Modeling aging and retinal degeneration with mitochondrial DNA mutation burden.

IF 8 1区 医学 Q1 CELL BIOLOGY Aging Cell Pub Date : 2024-08-29 DOI:10.1111/acel.14282
John Sturgis, Rupesh Singh, Quinn R Caron, Ivy S Samuels, Thomas Micheal Shiju, Aditi Mukkara, Paul Freedman, Vera L Bonilha
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Abstract

Somatic mitochondrial DNA (mtDNA) mutation accumulation has been observed in individuals with retinal degenerative disorders. To study the effects of aging and mtDNA mutation accumulation in the retina, a polymerase gamma (POLG) exonuclease-deficient model, the PolgD257A mutator mice (D257A), was used. POLG is an enzyme responsible for regulating mtDNA replication and repair. Retinas of young and older mice with this mutation were analyzed in vivo and ex vivo to provide new insights into the contribution of age-related mitochondrial (mt) dysfunction due to mtDNA damage. Optical coherence tomography (OCT) image analysis revealed a decrease in retinal and photoreceptor thickness starting at 6 months of age in mice with the D257A mutation compared to wild-type (WT) mice. Electroretinography (ERG) testing showed a significant decrease in all recorded responses at 6 months of age. Sections labeled with markers of different types of retinal cells, including cones, rods, and bipolar cells, exhibited decreased labeling starting at 6 months. However, electron microscopy analysis revealed differences in retinal pigment epithelium (RPE) mt morphology beginning at 3 months. Interestingly, there was no increase in oxidative stress and parkin-mediated mitophagy in the ages analyzed in the retina or RPE of D257A mice. Additionally, D257A RPE exhibited an accelerated rate of autofluorescence cytoplasmic granule formation and accumulation. Mt markers displayed different abundance in protein lysates obtained from retina and RPE samples. These findings suggest that the accumulation of mtDNA mutations leads to impaired mt function and accelerated aging, resulting in retinal degeneration.

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利用线粒体 DNA 变异负荷模拟衰老和视网膜变性。
在视网膜退行性疾病患者中观察到体细胞线粒体 DNA(mtDNA)突变积累。为了研究衰老和视网膜中 mtDNA 突变积累的影响,我们使用了聚合酶γ(POLG)外切酶缺陷模型,即 PolgD257A 突变小鼠(D257A)。POLG 是一种负责调节 mtDNA 复制和修复的酶。对具有这种突变的年轻小鼠和老年小鼠的视网膜进行了体内和体外分析,以便对与年龄相关的线粒体(mt)功能障碍(由于 mtDNA 损伤)的贡献提供新的见解。光学相干断层扫描(OCT)图像分析显示,与野生型(WT)小鼠相比,D257A突变小鼠从6个月大开始视网膜和感光体厚度就开始下降。视网膜电图(ERG)测试显示,在小鼠6个月大时,所有记录到的反应都显著下降。用不同类型视网膜细胞(包括视锥、视杆细胞和双极细胞)的标记物标记的切片显示,6 个月大时标记物减少。然而,电子显微镜分析显示,视网膜色素上皮(RPE)mt 形态从 3 个月开始出现差异。有趣的是,在 D257A 小鼠视网膜或 RPE 的分析年龄中,氧化应激和 parkin 介导的有丝分裂没有增加。此外,D257A RPE 的自发荧光细胞质颗粒形成和积累速度加快。在视网膜和 RPE 样品的蛋白质裂解液中,Mt 标记显示出不同的丰度。这些发现表明,mtDNA 突变的积累会导致 mt 功能受损和加速衰老,从而导致视网膜退化。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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