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Related Concept Videos

Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

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The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
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Drug Toxicity: Dose-Dependent Reactions01:24

Drug Toxicity: Dose-Dependent Reactions

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Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
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The Electron Transport Chain01:30

The Electron Transport Chain

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The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q...
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Mitochondrial Membranes01:45

Mitochondrial Membranes

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A single mitochondrion is a bean-shaped organelle enclosed by a double-membrane system. The outer membrane of mitochondria is smooth and contains many porins - the integral membrane transporters. Porins enable free diffusion of ions and small uncharged molecules through the outer mitochondrial membrane but limit the transport of molecules larger than 5000 Daltons. Further, the outer mitochondrial membrane forms a unique structure called membrane contact sites with other subcellular organelles,...
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Drug toxicity: Idiosyncratic Reactions01:16

Drug toxicity: Idiosyncratic Reactions

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Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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Related Experiment Video

Updated: Apr 12, 2026

Exploring Mitochondrial Energy Metabolism of Single 3D Microtissue Spheroids Using Extracellular Flux Analysis
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Multiple Targets for Drug-Induced Mitochondrial Toxicity.

Kendall B Wallace1

  • 1University of Minnesota Medical School, Duluth, MN 55812 USA. kwallace@d.umn.edu.

Current Medicinal Chemistry
|May 15, 2015
PubMed
Summary

Mitochondrial toxicity is a key factor in drug failure. This review explores secondary mechanisms beyond electron transport chain inhibition, highlighting broader impacts on drug discovery and development.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Mitochondrial toxicity is a significant cause of drug attrition and regulatory warnings.
  • Current research primarily focuses on direct inhibition of the mitochondrial electron transport chain (ETC) or oxidative phosphorylation uncoupling.
  • A broader spectrum of mitochondrial toxicities, including those affecting ETC assembly and substrate availability, remains underappreciated.

Purpose of the Study:

  • To elucidate the complex molecular events and biochemical pathways involved in maintaining mitochondrial integrity.
  • To expand the understanding of drug-induced mitochondrial toxicities beyond direct ETC inhibition.
  • To highlight secondary targets of drug toxicity that contribute to drug development failures.

Main Methods:

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  • Review of existing literature on mitochondrial toxicity mechanisms.
  • Analysis of biochemical pathways essential for mitochondrial function and homeostasis.
  • Case examples of drugs interfering with mitochondrial pathways.

    • Main Results:

    • Mitochondrial toxicity encompasses a wider range of mechanisms than previously emphasized.
    • Drugs can impair mitochondrial function by affecting ETC molecular regulation, assembly, or substrate supply.
    • These secondary toxicities represent a substantial, often overlooked, cause of drug failure.

    Conclusions:

    • Recognizing the broader scope of mitochondrial toxicities is crucial for improving drug discovery and development.
    • Targeting secondary mitochondrial pathways may reduce preclinical attrition and post-market drug withdrawals.
    • Further research into these complex mechanisms can enhance drug safety and efficacy.