Benning Friederike M C, Bell Tristan A, Nguyen Tran H, Syau Della, Connell Louise B, Coughlin Margaret, Nordstrom Anja E H, Ericsson Maria, daCosta Corrie J B, Chao Luke H
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
bioRxiv. 2025 Jan 17:2024.04.26.591372. doi: 10.1101/2024.04.26.591372.
In eukaryotes, cellular respiration takes place in the cristae of mitochondria. The mitochondrial inner membrane protein Mic60, a core component of the mitochondrial contact site and cristae organizing system (MICOS), is crucial for the organization and stabilization of crista junctions and its associated functions. While the C-terminal Mitofilin domain of Mic60 is necessary for cellular respiration, the sequence determinants for this function have remained unclear. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast-lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors, we identified four residues sufficient to explain the respiratory difference between yeast- and animal-derived Mitofilin ancestors. Our results provide a foundation for investigating the conservation of Mic60-mediated cristae junction interactions.
在真核生物中，细胞呼吸发生在线粒体的嵴中。线粒体内膜蛋白Mic60是线粒体接触位点和嵴组织系统（MICOS）的核心组成部分，对于嵴连接的组织和稳定及其相关功能至关重要。虽然Mic60的C末端Mitofilin结构域对于细胞呼吸是必需的，但该功能的序列决定因素仍不清楚。在这里，我们使用祖先序列重建来生成直至并包括最后一个后鞭毛生物共同祖先（LOCA）的Mitofilin祖先。我们发现，早在LOCA的酵母谱系衍生的Mitofilin祖先就能挽救呼吸作用。通过比较Mitofilin祖先，我们确定了四个足以解释酵母和动物衍生的Mitofilin祖先之间呼吸差异的残基。我们的结果为研究Mic60介导的嵴连接相互作用的保守性提供了基础。
