistance. Understanding the function of Slc25a10 through these models provides insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Wang, Gaoyuan, Xia, Jianjun, Chen, Cheng, Chen, Xiaoyu, Xu, Bin. 2020. SLC25A10 performs an oncogenic role in human osteosarcoma. In Oncology letters, 20, 2. doi:10.3892/ol.2020.11863. https://pubmed.ncbi.nlm.nih.gov/32774476/

2. Jang, Sehwan, Chapa-Dubocq, Xavier R, Tyurina, Yulia Y, Kagan, Valerian E, Javadov, Sabzali. 2021. Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes. In Redox biology, 45, 102021. doi:10.1016/j.redox.2021.102021. https://pubmed.ncbi.nlm.nih.gov/34102574/

3. Punzi, Giuseppe, Porcelli, Vito, Ruggiu, Matteo, Palmieri, Ferdinando, De Grassi, Anna. . SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. In Human molecular genetics, 27, 499-504. doi:10.1093/hmg/ddx419. https://pubmed.ncbi.nlm.nih.gov/29211846/

4. Ma, Senlin, Song, Yun, Xu, Yanxin, Wang, Bin, Chen, Mingquan. 2024. Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis. In Journal of cardiovascular translational research, 17, 946-958. doi:10.1007/s12265-024-10503-z. https://pubmed.ncbi.nlm.nih.gov/38568407/

5. Zhou, Borong, Mai, Zhongchao, Ye, Ying, Xia, Wei, Qiu, Xiaofeng. 2022. The role of PYCR1 in inhibiting 5-fluorouracil-induced ferroptosis and apoptosis through SLC25A10 in colorectal cancer. In Human cell, 35, 1900-1911. doi:10.1007/s13577-022-00775-5. https://pubmed.ncbi.nlm.nih.gov/36104652/

6. Zhou, Xiaoshan, Paredes, João A, Krishnan, Shuba, Curbo, Sophie, Karlsson, Anna. . The mitochondrial carrier SLC25A10 regulates cancer cell growth. In Oncotarget, 6, 9271-83. doi:. https://pubmed.ncbi.nlm.nih.gov/25797253/

7. Cai, Tingting, Hua, Bingxuan, Luo, Dawei, Hua, Luchun, Lu, Chao. 2019. The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10. In Biochimica et biophysica acta. Molecular cell research, 1866, 1310-1321. doi:10.1016/j.bbamcr.2019.03.016. https://pubmed.ncbi.nlm.nih.gov/30943427/

8. Hlouschek, Julian, Ritter, Violetta, Wirsdörfer, Florian, Jendrossek, Verena, Matschke, Johann. 2018. Targeting SLC25A10 alleviates improved antioxidant capacity and associated radioresistance of cancer cells induced by chronic-cycling hypoxia. In Cancer letters, 439, 24-38. doi:10.1016/j.canlet.2018.09.002. https://pubmed.ncbi.nlm.nih.gov/30205167/

9. Zhao, Qian, Zhou, Xiaoshan, Curbo, Sophie, Karlsson, Anna. 2018. Metformin downregulates the mitochondrial carrier SLC25A10 in a glucose dependent manner. In Biochemical pharmacology, 156, 444-450. doi:10.1016/j.bcp.2018.09.015. https://pubmed.ncbi.nlm.nih.gov/30222970/

10. Xu, Tao, Chen, Guilan. 2024. MPV17 Prevents Myocardial Ferroptosis and Ischemic Cardiac Injury through Maintaining SLC25A10-Mediated Mitochondrial Glutathione Import. In International journal of molecular sciences, 25, . doi:10.3390/ijms251910832. https://pubmed.ncbi.nlm.nih.gov/39409161/