The BBSome regulates mitochondria dynamics and function.
The BBSome regulates mitochondria dynamics and function.
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BBSOME调节线粒体动力学和功能。
DOI：
10.1016/j.molmet.2022.101654
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发表时间：
2023-01
影响因子：
8.1
通讯作者：
Rahmouni, Kamal
中科院分区：
文献类型：
--
作者：
Guo, Deng-Fu;Merrill, Ronald A.;Qian, Lan;Hsu, Ying;Zhang, Qihong;Lin, Zhihong;Thedens, Daniel R.;Usachev, Yuriy M.;Grumbach, Isabella;Sheffield, Val C.;Strack, Stefan;Rahmouni, Kamal
线粒体在调节代谢功能和其他生理过程中的重要作用已经引起了人们对了解控制这种细胞器功能的机制的极大兴趣。我们评估了BBSome（一种由八种Bardet-Biedl综合征（BBS）蛋白组成的蛋白质复合物）在线粒体动态和功能控制中的作用。我们使用了一种多学科方法，包括CRISPR/Cas9技术介导的稳定的Bbs1基因敲除下丘脑N39神经元细胞系的产生。我们还分析了编码a激酶锚定蛋白1 （AKAP1）基因存在或缺失的BBSome缺陷小鼠的表型。我们的数据表明，BBSome在线粒体动力学和功能的调节中起着重要作用。BBSome的破坏导致细胞系、患者的成纤维细胞以及小鼠的下丘脑神经元和棕色脂肪细胞的线粒体灌注不足。线粒体的形态变化转化为功能异常，如氧消耗率降低、线粒体分布和钙处理改变。从机制上讲，我们证明BBSome通过调节线粒体分裂的关键调节剂动力蛋白样蛋白1 （DRP1）的磷酸化和转运到线粒体来调节其活性。值得注意的是，通过删除一个编码AKAP1的基因拷贝来挽救DRP1活性的下降，可以有效地使BBSome缺陷引起的线粒体形态和活性缺陷正常化。重要的是，这与由脑卒中缺失引起的几种表型的改善有关，如神经解剖异常、代谢改变和肥胖，这突出了线粒体缺陷在脑卒中病理生理中的重要性。这些发现证明了BBSome在线粒体功能调节中的关键作用，并指出线粒体缺陷是BBS的关键疾病机制。一些缺陷影响线粒体的形态和功能。bbsome介导的线粒体调控涉及DRP1。Akap1杂合性修复了BBSome缺乏症引起的线粒体缺陷。线粒体缺陷的修复改善了BBSome缺乏引起的瘦素抵抗和肥胖。
The essential role of mitochondria in regulation of metabolic function and other physiological processes has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. We assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, in the control of mitochondria dynamic and function. We used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of a stable Bbs1 gene knockout hypothalamic N39 neuronal cell line. We also analyzed the phenotype of BBSome deficient mice in presence or absence of the gene encoding A-kinase anchoring protein 1 (AKAP1). Our data show that the BBSome play an important role in the regulation of mitochondria dynamics and function. Disruption of the BBSome cause mitochondria hyperfusion in cell lines, fibroblasts derived from patients as well as in hypothalamic neurons and brown adipocytes of mice. The morphological changes in mitochondria translate into functional abnormalities as indicated by the reduced oxygen consumption rate and altered mitochondrial distribution and calcium handling. Mechanistically, we demonstrate that the BBSome modulates the activity of dynamin-like protein 1 (DRP1), a key regulator of mitochondrial fission, by regulating its phosphorylation and translocation to the mitochondria. Notably, rescuing the decrease in DRP1 activity through deletion of one copy of the gene encoding AKAP1 was effective to normalize the defects in mitochondrial morphology and activity induced by BBSome deficiency. Importantly, this was associated with improvement in several of the phenotypes caused by loss of the BBSome such as the neuroanatomical abnormalities, metabolic alterations and obesity highlighting the importance of mitochondria defects in the pathophysiology of BBS. These findings demonstrate a critical role of the BBSome in the modulation of mitochondria function and point to mitochondrial defects as a key disease mechanism in BBS. BBSome deficiency affect mitochondria morphology and function. BBSome-mediated control of mitochondria involves DRP1. Akap1 heterozygosity rescues the mitochondria defects evoked by BBSome deficiency. Rescue of the mitochondria defects improves the leptin resistance and obesity induced by BBSome deficiency.
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影响因子：
9.8
作者：
Merrill RA;Dagda RK;Dickey AS;Cribbs JT;Green SH;Usachev YM;Strack S
通讯作者：
Strack S
影响因子：
158.5
作者：
GREEN, JS;PARFREY, PS;PRYSEPHILLIPS, W
通讯作者：
PRYSEPHILLIPS, W
影响因子：
3.8
作者：
Anosov, Mariana;Birk, Ruth
通讯作者：
Birk, Ruth
影响因子：
8.8
作者：
López-Doménech G;Higgs NF;Vaccaro V;Roš H;Arancibia-Cárcamo IL;MacAskill AF;Kittler JT
通讯作者：
Kittler JT
影响因子：
9
作者：
Edwards, Genea;Perkins, Guy A.;Ju, Won-Kyu
通讯作者：
Ju, Won-Kyu