Metabolism, infection and immunity in inborn errors of mitochondrial metabolism

我们的转化研究计划的总体目标是了解免疫系统的激活和线粒体代谢（即免疫代谢）之间的相互作用，使用线粒体疾病作为模型系统。 我们的临床方案是我们跨国研究的基础。最近，我们描述了一组患有线粒体疾病的儿科患者对疫苗可预防疾病的易感性。为了探讨记忆B细胞功能低下的机制，我们建立了细胞色素c氧化酶（考克斯，OXPHOS中的复合物IV）缺陷的小鼠模型。初步数据表明，考克斯缺陷导致长期记忆B细胞的扰动。 认识到线粒体疾病患者中涉及T细胞记忆应答的免疫表型，我们通过靶向考克斯的组装因子COX10构建了T细胞考克斯缺陷模型（Cell Metab，2017）。利用这个模型，我们证明了考克斯作为一个代谢检查点的独特作用，在T细胞活化介导的凋亡。在这篇文章之后，我们使用CRISPR创建了一个SURF 1缺陷的小鼠模型。SURF 1是另一种考克斯组装因子，可导致人类严重的线粒体疾病。令我们惊讶的是，尽管具有低考克斯活性，该小鼠模型显示正常的T细胞功能，不像COX 10缺陷小鼠。这两种模型将使我们能够剖析考克斯功能域和它们在T细胞功能中的作用。此外，我们还将探索旨在通过在T细胞中表达替代氧化酶（AOX）来绕过COX10小鼠中的考克斯缺陷的疗法。 继续关于线粒体代谢在T细胞中的作用这一主题，我们参与了一个国际合作项目，解决了关于线粒体脂肪酸氧化在T细胞中的作用的基本问题。公认的教条是，线粒体脂肪酸氧化促进记忆T细胞的形成。使用患者的临床数据和脂肪酸氧化的小鼠模型，我们帮助证明线粒体脂肪酸氧化是确定T细胞记忆表型的关键。因此，我们贡献了一个开创性的出版物（Cell Metab，2018）和高调的审查（Immunol Rev 2018）挑战这一教条。 上述两项成就突出了临床研究在我们的计划中发挥的核心作用。基于我们以患者为中心的方法来解决免疫代谢中的基本问题，我们发表了一篇综述，赞扬了研究线粒体疾病作为模型系统的优点，以回答有关线粒体在免疫细胞功能中的作用的关键问题（Metabolism 2018）。 除了在T细胞免疫代谢方面的工作外，我们还继续探索免疫系统在调节终末器官代谢中的作用。 使用代谢组学方法和复杂的数据简化技术，我们表征了线粒体长链脂肪酸氧化小鼠模型中因感染而发生的代谢紊乱的病理生理学（Mol Genet Metab，2018）。这篇论文和一篇关于免疫系统在感染期间促进肝脏代谢失调的作用的综述（Mol Genet Metab，2017）强调了先天免疫系统和常驻巨噬细胞（例如库普弗细胞）在调节终末器官代谢中的作用（J Mol Med，2019）。最近，我们发表了线粒体肝病的小鼠模型，其中靶向免疫系统被探索为治疗途径（Jestin等人，Mol Metab，2020）。

The overall goal of our translational research program is to understand the interplay between activation of the immune system and mitochondrial metabolism (i.e. immunometabolism) using mitochondrial disease as a model system. Our clinical protocol serves as the basis for our transnational studies. Recently, we described vulnerability to vaccine preventable diseases in a cohort of pediatric patients with mitochondrial disease. To explore the mechanisms involved in depressed memory B-cell function, we have created a mouse model of cytochrome c oxidase (COX, complex IV in OXPHOS) deficiency. Preliminary data suggests that COX deficiency results in perturbations in long lived memory B-cells. Recognizing an immune phenotype involving T-cell memory responses in our patients with mitochondrial disease, we constructed a model of T-cell COX deficiency by targeting COX10, an assembly factor for COX (Cell Metab, 2017). Using this model, we demonstrated the unique role of COX as a metabolic checkpoint in T-cell activation by mediating apoptosis. Following up on this publication, we created a mouse model of SURF1 deficiency using CRISPR. SURF1 is another COX assembly factor that produces severe mitochondrial disease in humans. To our surprise, despite having low COX activity, this mouse model displays normal T-cell function, unlike COX10 deficient mice. Both models will allow us to dissect COX functional domains and their role in T-cell function. Furthermore, we will also explore therapies aimed at bypassing COX deficiency in COX10 mice by expressing an alternative oxidase (AOX) in T-cells. Continuing on this theme of the role of mitochondrial metabolism in T-cells, we have been involved in an international collaborative project addressing a fundamental question regarding the role of mitochondrial fatty acid oxidation in T-cells. The accepted dogma is that mitochondrial fatty acid oxidation promotes memory T-cell formation. Using patient clinical data and mouse models of fatty acid oxidation, we aided in demonstrating that mitochondrial fatty acid oxidation was dispensable for determining T-cell memory phenotypes. As s result, we contributed to a seminal publication (Cell Metab, 2018) and high profile review (Immunol Rev 2018) challenging this dogma. Both of the aforementioned accomplishments highlight the central role clinical research plays in our program. Based on our patient-centered approach to addressing fundamental questions in immunometabolism, we published a review extolling the virtues of studying mitochondrial disease as a model system for answering critical questions regarding the role of the mitochondria in immune cell function (Metabolism 2018). In addition to work in T-cell immunometabolism, we have also continued to explore the role of the immune system in modulating end organ metabolism. Using a metabolomics approach with complex data reduction techniques, we characterized the pathophysiology of metabolic perturbations that occur as a result of infection in a mouse model of mitochondrial long chain fatty acid oxidation (Mol Genet Metab, 2018). This paper and a review on the role of the immune system in promoting metabolic dysregulation in the liver during infection (Mol Genet Metab, 2017) highlights the role of the innate immune system and resident macrophages (e.g. Kupffer cells) in modulating end organ metabolism (J Mol Med, 2019). Recently, we published a mouse model of mitochondrial hepatopathy where targeting the immune system was being explored as a therapeutic avenue (Jestin et al., Mol Metab, 2020).