Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2020-05-14 DOI:10.15698/cst2020.06.222
Zhiyong Chen, Marine Berquez, Alessandro Luciani
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引用次数: 9

Abstract

Dysregulation of the mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of intermediary metabolism caused by the deficiency of methylmalonyl-CoA mutase (MMUT) - a mitochondrial enzyme that mediates the degradation of certain amino acids and lipids. The loss of MMUT activity triggers an accumulation of toxic endogenous metabolites causing severe organ dysfunctions and life-threatening complications. How MMUT deficiency instigates mitochondrial distress and tissue damage remains poorly understood. Using cell and animal-based models, we recently discovered that MMUT deficiency disables the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, impeding their delivery and subsequent dismantling by macroautophagy/autophagy-lysosome degradation systems (Luciani et al. Nat Commun. 11(1):970). This promotes an accumulation of damaged and/or dysfunctional mitochondria that spark epithelial distress and tissue damage. Using a systems biology approach based on drug-disease network perturbation modeling, we predicted targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived kidney cells and ameliorates disease-relevant phenotypes in mmut-deficient zebrafish. These results unveil a link between primary MMUT deficiency, defective mitophagy, and cell distress, offering promising therapeutic avenues for MMA and other mitochondria-related diseases.

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线粒体、线粒体自噬和代谢性疾病:走向拼图。
线粒体网络在终末分化细胞中的失调有助于广泛的疾病。甲基丙二酸血症(MMA)是一种常染色体隐性先天性中间代谢错误,由甲基丙二酰辅酶a变化酶(MMUT)缺乏引起,甲基丙二酰辅酶a变化酶是一种介导某些氨基酸和脂质降解的线粒体酶。MMUT活性的丧失会引发有毒内源性代谢物的积累,导致严重的器官功能障碍和危及生命的并发症。MMUT缺乏如何引发线粒体窘迫和组织损伤仍然知之甚少。利用细胞和动物模型,我们最近发现MMUT缺陷使pink1诱导的PRKN/Parkin易位到mma损伤的线粒体,阻碍了它们的递送和随后被巨噬/自噬溶酶体降解系统拆除(Luciani等)。自然科学,11(1):970。这促进了受损和/或功能失调线粒体的积累,从而引发上皮窘迫和组织损伤。利用基于药物-疾病网络扰动模型的系统生物学方法,我们预测了靶向通路,其调节可修复患者源性肾细胞中的线粒体功能障碍,并改善mutt缺陷斑马鱼的疾病相关表型。这些结果揭示了原发性MMUT缺陷、线粒体自噬缺陷和细胞窘迫之间的联系,为MMA和其他线粒体相关疾病提供了有希望的治疗途径。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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