Mitochondriopathy and Glycogen Storage Diseases (GSD) and Genetic Markers

By SWA

Drug-Induced Mitochondrial Damage: Mechanisms, Medications, and Clinical Implications

Introduction

Mitochondria, often referred to as the “powerhouses of the cell,” are essential organelles responsible for producing ATP (adenosine triphosphate) through oxidative phosphorylation. Beyond energy production, they play vital roles in cellular metabolism, calcium homeostasis, apoptosis, and the generation of reactive oxygen species (ROS). Because of their central role in cell health, mitochondrial dysfunction can contribute to a wide range of diseases, including neurodegenerative disorders, myopathies, metabolic syndromes, and even cancer.

One underrecognized source of mitochondrial dysfunction is drug-induced toxicity. Many commonly prescribed and over-the-counter medications can impair mitochondrial function either directly or indirectly. Understanding the mechanisms and risks is crucial for healthcare professionals and patients alike.

Mechanisms of Mitochondrial Toxicity

Drugs may impair mitochondria through several pathways:

  1. Inhibition of the Electron Transport Chain (ETC)
    Drugs can block complexes I–V of the mitochondrial respiratory chain, reducing ATP production and increasing ROS formation.

  2. Inhibition of Mitochondrial DNA Replication or Transcription
    Some drugs interfere with mitochondrial DNA (mtDNA) polymerases or transcription machinery, leading to mtDNA depletion or mutation.

  3. Impairment of Fatty Acid Oxidation
    Drugs may inhibit enzymes involved in β-oxidation, leading to energy deficiency, especially in liver and muscle tissues.

  4. Uncoupling Oxidative Phosphorylation
    Some agents disrupt the proton gradient across the mitochondrial membrane, reducing ATP generation efficiency.

  5. Induction of Mitochondrial Permeability Transition
    Drugs may trigger the opening of mitochondrial permeability transition pores (mPTPs), initiating apoptosis or necrosis.

Drugs Known to Cause Mitochondrial Damage

1. Antiretroviral Drugs (e.g., NRTIs)

  • Examples: Zidovudine (AZT), Stavudine (d4T), Didanosine (ddI)

  • Mechanism: Inhibit mitochondrial DNA polymerase-γ, leading to mtDNA depletion.

  • Clinical Manifestations: Myopathy, lactic acidosis, peripheral neuropathy, hepatic steatosis.

2. Statins

  • Examples: Simvastatin, Atorvastatin

  • Mechanism: Inhibit HMG-CoA reductase, lowering coenzyme Q10 (ubiquinone), which is crucial for electron transport.

  • Clinical Manifestations: Myalgia, muscle weakness, fatigue.

3. Antibiotics

  • Aminoglycosides (e.g., Gentamicin):

    • Cause oxidative stress and affect mitochondrial protein synthesis.

  • Tetracyclines (e.g., Doxycycline):

    • Inhibit mitochondrial ribosomes due to similarities with bacterial ribosomes.

  • Chloramphenicol:

    • Potent inhibitor of mitochondrial protein synthesis, particularly harmful in infants.

4. Chemotherapy Agents

  • Doxorubicin:

    • Causes oxidative stress and mtDNA damage, especially in cardiac cells.

  • Cisplatin:

    • Induces mitochondrial apoptosis via ROS and mitochondrial DNA damage.

  • Valproic Acid:

    • Impairs β-oxidation and carnitine metabolism.

5. Psychiatric and Neurological Drugs

  • Valproate:

    • Inhibits fatty acid metabolism and can cause hepatotoxicity in susceptible individuals (especially those with POLG mutations).

  • Antipsychotics (e.g., Risperidone, Olanzapine):

    • Can alter mitochondrial dynamics and induce oxidative stress.

  • SSRIs and TCAs:

    • Some evidence suggests interference with mitochondrial respiration and membrane potential.

6. Analgesics and Anesthetics

  • Acetaminophen:

    • In overdose, causes mitochondrial oxidative stress and hepatotoxicity.

  • Propofol:

    • High doses or prolonged infusion can lead to Propofol Infusion Syndrome, involving mitochondrial failure in muscle and heart tissue.

Genetic Susceptibility and Mitochondrial Toxicity

Genetic variants, particularly in POLG (mitochondrial DNA polymerase), TFAM (transcription factor A, mitochondrial), and various mtDNA haplogroups, can increase susceptibility to drug-induced mitochondrial damage. For example, individuals with POLG mutations are at significantly increased risk of liver failure when treated with valproic acid.

Clinical Implications

  1. Diagnosis: Mitochondrial toxicity should be considered when patients present with:

    • New-onset muscle weakness

    • Fatigue

    • Hepatic dysfunction

    • Neurological symptoms

    • Lactic acidosis without clear cause

  2. Monitoring:

    • Monitor liver enzymes, lactate levels, and creatine kinase in high-risk drugs or patients.

    • Periodic assessment of coenzyme Q10 or mitochondrial function tests (e.g., muscle biopsy, respirometry) may be indicated in complex cases.

  3. Management:

    • Discontinuation or dose reduction of the offending drug

    • Supportive treatment: antioxidants (e.g., coenzyme Q10, alpha-lipoic acid), carnitine supplementation

    • Avoidance of known mitochondrial toxins in patients with confirmed or suspected mitochondrial disorders

  4. Genetic Testing:

    • In patients with unexplained drug toxicity, testing for mtDNA mutations or nuclear gene variants (e.g., POLG) may guide safer prescribing.

Conclusion

While mitochondrial toxicity is not commonly the first consideration in adverse drug reactions, it plays a significant role in various clinical syndromes. Awareness of high-risk drugs, mechanisms of mitochondrial impairment, and patient-specific factors can guide safer and more effective pharmacological strategies. As personalized medicine evolves, integrating mitochondrial health into drug safety assessments will become increasingly important.

Reference: 

Glycogen Storage Disease (GSD):
https://my.clevelandclinic.org/health/diseases/15553-glycogen-storage-disease-gsd

Glycogen Storage Disease: https://www.hopkinsmedicine.org/health/conditions-and-diseases/glycogen-storage-disease#:~:text=disease%20in%20children-,Glycogen%20storage%20disease%20(GSD)%20is%20a%20rare%20condition%20that%20changes,show%20any%20signs%20of%20GSD.


© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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