How defective mitochondrial electrical activity leads to inherited blindness.
How defective mitochondrial electrical activity leads to inherited blindness.
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DOI：
10.1073/pnas.2315649120
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发表时间：
2023-11-07
影响因子：
11.1
通讯作者：
Burke, Peter J.
中科院分区：
文献类型：
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作者：
Burke, Peter J.
在线粒体内膜上产生电压的酶复合物的遗传缺陷是如何导致遗传性失明疾病莱伯遗传性视神经病（LHON）的？自从 Wallace 等人 (1) 通过对患者家谱进行仔细的遗传分析和对患者线粒体 DNA (mtDNA) 进行桑格测序，发现特定的 mtDNA 突变是 LHON 的病因以来，这个谜团已经困扰了医学三十多年，从而创立了目前蓬勃发展的线粒体医学领域 (2)。此后，研究人员发现了多种导致 LHON 的相似 mtDNA 突变 (3)。这些缺陷有一个共同的特征：它们位于编码膜蛋白的区域，这些膜蛋白在线粒体内膜上产生电压，利用储存在糖和脂肪中的化学能来驱动该过程。在 PNAS (4) 中，富勒等人。迈出了重要的一步，回答了这种遗传 mtDNA 缺陷如何导致 LHON 并导致失明的问题。尽管这仅涉及一种疾病，但 LHON 已成为线粒体功能如何影响多种（可能是所有）疾病的典型例子，因为它涉及所有器官。因此，富勒等人的工作。在 PNAS (4) 中，以及针对 LHON 的类似工作，虽然只针对一种疾病，但作为剖析能量、健康和生命之间联系的模型具有广泛的意义。
How does a genetic defect in an enzyme complex that generates an electrical voltage across the inner membrane of mitochondria cause the inherited blindness disease Leber’s Hereditary Optic Neuropathy (LHON)? This mystery has plagued medicine for over three decades ever since Wallace et al.(1) discovered, through careful genetic analysis of pa tient family trees and Sanger sequencing of patient mitochondrial DNA (mtDNA), that a specific mtDNA mutation is the cause of LHON, hence founding the now burgeoning field of mitochondrial medicine (2). Since then, researchers have identified multiple similar mtDNA mutations that cause LHON (3). These defects share a common feature: They are in regions that encode for the membrane proteins that create the voltage across the mitochondrial inner membrane, using the chemical energy stored in sugars and fats to drive the process. In PNAS (4), Fuller et al. take an important step to answer the question of how this genetic mtDNA defect leads to LHON and causes blindness. Although this deals with only one disease, LHON has become the canonical, marquee example of how mitochondrial function impacts multiple (possibly all) diseases, since it involves all organs. Thus, the work by Fuller et al. in PNAS (4), and similar work addressing LHON, while addressing only one disease, has broad significance as a model for dissecting the link between energy, health, and life.