Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling.
Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling.
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DOI：
10.1091/mbc.e13-03-0121
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发表时间：
2013-06
影响因子：
3.3
通讯作者：
Claypool SM
中科院分区：
文献类型：
--
作者：
Baile MG;Whited K;Claypool SM
我们对临床相关的他法津介导的心磷脂（CL）重塑途径的了解尚不完整。在这项研究中，已经确定了CL重塑所需的一个新的运输步骤。此外，研究表明，通过这种CL重塑途径的通量是由线粒体电化学梯度的强度控制的。线粒体特异性脂质心磷脂（CL）在其中的许多过程中是必需的。CL在内膜面向基质的小叶上合成后，经过酰基链重塑形成最终形态。在酵母中，这个过程是由转酰基酶他法津完成的，它与膜间空间（IMS）面膜小叶相关。TAZ1基因突变导致x连锁心肌病巴斯综合征。令人惊讶的是，尽管有这种明确的病理生理关联，但CL重塑的生理重要性尚未得到解决。在本文中，我们发现启动CL重塑的脂肪酶Cld1p与线粒体IM的面向基质的小叶有关。因此，Cld1p产生的单聚心磷脂必须被运输到面向ims的膜小叶上，以获得他法嗪，从而确定了CL重塑所需的一个先前未知的步骤。此外，我们发现Cld1p是CL重塑的主要调控位点；并且，像CL生物合成一样，在需要线粒体产生能量的生长条件下，CL重塑得到增强。然而，与CL生物合成不同的是，线粒体膜电位的耗散刺激CL重塑，确定了一种将CL重塑与氧化磷酸化能力联系起来的新型反馈机制。
Our understanding of the clinically relevant tafazzin-mediated cardiolipin (CL) remodeling pathway is incomplete. In this study, a new trafficking step required for CL remodeling has been identified. Further, it is demonstrated that flux through this CL remodeling pathway is controlled by the strength of the mitochondrial electrochemical gradient. The mitochondrial-specific lipid cardiolipin (CL) is required for numerous processes therein. After its synthesis on the matrix-facing leaflet of the inner membrane (IM), CL undergoes acyl chain remodeling to achieve its final form. In yeast, this process is completed by the transacylase tafazzin, which associates with intermembrane space (IMS)-facing membrane leaflets. Mutations in TAZ1 result in the X-linked cardiomyopathy Barth syndrome. Amazingly, despite this clear pathophysiological association, the physiological importance of CL remodeling is unresolved. In this paper, we show that the lipase initiating CL remodeling, Cld1p, is associated with the matrix-facing leaflet of the mitochondrial IM. Thus monolysocardiolipin generated by Cld1p must be transported to IMS-facing membrane leaflets to gain access to tafazzin, identifying a previously unknown step required for CL remodeling. Additionally, we show that Cld1p is the major site of regulation in CL remodeling; and that, like CL biosynthesis, CL remodeling is augmented in growth conditions requiring mitochondrially produced energy. However, unlike CL biosynthesis, dissipation of the mitochondrial membrane potential stimulates CL remodeling, identifying a novel feedback mechanism linking CL remodeling to oxidative phosphorylation capacity.