Targeting the cellular metabolism to treat tissue-specific mitochondrial diseases

靶向细胞代谢来治疗组织特异性线粒体疾病

• 批准号: MR/V009346/1
• 负责人: Rita Horvath
• 金额: $ 114.71万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009346%2F1
• 关键词: Targeting; cellular; metabolism; treat; tissue

The mitochondria are specialised units (organelles) within cells that are responsible for transforming nutrients into energy. Mitochondria contain their own genetic material (mtDNA) which is replicated independently from the DNA in the nucleus. mtDNA is very small and only contains the information for 13 proteins; all other proteins that the mitochondria need to function are coded in the nuclear DNA. Changes in either mtDNA or nuclear DNA can cause mitochondrial diseases. These are disabling or fatal conditions, affecting the brain, liver, skeletal muscle, heart and other organs, and currently there are no effective cures. Although all mitochondrial diseases have a similar mechanism, they can affect the body in strikingly different ways. To date, the reasons for this are poorly understood.We study an unusual mitochondrial disease named reversible infantile respiratory chain deficiency (RIRCD). RIRCD is characterised by severe muscle weakness before 3 months of age, followed by a spontaneous recovery after 6 months of age in surviving children. RIRCD is caused by a spelling error(=mutation) in the mtDNA. Interestingly, many more people carry this mutation without getting ill, however only around 100 are affected by RIRCD worldwide. We demonstrate that a second change in the nuclear DNA in addition to the mtDNA mutation is needed to cause RIRCD. The mutation that underlies RIRCD is situated in a part of the mtDNA molecule called transfer-RNA (tRNA). tRNAs deliver the appropriate amino acids to a machinery called ribosome, which puts the amino acids together into a protein; this process is called translation. If there are not enough amino acids available or if the tRNA is modified by a mutation, the tRNA could stay empty. Empty tRNAs are a negative sign and can be detected by a protein called GCN2. GCN2 triggers a reaction of the cell called the integrated stress response (ISR). This stress response leads to changes that either help the cell adapt to the stress or cause its death if it lasts too long. Our hypothesis is that the total amount of tRNAs and the empty tRNAs can differ in different cell types. A higher amount of empty tRNAs could trigger a stronger stress response, which could have a negative or positive impact on the cell. We will analyse skin cells obtained from patients with various mitochondrial diseases and healthy controls. The organs affected by the disease (brain, muscles, heart) are not easily accessible for analysis. Therefore, we will turn the skin cells into stem cells through a process called reprogramming. From the stem cells we can derive brain, heart and muscle cells. By looking at different cell types from the same person we are able to compare their reactions in stress situations. We will check if levels of empty tRNAs or ISR are different in the different cell types. We will add certain amino acids to see if this can reduce the amount of empty tRNA and the stress response.Another model that we will use are zebrafish. We can introduce different mutations into the zebrafish DNA and look at how the different organs (such as brain, heart and skeletal muscle) are affected. We will look at tRNA amounts and ISR in different organs of the fish. These experiments will help to explain why tissues are affected in a different way despite carrying the same mutations.The spontaneous recovery of patients with RIRCD is very unusual. We will compare the cells from RIRCD patients with cells from other mitochondrial diseases caused by changes affecting tRNAs but the patients do not recover. We believe that the changes induced by ISR are helping the RIRCD cells to change their way of functioning and mobilise different energy sources, eventually leading to the recovery. We don't know, however why this does not happen in other mitochondrial diseases. If we understand the differences between RIRCD and other mitochondrial diseases we might be able to find a way to treat other forms of mitochondrial disease.

线粒体是细胞内的专门单位（细胞器），负责将营养物质转化为能量。线粒体含有它们自己的遗传物质（mtDNA），其独立于细胞核中的DNA复制。线粒体DNA非常小，只包含13种蛋白质的信息;线粒体功能所需的所有其他蛋白质都编码在核DNA中。线粒体DNA或核DNA的变化都可能导致线粒体疾病。这些都是致残或致命的疾病，影响大脑，肝脏，骨骼肌，心脏和其他器官，目前还没有有效的治疗方法。虽然所有线粒体疾病都有类似的机制，但它们可以以截然不同的方式影响身体。迄今为止，其原因尚不清楚。我们研究了一种不寻常的线粒体疾病，称为可逆性婴儿呼吸链缺陷症（RIRCD）。RIRCD的特征是在3个月大之前出现严重的肌无力，随后存活儿童在6个月大之后自发恢复。RIRCD是由mtDNA中的拼写错误（=突变）引起的。有趣的是，更多的人携带这种突变而不生病，但全世界只有大约100人受到RIRCD的影响。我们证明，除了线粒体DNA突变的核DNA的第二个变化是需要引起RIRCD。作为RIRCD基础的突变位于mtDNA分子的一部分，称为转移RNA（tRNA）。tRNA将适当的氨基酸运送到一种叫做核糖体的机器上，核糖体将氨基酸组合成蛋白质;这个过程称为翻译。如果没有足够的氨基酸可用，或者如果tRNA被突变修饰，tRNA可能会保持空白。空的tRNA是一种阴性信号，可以被一种叫做GCN 2的蛋白质检测到。GCN 2触发细胞的反应，称为综合应激反应（ISR）。这种压力反应导致的变化要么帮助细胞适应压力，要么在压力持续太久时导致细胞死亡。我们的假设是，在不同的细胞类型中，tRNA和空tRNA的总量可能不同。更高数量的空tRNA可以引发更强的应激反应，这可能对细胞产生负面或正面的影响。我们将分析从患有各种线粒体疾病的患者和健康对照组中获得的皮肤细胞。受疾病影响的器官（大脑，肌肉，心脏）不容易进行分析。因此，我们将通过一个称为重编程的过程将皮肤细胞转化为干细胞。从干细胞中我们可以获得脑、心脏和肌肉细胞。通过观察同一个人的不同细胞类型，我们能够比较他们在压力情况下的反应。我们将检查空tRNA或ISR的水平在不同细胞类型中是否不同。我们将添加某些氨基酸，看看这是否可以减少空tRNA的数量和应激反应。我们将使用的另一个模型是斑马鱼。我们可以将不同的突变引入斑马鱼的DNA，并观察不同的器官（如大脑，心脏和骨骼肌）是如何受到影响的。我们将研究鱼的不同器官中的tRNA量和ISR。这些实验将有助于解释为什么携带相同突变的组织会以不同的方式受到影响。RIRCD患者的自发恢复是非常罕见的。我们将比较RIRCD患者的细胞与其他线粒体疾病的细胞，这些疾病是由影响tRNA的变化引起的，但患者没有恢复。我们相信，ISR引起的变化正在帮助RIRCD细胞改变其功能方式并动员不同的能量来源，最终导致恢复。我们不知道，但是，为什么这不会发生在其他线粒体疾病。如果我们了解RIRCD和其他线粒体疾病之间的差异，我们可能能够找到一种治疗其他形式线粒体疾病的方法。

项目成果

Muscle fat replacement and modified ragged red fibers in two patients with reversible infantile respiratory chain deficiency.

两名患有可逆性婴儿呼吸链缺陷的患者的肌肉脂肪替代和改良的粗糙红纤维。

• DOI: 10.1016/j.nmd.2021.02.017
• 发表时间: 2021
• 期刊: NMD
• 作者: Cotta A

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder

• DOI: 10.1016/j.gim.2023.100938
• 发表时间: 2023-07
• 期刊: Genetics in Medicine
• 影响因子: 8.8
• 作者: A. Accogli;Sheng-Jia Lin;M. Severino;Sung-Hoon Kim;K. Huang;C. Rocca;M. Landsverk;M. Zaki;A. Al-Maawali;Varunvenkat M Srinivasan;K. Al-Thihli;G. Schaefer;M. Davis;D. Tonduti;C. Doneda;Lara M. Marten;C. Mühlhausen;M. Gomez;E. Lamantea;Rafael Mena;M. Nizon;V. Procaccio;Amber Begtrup;A. Telegrafi;H. Cui;H. L. Schulz;J. Mohr;S. Biskup;M. Loos;H. Aráoz;V. Salpietro;L. Keppen;M. Chitre;Cassidy Petree;L. Raymond;J. Vogt;Lindsey B. Swayer;Alice A. Basinger;Signe V Pedersen;T. Pearson;D. Grange;Lokesh Lingapp;Paige McDunnah;R. Horvath;B. Cogné;B. Isidor;Andreas Hahn;K. Gripp;S. M. Jafarnejad;E. Ostergaard;C. Prada;D. Ghezzi;Vykuntaraju K. Gowda;R. Taylor;N. Sonenberg;H. Houlden;M. Sissler;G. Varshney;R. Maroofian

Correction: Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome.

更正：继发于新型 CHKB 突变的巨圆锥型先天性肌营养不良症类似于非典型 Rett 综合征。

• DOI: 10.1038/s10038-021-00920-2
• 发表时间: 2021
• 期刊: Journal of human genetics
• 影响因子: 3.5
• 作者: Bardhan M

EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders.

EURO-NMD 注册中心：联合 FAIR 基础设施、创新技术和以患者为中心的罕见神经肌肉疾病注册中心概念。

• DOI: 10.1186/s13023-024-03059-3
• 发表时间: 2024
• 期刊: Orphanet journal of rare diseases
• 影响因子: 3.7
• 作者: Atalaia A

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.

医疗行动本体论：用于注释和分析人类疾病的治疗和临床管理的工具。

• DOI: 10.1016/j.medj.2023.10.003
• 发表时间: 2023
• 期刊: Med (New York, N.Y.)
• 作者: Carmody LC