脂滴-线粒体接触点在肝脏代谢障碍与缺血再灌注损伤中的研究进展

Research advances in the lipid droplet-mitochondria contact interface in hepatic metabolic injury and ischemia-reperfusion injury

摘要

脂滴-线粒体接触点是连接脂质储存、脂肪酸氧化与线粒体稳态的膜接触位点。肝脏因同时承担脂质合成、储存、氧化和输出功能，是观察该接触点在生理适应和病理重塑中作用的理想场所。越来越多研究表明，在慢性脂质过载导致的肝脏代谢损伤及急性缺血再灌注损伤中，该接触点均处于“脂质流量调控-线粒体应激阈值-炎症损伤放大”的交汇点。代谢应激早期，适度脂滴形成和脂滴-线粒体耦联有助于脂质封存、脂肪酸分流和能量适应；而在持续脂质负荷或再灌注氧化打击下，脂滴动员与线粒体摄取/氧化能力失衡，可导致脂毒性放大、活性氧爆发、线粒体DNA外泄及无菌性炎症。近年来，超分辨成像、邻近标记、空间蛋白质组学等技术推动该领域从形态学共定位研究转向结构-组成-功能闭环解析。文章围绕脂滴-线粒体接触点的结构基础、功能异质性及其在肝脏代谢损伤和缺血再灌注损伤中的作用进行综述，并探讨其作为疾病分层指标和潜在干预靶点的转化前景。

Abstract

Lipid droplet - mitochondria contact sites are important membrane contact sites that connect lipid storage，fatty acid oxidation，and mitochondrial homeostasis. As the liver is responsible for lipid synthesis，storage，oxidation，and export，it provides an ideal setting for investigating the roles of these contact sites in physiological adaptation and pathological remodeling. Growing evidence suggests that，both in chronic lipid overload-induced hepatic metabolic injury and in acute hepatic ischemia-reperfusion injury，lipid droplet - mitochondria contact sites are positioned at the intersection of lipid flux regulation，mitochondrial stress thresholds，and inflammatory injury amplification. During the early stage of metabolic stress，moderate lipid droplet formation and lipid droplet - mitochondrial coupling may facilitate lipid sequestration，fatty acid partitioning，and energy adaptation. However，under persistent lipid burden or reperfusion-associated oxidative stress，a mismatch between lipid droplet mobilization and mitochondrial uptake/oxidative capacity may lead to amplified lipotoxicity，reactive oxygen species bursts，mitochondrial DNA leakage，and sterile inflammation. In recent years，advances in super-resolution imaging，proximity labeling and spatial proteomics have promoted a shift in this field from morphological colocalization studies toward closed-loop analysis of structure，composition，and function. This review summarizes the structural basis and functional heterogeneity of lipid droplet-mitochondria contact sites，as well as their roles in hepatic metabolic injury and ischemia-reperfusion injury，and discusses their translational potential as disease stratification markers and therapeutic targets.

关键词

脂滴 / 线粒体 / 膜接触位点 / 肝脏代谢损伤 / 肝脏缺血再灌注损伤 / 脂毒性 / 线粒体稳态

Key words

lipid droplet / mitochondria / membrane contact site / hepatic metabolic injury / hepatic ischemia-reperfusion injury / lipotoxicity / mitochondrial homeostasis

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基金资助

科技部-国家重点研发计划(2022YFF0713000)