Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients

Irena J.J. Muffels*, Richard Rodenburg, Hanneke L.D. Willemen, Désirée van Haaften-Visser, Hans Waterham, Niels Eijkelkamp, Sabine A. Fuchs, Peter M. van Hasselt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number111496
JournaliScience
Volume28
Issue number1
DOIs
Publication statusPublished - 17 Jan 2025

Keywords

  • Biological sciences
  • Genetics
  • Health sciences
  • Human genetics
  • Medicine
  • Natural sciences

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