Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.
Impaired Mitochondrial Energy Production Causes Light-Induced Photoreceptor Degeneration Independent of Oxidative Stress.
复制标题
线粒体能量产生受损会导致光诱导的光感受器变性与氧化应激无关。
DOI：
10.1371/journal.pbio.1002197
复制
发表时间：
2015-07
期刊：
影响因子：
9.8
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
Jaiswal M;Haelterman NA;Sandoval H;Xiong B;Donti T;Kalsotra A;Yamamoto S;Cooper TA;Graham BH;Bellen HJ
两种损伤通常是多种眼病的基础，包括青光眼、视神经萎缩和视网膜变性——线粒体功能缺陷和视紫红质异常运输。虽然线粒体缺陷通常与氧化应激有关，但它们与视紫红质运输没有联系。在一项旨在分离引起光感受器变性的突变的无偏前遗传筛选中，我们发现了核编码线粒体基因ppr的突变，ppr是人类LRPPRC的同源基因。我们发现ppr是防止光诱导变性所必需的。它的功能对于在重复光照下维持光感受器的膜去极化至关重要，ppr突变体的光传导级联受损导致Rhodopsin1过度内吞。此外，ppr缺失导致线粒体rna减少，电子传递链活性降低，ATP水平降低。然而，氧化应激并不是诱导的。我们提出ppr突变体中ATP水平的降低是光导缺陷的基础，导致光暴露时Rhodopsin1内吞作用增加，导致独立于氧化应激的光感受器变性。筛选中分离的另外两个基因丙酮酸脱氢酶和柠檬酸合酶的特性支持了这一假设。它们的丢失还会导致光诱导变性、过度的视紫红质1内吞作用和ATP减少，而不会同时发生氧化应激，这与线粒体基因中的许多其他突变不同，这些突变与氧化应激升高和不依赖光的光感受器死亡有关。一些线粒体疾病通过增加氧化应激导致失明。这项研究表明，在其他这类疾病中，光激活的光感受器退化是因为线粒体能量产生的不足损害了视紫质的运输并诱发了毒性。线粒体功能障碍与许多代谢和神经系统疾病有关，如Leigh综合征和进行性失明。氧化应激增加通常与线粒体功能障碍有关，被认为是疾病进展的常见原因。在这里，我们发现了编码线粒体蛋白的核基因，线粒体蛋白的缺失会导致光感受器神经元的死亡。与通常认为这种退化是由氧化应激水平升高引发的观点相反，我们发现氧化应激水平没有变化。我们发现用光激活光感受器神经元会显著增加能量的产生，并且这个过程是维持它们活动所必需的。线粒体功能障碍损害了这种能力，并导致光反应的过早终止。这反过来又损害了光感受器中视紫红质的循环，并且视紫红质在细胞中积累诱导毒性。这种独特的退化机制表明，不同的线粒体疾病可能遵循不同的疾病进展路径，因此对治疗的反应也不同。
Two insults often underlie a variety of eye diseases including glaucoma, optic atrophy, and retinal degeneration—defects in mitochondrial function and aberrant Rhodopsin trafficking. Although mitochondrial defects are often associated with oxidative stress, they have not been linked to Rhodopsin trafficking. In an unbiased forward genetic screen designed to isolate mutations that cause photoreceptor degeneration, we identified mutations in a nuclear-encoded mitochondrial gene, ppr, a homolog of human LRPPRC. We found that ppr is required for protection against light-induced degeneration. Its function is essential to maintain membrane depolarization of the photoreceptors upon repetitive light exposure, and an impaired phototransduction cascade in ppr mutants results in excessive Rhodopsin1 endocytosis. Moreover, loss of ppr results in a reduction in mitochondrial RNAs, reduced electron transport chain activity, and reduced ATP levels. Oxidative stress, however, is not induced. We propose that the reduced ATP level in ppr mutants underlies the phototransduction defect, leading to increased Rhodopsin1 endocytosis during light exposure, causing photoreceptor degeneration independent of oxidative stress. This hypothesis is bolstered by characterization of two other genes isolated in the screen, pyruvate dehydrogenase and citrate synthase. Their loss also causes a light-induced degeneration, excessive Rhodopsin1 endocytosis and reduced ATP without concurrent oxidative stress, unlike many other mutations in mitochondrial genes that are associated with elevated oxidative stress and light-independent photoreceptor demise. Some mitochondrial disorders cause blindness through increased oxidative stress. This study shows that in other such disorders, light-activated photoreceptors degenerate because the shortfall in mitochondrial energy production impairs rhodopsin trafficking and induces toxicity. Mitochondrial dysfunction is associated with a number of metabolic and neurological diseases such as Leigh syndrome and progressive blindness. Increased oxidative stress, which is often associated with mitochondrial dysfunction, is thought to be a common cause of disease progression. Here, we identified nuclear genes that encode mitochondrial proteins, whose loss causes the demise of photoreceptor neurons. Contrary to the common idea that this degeneration is triggered by elevated levels of oxidative stress, we find no change in the levels of oxidative stress. We show that activating photoreceptor neurons with light significantly increases energy production, and that this process is required to sustain their activity. Mitochondrial dysfunction impairs this capacity and leads to a premature termination of the light response. This in turn impairs the cycling of the light-sensitive receptor Rhodopsin in photoreceptors, and Rhodopsin accumulates in the cell inducing toxicity. This distinct mechanism of degeneration suggests that different mitochondrial diseases may follow different paths of disease progression and would hence respond differently to treatments.