摘要
线粒体疾病可能由母系遗传线粒体DNA(mtDNA)突变或编码线粒体蛋白质的核基因突变引起。它们的双基因组特性使线粒体疾病成为一个非常异质的疾病群体,可以在任何年龄出现,并且可以影响任何类型的组织。自噬溶酶体降解途径通过一种称为有丝分裂的特异性质量控制机制,在清除功能紊乱和多余线粒体方面起着重要作用。线粒体可能以自噬性降解为目标,原因有多种,包括循环的基础代谢、饥饿诱导的降解和损伤引起的降解。虽然核心自噬机制是高度保守和常见的大多数途径,信号途径导致选择性降解受损线粒体仍然不完全了解。营养缺乏引起的1型有丝分裂依赖于PI3K(磷酸肌醇3-激酶)形成自噬体,但不依赖于有丝分裂蛋白、PINK1(PTEN诱导的假定激酶1)和帕金森。而2型由损伤引起的有丝分裂依赖于PINK1和PARKIN,但不需要PI3K。 自噬和有丝分裂在人类疾病中起着重要作用,因此可以作为治疗线粒体和神经退行性疾病的治疗靶点。因此,我们回顾了已知的自噬调节剂(爱卡和二甲双胍)的药物,并可能通过激活AMP活化蛋白激酶信号通路来影响这一点。此外,我们回顾了辅酶Q和奎宁-依德苯甲酮等补充剂的可用数据,我们认为通过有益于线粒体功能来挽救线粒体疾病中增加的有丝分裂。
关键词: 有丝分裂, AICAR
Current Medicinal Chemistry
Title:Modulating Mitophagy in Mitochondrial Disease
Volume: 25 Issue: 40
关键词: 有丝分裂, AICAR
摘要: Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue.
The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN-induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K.
Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may affect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed the data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function.
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Cite this article as:
Modulating Mitophagy in Mitochondrial Disease, Current Medicinal Chemistry 2018; 25 (40) . https://dx.doi.org/10.2174/0929867324666170616101741
DOI https://dx.doi.org/10.2174/0929867324666170616101741 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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