Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease
Clinical and Translational Science, vol. 16, pp. 1258–1271
Abstract
The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF-15, IL-6, NT-proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide-adenine-dinucleotide-hydrogen (NADH) content in skin as well as reduced passive leg movement-induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood-based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis.
Authors 12
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Sebastiaan J. W. van Kraaij Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
Leiden University Medical Centre, Leiden, The Netherlands
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Bastiaan Smal Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Affiliation as printed
OMEICOS Therapeutics GmbH Berlin Germany
OMEICOS Therapeutics GmbH, Berlin, Germany
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Affiliation as printed
OMEICOS Therapeutics GmbH Berlin Germany
OMEICOS Therapeutics GmbH, Berlin, Germany
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Affiliation as printed
OMEICOS Therapeutics GmbH Berlin Germany
OMEICOS Therapeutics GmbH, Berlin, Germany
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Affiliation as printed
HealthTwiSt GmbH Berlin Germany
HealthTwiSt GmbH, Berlin, Germany
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Affiliation as printed
BioEnergetics LLC Boston Massachusetts USA
BioEnergetics LLC, Boston, Massachusetts, USA
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Erica Surya Klaassen Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
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Affiliation as printed
OMEICOS Therapeutics GmbH Berlin Germany
OMEICOS Therapeutics GmbH, Berlin, Germany
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Affiliation as printed
Max Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin Germany
OMEICOS Therapeutics GmbH Berlin Germany
OMEICOS Therapeutics GmbH, Berlin, Germany
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Pim Gal Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
Leiden University Medical Centre, Leiden, The Netherlands
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Matthijs Moerland corresponding Aachen Centre for Human Drug Research Leiden the Netherlands Centre for Human Drug Research (CHDR)
Leiden University · Leiden University Medical Center · Centre for Human Drug Research
Affiliation as printed
Centre for Human Drug Research Leiden The Netherlands
Leiden University Medical Centre Leiden The Netherlands
Centre for Human Drug Research, Leiden, The Netherlands
Leiden University Medical Centre, Leiden, The Netherlands
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