Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.
Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity.
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DOI：
10.1172/jci162957
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发表时间：
2023-05-15
影响因子：
15.9
通讯作者：
Pujol, Aurora
中科院分区：
文献类型：
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作者：
Planas-Serra, Laura;Launay, Nathalie;Goicoechea, Leire;Heron, Benedicte;Jou, Cristina;Julia-Palacios, Natalia;Ruiz, Montserrat;Fourcade, Stephane;Casasnovas, Carlos;De La Torre, Carolina;Gelot, Antoinette;Marsal, Maria;Loza-Alvarez, Pablo;Garcia-Cazorla, Angels;Fatemi, Ali;Ferrer, Isidre;Portero-Otin, Manel;Area-Gomez, Estela;Pujol, Aurora
鞘脂作为膜成分和信号分子，在从神经发育障碍到癌症等人类疾病中发挥着至关重要的作用，溶酶体中鞘脂代谢的先天性错误就是最好的例证。二氢神经酰胺去饱和酶 Δ4-二氢神经酰胺去饱和酶 1 (DEGS1) 作用于鞘脂途径的最后一步，即从头神经酰胺生物合成。 DEGS1 缺陷会导致最近描述的低髓鞘性脑白质营养不良-18 (HLD18) (OMIM #618404)。在这里，我们揭示 DEGS1 是一种线粒体相关内质网膜驻留（MAM 驻留）酶，完善了之前将 DEGS1 仅定位于内质网的报道。使用患者成纤维细胞、多组学和酶测定，我们表明 DEGS1 缺陷破坏了 MAM 的主要核心功能：（a）线粒体动力学，与动力相关蛋白 1 激活减少相关的过度融合的线粒体网络； (b) 胆固醇代谢，甾醇O-酰基转移酶活性受损，胆固醇酯减少； (c) 磷脂代谢，磷脂酸和磷脂酰丝氨酸增加，磷脂酰乙醇胺减少； (d) 脂滴的生物发生，其尺寸和数量增加。此外，我们检测到成纤维细胞中线粒体超氧化物种类的产生增加，以及患者肌肉活检组织中线粒体呼吸损伤。我们的研究结果揭示了 HLD18 的病理生理学，并拓宽了我们对鞘脂代谢在 MAM 功能中的作用的理解。
Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane–resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.