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Mitochondrial medicine. New strategies to evaluate drug toxicity and develop pharmacological protection of the cell’s powerhouse.

Piel, Sarah LU (2018)
Abstract
Mitochondria produce the majority of the cell’s energy. Any dysfunction in, or interference with mitochondrial function can have severe consequences. And yet, it was only within the last decades that screening for potential mitochondrial toxicity was included as routine toxicity assay during early drug development. Despite improved recognition of drug-related side effects on mitochondrial function and progress in method development, translation from the in vitro to the in vivo situation and from animal to human tissues still remain obstacles. Mitochondrial dysfunction can also have genetic origin, with similar consequences.
In the present thesis, we evaluated human peripheral blood cells as a model to investigate potential... (More)
Mitochondria produce the majority of the cell’s energy. Any dysfunction in, or interference with mitochondrial function can have severe consequences. And yet, it was only within the last decades that screening for potential mitochondrial toxicity was included as routine toxicity assay during early drug development. Despite improved recognition of drug-related side effects on mitochondrial function and progress in method development, translation from the in vitro to the in vivo situation and from animal to human tissues still remain obstacles. Mitochondrial dysfunction can also have genetic origin, with similar consequences.
In the present thesis, we evaluated human peripheral blood cells as a model to investigate potential drug-induced mitochondrial toxicity. We demonstrated that the antidiabetic drug metformin and the analgesic drug acetaminophen induce mitochondrial dysfunction and increase cellular lactate production through inhibition of complex I function at concentrations relevant for clinical intoxication. Complex I function was also inhibited by the formulation excipient Kolliphor® EL, indicating that drug-induced mitochondrial toxicity is not only induced by active pharmaceutical ingredients.
Current treatment options for mitochondrial disease are limited. Succinate, a natural metabolite of the TCA cycle and a direct substrate of complex II of the respiratory chain that can increase mitochondrial function has shown to improve clinical symptoms in case studies. However, it has limited cell-permeability. We developed novel cell-permeable succinate prodrugs and characterized them using human peripheral blood cells. We demonstrated improved oxidative phosphorylation in different models of mitochondrial dysfunction. Methylene blue, which has previously been described to improve mitochondrial function in experimental models, failed to improve oxidative phosphorylation in human peripheral blood cells under the same conditions.
To investigate the bioenergetic response of human peripheral blood cells relative to other, more metabolically active tissues we further evaluated mitochondrial inhibitors and pharmacological treatment strategies in muscle fibres and human-derived primary cells and cell lines. Changes in the respiratory profiles of human peripheral blood cells reflected changes in the respiratory profiles of other, more metabolically active human cells.
In conclusion, we demonstrate that human peripheral blood cells are a suitable model for evaluation of potential drug-induced mitochondrial toxicity and pharmacological bypass strategies for the support of mitochondrial function. Human peripheral blood cells, in this context, reflect the metabolic responses of other, more metabolically active human cells.
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author
supervisor
opponent
  • M.D., Ph.D. Protti, Alessandro, Dipartmento di Anestesia, Rianimazione ed Emergenza-Urgenza, Fondazione IRCCS Ca’Granda-Ospedale Maggiore Policlinico, Milan, Italy
organization
publishing date
type
Thesis
publication status
published
subject
keywords
mitochondria, drug-induced mitochondrial toxicity, mitochondrial disease, mitochondrial medicine, drug development, succinate, methylene blue, metformin, acetaminophen, paracetamol, Kolliphor® EL
pages
77 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund
defense date
2018-04-06 09:00
ISBN
978-91-7619-593-2
language
English
LU publication?
no
id
86ddb2bd-297e-4c00-a88a-9a0b540c885d
date added to LUP
2018-03-14 09:40:48
date last changed
2018-11-21 21:38:37
@phdthesis{86ddb2bd-297e-4c00-a88a-9a0b540c885d,
  abstract     = {Mitochondria produce the majority of the cell’s energy. Any dysfunction in, or interference with mitochondrial function can have severe consequences. And yet, it was only within the last decades that screening for potential mitochondrial toxicity was included as routine toxicity assay during early drug development. Despite improved recognition of drug-related side effects on mitochondrial function and progress in method development, translation from the in vitro to the in vivo situation and from animal to human tissues still remain obstacles. Mitochondrial dysfunction can also have genetic origin, with similar consequences. <br/>In the present thesis, we evaluated human peripheral blood cells as a model to investigate potential drug-induced mitochondrial toxicity. We demonstrated that the antidiabetic drug metformin and the analgesic drug acetaminophen induce mitochondrial dysfunction and increase cellular lactate production through inhibition of complex I function at concentrations relevant for clinical intoxication. Complex I function was also inhibited by the formulation excipient Kolliphor® EL, indicating that drug-induced mitochondrial toxicity is not only induced by active pharmaceutical ingredients. <br/>Current treatment options for mitochondrial disease are limited. Succinate, a natural metabolite of the TCA cycle and a direct substrate of complex II of the respiratory chain that can increase mitochondrial function has shown to improve clinical symptoms in case studies. However, it has limited cell-permeability. We developed novel cell-permeable succinate prodrugs and characterized them using human peripheral blood cells. We demonstrated improved oxidative phosphorylation in different models of mitochondrial dysfunction. Methylene blue, which has previously been described to improve mitochondrial function in experimental models, failed to improve oxidative phosphorylation in human peripheral blood cells under the same conditions. <br/>To investigate the bioenergetic response of human peripheral blood cells relative to other, more metabolically active tissues we further evaluated mitochondrial inhibitors and pharmacological treatment strategies in muscle fibres and human-derived primary cells and cell lines. Changes in the respiratory profiles of human peripheral blood cells reflected changes in the respiratory profiles of other, more metabolically active human cells. <br/>In conclusion, we demonstrate that human peripheral blood cells are a suitable model for evaluation of potential drug-induced mitochondrial toxicity and pharmacological bypass strategies for the support of mitochondrial function. Human peripheral blood cells, in this context, reflect the metabolic responses of other, more metabolically active human cells. <br/>},
  author       = {Piel, Sarah},
  isbn         = {978-91-7619-593-2},
  keyword      = {mitochondria,drug-induced mitochondrial toxicity,mitochondrial disease,mitochondrial medicine,drug development,succinate,methylene blue,metformin,acetaminophen,paracetamol,Kolliphor® EL},
  language     = {eng},
  pages        = {77},
  publisher    = {Lund University, Faculty of Medicine},
  title        = {Mitochondrial medicine. New strategies to evaluate drug toxicity and develop pharmacological protection of the cell’s powerhouse.},
  year         = {2018},
}