TY - JOUR
T1 - Imaging flow cytometry reveals divergent mitochondrial phenotypes in mitochondrial disease patients
AU - Muffels, Irena J.J.
AU - Rodenburg, Richard
AU - Willemen, Hanneke L.D.
AU - van Haaften-Visser, Désirée
AU - Waterham, Hans
AU - Eijkelkamp, Niels
AU - Fuchs, Sabine A.
AU - van Hasselt, Peter M.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2025/1/17
Y1 - 2025/1/17
N2 - 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.
AB - 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.
KW - Biological sciences
KW - Genetics
KW - Health sciences
KW - Human genetics
KW - Medicine
KW - Natural sciences
UR - http://www.scopus.com/inward/record.url?scp=85212059688&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.111496
DO - 10.1016/j.isci.2024.111496
M3 - Article
AN - SCOPUS:85212059688
VL - 28
JO - iScience
JF - iScience
IS - 1
M1 - 111496
ER -