Muffels Irena J J, Rodenburg Richard, Willemen Hanneke L D, van Haaften-Visser Désirée, Waterham Hans, Eijkelkamp Niels, Fuchs Sabine A, van Hasselt Peter M
Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht 3584 EA, the Netherlands.
Nijmegen Center for Mitochondrial Disorders, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, the Netherlands.
iScience. 2024 Nov 28;28(1):111496. doi: 10.1016/j.isci.2024.111496. eCollection 2025 Jan 17.
Traditional classification by clinical phenotype or oxidative phosphorylation (OXPHOS) complex deficiencies often fails to clarify complex genotype-phenotype correlations in mitochondrial disease. A multimodal functional assessment may better reveal underlying disease patterns. Using imaging flow cytometry (IFC), we evaluated mitochondrial fragmentation, swelling, membrane potential, reactive oxygen species (ROS) production, and mitochondrial mass in fibroblasts from 31 mitochondrial disease patients. Significant changes were observed in 97% of patients, forming two overarching groups with distinct responses to mitochondrial pathology. One group displayed low-to-normal membrane potential, indicating a hypometabolic state, while the other showed elevated membrane potential and swelling, suggesting a hypermetabolic state. Literature analysis linked these clusters to complex I stability defects (hypometabolic) and proton pumping activity (hypermetabolic). Thus, our IFC-based platform offers a novel approach to identify disease-specific patterns through functional responses, supporting improved diagnostic and therapeutic strategies.
传统上依据临床表型或氧化磷酸化（OXPHOS）复合体缺陷进行的分类，往往无法厘清线粒体疾病中复杂的基因型-表型相关性。多模式功能评估或许能更好地揭示潜在的疾病模式。我们运用成像流式细胞术（IFC），评估了31例线粒体疾病患者成纤维细胞中的线粒体碎片化、肿胀、膜电位、活性氧（ROS）生成及线粒体质量。97%的患者出现了显著变化，形成了两个对线粒体病理有不同反应的总体组。一组表现出低至正常的膜电位，表明处于低代谢状态，而另一组则显示膜电位升高和肿胀，提示处于高代谢状态。文献分析将这些聚类与复合体I稳定性缺陷（低代谢）和质子泵活性（高代谢）联系起来。因此，我们基于IFC的平台提供了一种通过功能反应识别疾病特异性模式的新方法，有助于改进诊断和治疗策略。
