Mitochondrial dysfunction in drug and chemical toxicity: mechanism, target identification and therapeutic development

Project: Research

Project Details

Description

The current project aims to assess how the mitochondrial function in human peripheral blood cells is affected by exposure to marketed drugs and potential drug-candidates using high-resolution respirometry. The mitochondrial electron transport system (ETS), where most of the ATP normally is generated in the eukaryotic cell, consists of five protein-complexes. High-energy electrons are propagated through the ETS to pump protons over the inner mitochondrial membrane, thus establishing a proton gradient which is used to produce ATP. Four of the five mitochondrial complexes consist of proteins encoded from both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), and one complex (complex II) is encoded solely from nDNA. The function and structure of the different complexes of the ETS have been shown to be altered in many diseases were mitochondrial dysfunction is a part of the pathogenesis, causing energy deficiency and elevated production of reactive oxygen species (ROS) as well as defect regulation of the cell-signaling. Alterations to the proteins forming the complexes can either be acquired or inherited. Drug candidates under development are routinely being screened for mitochondrial toxicity in animal models using isolated animal-derived mitochondria. Even so, there are cases of withdrawal of marketed drugs due to mitochondrial toxicity. There are also known or hypothesized mitochondrial effects of several drugs in clinical praxis. As an example, a rare but potentially lethal adverse effect of Metformin, a common anti-diabetic drug, is lactic acidosis where mitochondrial dysfunction is implicated in the pathogenesis. Mitochondrial dysfunction is a field of research attracting increased attention. Drugs with a specific effect on the mitochondrial function could potentially be of significant clinical importance, since few causal treatments for mitochondrial dysfunction exist to date. Several possible drugs are proposed as being active on mitochondrial function such as idebenone, a synthetic analogue of ubiquinone, a protein of the ETS. At this time there is very scarce scientific evidence for any clinical advantage with idebenone. The dye Methylene blue is suggested as an alternative electron carrier, shuttling electrons directly to cytochrome c in the ETS, and thus bypassing up-stream ETS-defects. Methylene blue is in clinical use off-label in intensive care for severe cases of multiple organ failure of suspected mitochondrial genesis. New drug candidates for ETS-dysfunctions, synthetic substrates to the ETS and the Krebs cycle are under development at the company Neurovive Pharmaceutical AB. Several drugs are known to have effect on mitochondrial function, mainly from experiments with isolated, rodent-derived tissue mitochondria. We hypothesize that these effects, whether positive or negative, can be demonstrated in peripheral human blood cells.
AcronymMitoTox
StatusActive
Effective start/end date2013/04/01 → …

Collaborative partners

  • Lund University (lead)
  • The Children's Hospital of Philadelphia
  • Victor Babes University of Medicine and Pharmacy

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

UKÄ subject classification

  • Cell and Molecular Biology
  • Biomedical Laboratory Science/Technology
  • Pharmacology and Toxicology

Free keywords

  • mitochondria
  • ETS
  • drug toxicity
  • complex I
  • blood cells
  • high-resolution respirometry
  • mitochondrial disease