Mitochondrial Dysfunction, Oxidative Stress and Low-Dose Ozone as a Redox Bioregulator: A Systematic Review (2024)

Background

Mitochondria produce most of a cell's energy, and they also produce reactive oxygen species (ROS) as a by-product. In health, the cell's own antioxidant systems - glutathione, superoxide dismutase, catalase and their partner enzymes - keep those species in check. When ROS production outruns the defences, the result is oxidative stress, and the mitochondria themselves are among the first structures damaged. That cycle sits behind a long list of conditions: chronic inflammatory disease, diabetes and its complications, ageing, and the tissue injury that follows a blocked blood supply being restored.

Dr Renate Viebahn-Haensler, of the German Medical Society for the Use of Ozone in Prevention and Therapy, and Professor Olga Sonia León Fernández of the University of Havana have each spent decades studying how ozone acts on this balance. Here they set out to review the published evidence systematically.

Study design

This is a systematic review of peer-reviewed preclinical and clinical studies of low-dose systemic ozone in ROS-driven mitochondrial pathologies. The authors included only studies that measured redox parameters - antioxidant enzymes, glutathione, or markers of oxidative damage - before and after treatment. Studies that reported clinical outcomes without measuring these parameters were left out.

The conditions covered were rheumatoid arthritis and knee osteoarthritis (human trials), type 2 diabetes and diabetic foot (animal and human), ageing (animal and human), cisplatin chemotherapy toxicity (animal), and ischaemia-reperfusion injury (animal). Human studies were mostly of modest size, typically 20 to 60 people per group. Systemic ozone in the reviewed studies was given by rectal insufflation or autohaemotherapy at the low concentrations used in standard systemic protocols.

The review received no external funding, and the authors declare no conflicts of interest.

Findings

The mechanism the authors describe. Ozone itself is gone within seconds of meeting body fluids. What acts is its reaction product - short-lived "ozone peroxides" - which nudge the glutathione balance and trigger a signalling cascade: the transcription factor Nrf2 moves into the cell nucleus and switches on the genes for the antioxidant enzymes. Because these peroxides are short-lived, unlike the long-chain lipid peroxides of uncontrolled oxidation, the authors argue they signal without adding to the oxidative burden.

The repair side rises. Across the included studies, glutathione rose by 21 to 140 per cent compared with untreated groups, depending on the condition. Superoxide dismutase rose by up to 94 per cent in rheumatoid arthritis. Catalase increases were documented across studies.

The damage side falls. Malondialdehyde, a marker of lipid oxidation, fell by 24 to 50 per cent in most conditions. In the human ageing study, glutathione was 48 per cent higher and malondialdehyde 43 per cent lower than in controls after four weeks. In osteoarthritis, glutathione rose 85 to 89 per cent and the inflammatory cytokine IL-6 fell 26 per cent. In rheumatoid arthritis, glutathione rose 25 to 41 per cent and malondialdehyde fell 31 to 50 per cent.

Mitochondria kept their structure. In animal models of ischaemia-reperfusion injury, electron microscopy showed "extensive integrity of the mitochondria" after ozone preconditioning, where untreated controls showed structural damage and lipid droplets. In cisplatin-treated animals, ozone pre-treatment kept kidney glutathione within the normal range.

Not every condition responded alike. Osteoarthritis showed a less consistent redox response than rheumatoid arthritis, which the authors read as disease-specific variability.

What the authors concluded

The authors conclude that "the repair side of the equilibrium increases by 21 up to 140% compared with the non-ozone-treated groups, and the stress markers are simultaneously reduced". They describe low-dose ozone as a redox bioregulator that restores the balance in ROS-induced mitochondrial pathologies, and propose that this is "the basic mechanism of action of systemic ozone applications", covering chronic inflammatory disease, silent inflammation and conditions associated with high oxidative stress. They state that larger clinical trials are "urgently needed" for indications beyond pain management.

Limitations of this study

The authors note that excluding studies without redox measurements narrows the evidence base; that the concentration-dependence of the Nrf2 response needs further investigation; and that responses varied between conditions. The human studies are small.

Two points for readers. This review measures the body's chemistry, not how people feel or function - it explains a mechanism rather than proving a clinical benefit for any one condition. And it does not cover long COVID, chronic fatigue or fibromyalgia; where those conditions show oxidative stress and mitochondrial dysfunction, any link to this review is an inference, not a tested result.

Related reading

Mechanisms of Action Involved in Ozone Therapy: Is Healing Induced via a Mild Oxidative Stress?

The Role of Nrf2 in the Antioxidant Response to Medical Ozone

Rectal Ozone Added to Methotrexate in Rheumatoid Arthritis: A 60-Patient Randomised Study - one of the human trials in this review, by the same Havana group.

Therapeutic Efficacy of Ozone in Patients with Diabetic Foot - another of the included human trials.

How Ozone Therapy Works: The Science in Plain Words

Viebahn-Haensler R, León Fernández OS. Mitochondrial Dysfunction, Its Oxidative Stress-Induced Pathologies and Redox Bioregulation through Low-Dose Medical Ozone: A Systematic Review. Molecules. 2024;29(12):2738. Published 8 June 2024. doi:10.3390/molecules29122738