SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.
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DOI：
10.15252/emmm.201506159
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发表时间：
2016-09
影响因子：
11.1
通讯作者：
Shoubridge EA
中科院分区：
文献类型：
--
作者：
Janer A;Prudent J;Paupe V;Fahiminiya S;Majewski J;Sgarioto N;Des Rosiers C;Forest A;Lin ZY;Gingras AC;Mitchell G;McBride HM;Shoubridge EA
线粒体形成一个动态网络，通过改变融合和裂变之间的平衡来响应生理信号和代谢应激。线粒体融合是由保守的 GTPases MFN1/2 和 OPA1 精心策划的，该过程在酵母中由线粒体代谢物载体家族蛋白 Ugo1 协调。我们在患有 Leigh 综合征的受试者中发现了 SLC25A46（Ugo1 的哺乳动物直系同源物）的纯合错义突变。 SLC25A46 是一种完整的外膜蛋白，与 MFN2、OPA1 以及线粒体接触位点和嵴组织系统 (MICOS) 复合体相互作用。该突变使蛋白质不稳定，导致线粒体过度融合、内质网 (ER) 形态改变、细胞呼吸受损和细胞过早衰老。成纤维细胞中的 MICOS 复合体被破坏，导致线粒体结构显着异常，嵴明显缩短。 SLC25A46 还与 ER 膜蛋白复合物 EMC 相互作用，并且受试者线粒体中的磷脂组成发生改变。这些结果表明，SLC25A46 在促进脂质转移的线粒体/ER 途径中发挥作用，并将改变的线粒体动力学与早发性神经退行性疾病和细胞命运决定联系起来。
Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early‐onset neurodegenerative disease and cell fate decisions.
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影响因子：
21.3
作者：
通讯作者：
--
影响因子：
30.8
作者：
Abrams AJ;Hufnagel RB;Rebelo A;Zanna C;Patel N;Gonzalez MA;Campeanu IJ;Griffin LB;Groenewald S;Strickland AV;Tao F;Speziani F;Abreu L;Schüle R;Caporali L;La Morgia C;Maresca A;Liguori R;Lodi R;Ahmed ZM;Sund KL;Wang X;Krueger LA;Peng Y;Prada CE;Prows CA;Schorry EK;Antonellis A;Zimmerman HH;Abdul-Rahman OA;Yang Y;Downes SM;Prince J;Fontanesi F;Barrientos A;Németh AH;Carelli V;Huang T;Zuchner S;Dallman JE
通讯作者：
Dallman JE
影响因子：
29
作者：
Civiletto G;Varanita T;Cerutti R;Gorletta T;Barbaro S;Marchet S;Lamperti C;Viscomi C;Scorrano L;Zeviani M
通讯作者：
Zeviani M
影响因子：
4.5
作者：
Coonrod, Emily M.;Karren, Mary Anne;Shaw, Janet M.
通讯作者：
Shaw, Janet M.
影响因子：
4
作者：
Anton, Fabian;Fres, Julia M.;Escobar-Henriques, Mafalda
通讯作者：
Escobar-Henriques, Mafalda