Publication year
2011Source
Current Pharmaceutical Design, 17, 36, (2011), pp. 4023-4033ISSN
Publication type
Article / Letter to editor

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Organization
Biochemistry (UMC)
Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
Cell Biology (UMC)
Journal title
Current Pharmaceutical Design
Volume
vol. 17
Issue
iss. 36
Page start
p. 4023
Page end
p. 4033
Subject
IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolism; NCMLS 4: Energy and redox metabolism IGMD 8: Mitochondrial medicine; IGMD 8: Mitochondrial medicine NCMLS 4: Energy and redox metabolismAbstract
Mitochondrial dysfunction has been implicated in many human diseases and off-target drug effects. Isolated deficiency of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system, can arise from mutations in nuclear DNA (nDNA)-encoded subunits. In humans, these mutations are generally associated with neurodegenerative disorders like Leigh or Leigh-like syndrome with onset in early childhood. Currently, no cure or mitigative treatment is available for these diseases. To aid the future design of rational treatment strategies, insight into the pathophysiology of CI mutations is required. To this end, we quantitatively compared various cell physiological readouts between fibroblasts from healthy individuals and patients with isolated CI deficiency. Here we review how this multivariate dataset was obtained and in which way explorative data analysis (EDA) techniques can be used for pattern analysis. Based upon 13 experimental parameters two patient groups were identified. These displayed a later (cluster I) or earlier (cluster II) age of disease onset and death. Relative to cluster I, cluster II patient cells displayed a larger reduction in CI activity, a larger increase in NADH/ROS levels, mitochondrial fragmentation and lower cellular levels of OXPHOS proteins. Our results highlight a connection between CI deficiency, ROS and mitochondrial morphology/function. This information not only contributes to our understanding of the pathophysiological mechanism of CI and mitochondrial deficiency but also suggests possible targets for cellular intervention strategies.
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- Faculty of Medical Sciences [81051]
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