The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.
The mitochondrial carrier SFXN1 is critical for complex III integrity and cellular metabolism.
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DOI：
10.1016/j.celrep.2021.108869
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发表时间：
2021-03-16
期刊：
影响因子：
8.8
通讯作者：
Claypool SM
中科院分区：
文献类型：
--
作者：
Acoba MG;Alpergin ESS;Renuse S;Fernández-Del-Río L;Lu YW;Khalimonchuk O;Clarke CF;Pandey A;Wolfgang MJ;Claypool SM
线粒体载体（MC）介导小分子穿过线粒体内膜（IMM），从而实现区室化反应之间的调节串扰。尽管MC代表了哺乳动物中最大的溶质载体家族，但大多数尚未经过全面的研究，限制了我们对其代谢贡献的了解。在这里，我们的功能特点SFXN 1，一个成员的非规范，sideroflexin家庭。我们发现，SFXN 1，一个完整的IMM蛋白与一个奇数的跨膜结构域，是一个TIM 22复杂的底物。SFXN 1缺乏导致线粒体呼吸链损伤，对复合物III（CIII）生物合成、活性和组装最有害，损害辅酶Q水平。CIII功能障碍独立于一碳代谢，这是SFXN 1作为线粒体丝氨酸转运蛋白的已知主要作用。相反，SFXN 1通过参与血红素和α-酮戊二酸代谢来支持CIII功能。我们的研究结果强调了基于SFXN 1的氨基酸转运影响线粒体和细胞代谢效率的多种方式。Acoba等人表明，氨基酸转运蛋白SFXN 1是TIM 22转位子的货物，其对于维持复合物III功能很重要，并支持辅酶Q、血红素和α-酮戊二酸代谢。
Mitochondrial carriers (MCs) mediate the passage of small molecules across the inner mitochondrial membrane (IMM), enabling regulated crosstalk between compartmentalized reactions. Despite MCs representing the largest family of solute carriers in mammals, most have not been subjected to a comprehensive investigation, limiting our understanding of their metabolic contributions. Here, we functionally characterize SFXN1, a member of the non-canonical, sideroflexin family. We find that SFXN1, an integral IMM protein with an uneven number of transmembrane domains, is a TIM22 complex substrate. SFXN1 deficiency leads to mitochondrial respiratory chain impairments, most detrimental to complex III (CIII) biogenesis, activity, and assembly, compromising coenzyme Q levels. The CIII dysfunction is independent of one-carbon metabolism, the known primary role for SFXN1 as a mitochondrial serine transporter. Instead, SFXN1 supports CIII function by participating in heme and α-ketoglutarate metabolism. Our findings highlight the multiple ways that SFXN1-based amino acid transport impacts mitochondrial and cellular metabolic efficiency. Acoba et al. show that the amino acid transporter SFXN1 is a cargo of the TIM22 translocon that is important for maintaining complex III function and supports coenzyme Q, heme, and α-ketoglutarate metabolism.
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