Mitochondrial Dysfunction, Its Oxidative Stress-Induced Pathologies and Redox Bioregulation through Low-Dose Medical Ozone. A Systematic Review.

Renate Viebahn-Haensler  * Olga León Fernández  *

,Abstract

Our hypothesis that controlled ozone applications interfere into the redox balance of the biological organism (first published in 1998 with a preclinical trial on protecting the liver from CCl4 intoxication), has been verified over the last 2 decades in reactive oxygen species (ROS)-induced mitochondrial pathologies, such as rheumatoid arthritis, osteoarthritis, aging processes, diabetes-2 and in prevention of intoxications. Low-dose ozone acts as a redox bioregulator: The restoration of the disturbed redox balance is comprehensible in a number of preclinical and clinical studies by a remarkable increase of the antioxidant repair markers, here mainly shown as glutathione increase and a reduction in oxidative stress markers, mainly malondialdehyde. The mechanism of action is shown, relevant data are displayed, evaluated and comprehensively discussed: The repair side of the equilibrium increases by 21% up to 140% compared to the non-ozone treated groups and depending on the indication; the stress markers are simultaneously reduced, the redox system regains its balance.

Keywords: 

redox bioregulation; mitochondriopathies; low-dose ozone concept; ozone therapy; oxidative stress; antioxidant capacity

1. Introduction

As powerplant of the cells, the mitochondria have the essential function and task of maintaining cellular metabolic balance: the provision of energy in the form of ATP (adenosine triphosphate) play a central role as well as the production of reactive oxygen species (ROS) and their protective antioxidants in order to maintain the redox balance.

A small part of energy is provided by the citrate cycle, in which “all” substances ingested with food are catabolized: fats, carbohydrates and proteins. In the matrix space of the mitochondrion, the citrate cycle is in close proximity to the enzyme complexes of oxidative phosphorylation, to which the reduction equivalents formed here are made available for the exergonic redox reactions. The lion’s share of ATP comes from the respiratory chain and oxidative phosphorylation (36 mol ATP/mol glucose), which is extremely dependent on an optimal oxygen supply due to the high oxygen requirement.

Defects in mitochondrial energy metabolism can lead to a variety of diseases, be they of genetic origin, defects in mitochondrial DNA (mtDNA) or due to the normal aging process, or an accumulation of mitochondrial defects that result in increasing ATP deficiency and an increased production of reactive oxygen species (ROS).

We here focus on diseases that are causally linked to high oxidative stress, overproduction of superoxide radicals and corresponding secondary products, the ROS, and lead to a disturbance of the mitochondrial and cellular redox balance.

Mitochondrial ROS production.

Among the enzyme complexes, located in the inner mitochondrial membrane,

complex IV is mainly responsible for the formation of superoxide radicals ⋅O-O. In a healthy, energetically intact system, the heme centers of the cytochrome complexes (Fe 2+Fe 3+ + e ) transfer 2 electrons per mole of oxygen, so that O2 is formally reduced to O2- or H2O. In the case of mitochondrial insufficiency, the electron transfer is also deficient, oxygen reduction stops with a one-electron transfer, forming O-O, the superoxide radical [1]. Among the ROS subsequently formed, H2O2 and the ⋅OH radicals have a special function: Essential for the defense against infections, H2O2 also acts as an important signal and regulatory molecule [2,3].

The mitochondria’s own antioxidant system -superoxide dismutase-2 (SOD2), catalase (CAT), glutathione peroxidase (GSHox), glutathione reductase (GSred) and others – responsible for maintaining the mitochondrial redox balance, also deals with external oxidative stress, thus forming a cellular ROS sink to a certain extent [4]. If the antioxidant system is overwhelmed, the redox balance shifts in favor of an overproduction of reactive oxygen species, with ⋅OH radicals ultimately being responsible for the degenerative processes due to their non-specific and high reactivity. Enzymes are blocked, metabolic pathways are slowed down, e.g., the citrate cycle. ATP production decreases and the cell switches its survival strategy to other metabolic pathways, such as anaerobic glycolysis in the cytoplasm (Warburg effect), which leads to neoplastic cells [5,6]. Mitochondrial dysfunction can therefore induce a variety of diseases: Cancer, vascular inflammatory processes and associated diseases, age-related diseases or neurodegenerative processes, as summarized in Table 1.

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