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SLP2和MIC13协同调节MICOS组装和嵴连接形成。

SLP2 and MIC13 synergistically coordinate MICOS assembly and crista junction formation.

作者信息

Naha Ritam, Strohm Rebecca, Schaumkessel Yulia, Urbach Jennifer, Wittig Ilka, Reichert Andreas S, Kondadi Arun Kumar, Anand Ruchika

机构信息

Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225 Duesseldorf, Germany.

Functional Proteomics, Institute for Cardiovascular Physiology, Faculty of Medicine, Goethe-University, 60590 Frankfurt am Main, Germany.

出版信息

iScience. 2024 Nov 23;27(12):111467. doi: 10.1016/j.isci.2024.111467. eCollection 2024 Dec 20.

DOI:10.1016/j.isci.2024.111467
PMID:39720525
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11667180/
Abstract

The MICOS complex, essential for cristae organization, comprises MIC10 and MIC60 subcomplexes, with MIC13 as a crucial subunit. mutations cause severe mitochondrial hepato-encephalopathy, cristae defects, and MIC10-subcomplex loss. We demonstrate that depletion of the mitochondrial protease YME1L in KO stabilizes MIC10-subcomplex, restoring MIC60-MIC10 interaction and crista junction (CJ) defects, indicating MIC13 is crucial for MIC10-subcomplex stabilization rather than MIC60-MIC10 bridging. We identified stomatin-like protein 2 (SLP2) as a key MIC13 interaction partner, essential for cristae morphology and CJ formation. SLP2 serves as an interaction hub for MICOS subunits and stabilizes MIC26 by protecting it from YME1L-mediated degradation. Deleting both and impairs MIC60-subcomplex assembly and its nanoscale organization. Restoring the MIC10-subcomplex in double KO cells through YME1L depletion reinstates MIC60-subcomplex assembly and cristae morphology. Overall, we propose SLP2 and the MIC10-subcomplex act as a proteolytically controlled 'seeder' complex, facilitating MICOS-MIB complex assembly and maintaining mitochondrial integrity.

摘要

线粒体内嵴组织所必需的MICOS复合物由MIC10和MIC60亚复合物组成，其中MIC13是关键亚基。突变会导致严重的线粒体性肝脑病变、嵴缺陷以及MIC10亚复合物缺失。我们证明，在敲除细胞中耗尽线粒体蛋白酶YME1L可稳定MIC10亚复合物，恢复MIC60与MIC10的相互作用以及嵴连接（CJ）缺陷，这表明MIC13对MIC10亚复合物的稳定至关重要，而非用于MIC60与MIC10的桥接。我们确定了类stomatin蛋白2（SLP2）是MIC13的关键相互作用伙伴，对嵴形态和CJ形成至关重要。SLP2作为MICOS亚基的相互作用枢纽，通过保护MIC26免受YME1L介导的降解来稳定MIC26。同时删除两者会损害MIC60亚复合物的组装及其纳米级组织。通过耗尽YME1L在双敲除细胞中恢复MIC10亚复合物可恢复MIC60亚复合物的组装和嵴形态。总体而言，我们提出SLP2和MIC10亚复合物作为受蛋白水解控制的“种子”复合物，促进MICOS - MIB复合物的组装并维持线粒体完整性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/4acd1c0d1f52/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/2dfd314a9957/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/419d99f9d35f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/f93c3c0666d0/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/d57f5b0f968a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/ab46f51e7075/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/38d620f701e6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/7163ca40e154/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/4acd1c0d1f52/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/2dfd314a9957/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/419d99f9d35f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/f93c3c0666d0/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/d57f5b0f968a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/ab46f51e7075/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/38d620f701e6/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/7163ca40e154/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22f2/11667180/4acd1c0d1f52/gr7.jpg

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A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes.一种 X 连锁的无意义 APOO/MIC26 变异导致具有早老症样表型的致死性线粒体疾病。
Clin Genet. 2023 Dec;104(6):659-668. doi: 10.1111/cge.14420. Epub 2023 Aug 30.
3
Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
多面线粒体：将线粒体科学从功能和功能障碍的局限中解放出来。
Nat Metab. 2023 Apr;5(4):546-562. doi: 10.1038/s42255-023-00783-1. Epub 2023 Apr 26.
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Structural insights into crista junction formation by the Mic60-Mic19 complex.Mic60-Mic19复合物形成嵴连接的结构见解。
Sci Adv. 2022 Sep 2;8(35):eabo4946. doi: 10.1126/sciadv.abo4946. Epub 2022 Aug 31.
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Mitochondrial developmental encephalopathy with bilateral optic neuropathy related to homozygous variants in IMMT gene.线粒体发育性脑病伴双侧视神经病变与 IMMT 基因纯合变异相关。
Clin Genet. 2022 Feb;101(2):233-241. doi: 10.1111/cge.14093. Epub 2021 Dec 5.
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Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes.MIC13 保守的 GxxxG 和 WN 基序对于桥接两个 MICOS 亚基复合物是必需的。
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