An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
An ER phospholipid hydrolase drives ER-associated mitochondrial constriction for fission and fusion.
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DOI：
10.7554/elife.84279
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发表时间：
2022-11-30
期刊：
影响因子：
7.7
通讯作者：
Voeltz GK
中科院分区：
文献类型：
--
作者：
Nguyen TT;Voeltz GK
线粒体是动态细胞器，在内质网 (ER)-线粒体膜接触位点 (MCS) 定义的统一平台上经历裂变和融合循环。这些 MCS 或节点共同定位裂变和聚变机制。我们着手确定内质网相关线粒体节点如何调节裂变和融合机器组装。我们使用与融合机制 Mfn1 连接的混杂生物素连接酶和蛋白质组学来鉴定 ER 膜蛋白 ABHD16A，作为节点形成的主要调节因子。在缺乏 ABHD16A 的情况下，裂变和融合机制无法募集到 ER 相关线粒体节点，并且裂变和融合率显着降低。 ABHD16A 含有酰基转移酶基序和 α/β 水解酶结构域，这些区域关键残基的点突变无法挽救 ER 相关线粒体热点的形成。这些数据表明 ABHD16A 通过改变 ER 线粒体 MCS 的磷脂组成来发挥作用。我们的数据展示了内质网膜蛋白的第一个例子，该蛋白调节线粒体裂变和融合机制的募集。
Mitochondria are dynamic organelles that undergo cycles of fission and fusion at a unified platform defined by endoplasmic reticulum (ER)-mitochondria membrane contact sites (MCSs). These MCSs or nodes co-localize fission and fusion machinery. We set out to identify how ER-associated mitochondrial nodes can regulate both fission and fusion machinery assembly. We have used a promiscuous biotin ligase linked to the fusion machinery, Mfn1, and proteomics to identify an ER membrane protein, ABHD16A, as a major regulator of node formation. In the absence of ABHD16A, fission and fusion machineries fail to recruit to ER-associated mitochondrial nodes, and fission and fusion rates are significantly reduced. ABHD16A contains an acyltransferase motif and an α/β hydrolase domain, and point mutations in critical residues of these regions fail to rescue the formation of ER-associated mitochondrial hot spots. These data suggest a mechanism whereby ABHD16A functions by altering phospholipid composition at ER-mitochondria MCSs. Our data present the first example of an ER membrane protein that regulates the recruitment of both fission and fusion machineries to mitochondria.