About a thousand genes in the human genome encode for membrane transporters. Among these, several solute carrier proteins (SLCs), representing the largest group of transporters, are still orphan and lack functional characterization. We reasoned that assessing genetic interactions among SLCs may be an efficient way to obtain functional information allowing their deorphanization. Here we describe a network of strong genetic interactions indicating a contribution to mitochondrial respiration and redox metabolism for SLC25A51/MCART1, an uncharacterized member of the SLC25 family of transporters. Through a combination of metabolomics, genomics and genetics approaches, we demonstrate a role for SLC25A51 as enabler of mitochondrial import of NAD, showcasing the potential of genetic interaction-driven functional gene deorphanization.

人类基因组中大约有一千个基因编码膜转运蛋白。其中，代表最大类转运蛋白的几种溶质载体蛋白（SLC）仍然是孤儿并且缺乏功能表征。我们推断，评估 SLC 之间的遗传相互作用可能是获取功能信息、使其脱孤儿化的有效方法。在这里，我们描述了一个强遗传相互作用网络，表明 SLC25A51/MCART1（SLC25 转运蛋白家族的一个未表征的成员）对线粒体呼吸和氧化还原代谢有贡献。通过结合代谢组学、基因组学和遗传学方法，我们证明了 SLC25A51 作为 NAD 线粒体输入推动者的作用，展示了遗传相互作用驱动的功能基因去孤儿化的潜力。