Influence of Microbial Metabolites on the Nonspecific Permeability of Mitochondrial Membranes under Conditions of Acidosis and Loading with Calcium and Iron Ions.

Nadezhda Fedotcheva,Natalia Beloborodova,Andrei Olenin

doi:10.3390/biomedicines9050558

Nadezhda Fedotcheva, Natalia Beloborodova + Show 1 more

Open Access

https://doi.org/10.3390/biomedicines9050558

Copy DOI

Abstract

Mitochondrial dysfunction is currently considered one of the main causes of multiple organ failure in chronic inflammation and sepsis. The participation of microbial metabolites in disorders of bioenergetic processes in mitochondria has been revealed, but their influence on the mitochondrial membrane permeability has not yet been studied. We tested the influence of various groups of microbial metabolites, including indolic and phenolic acids, trimethylamine-N-oxide (TMAO) and acetyl phosphate (AcP), on the nonspecific permeability of mitochondrial membranes under conditions of acidosis, imbalance of calcium ions and excess free iron, which are inherent in sepsis. Changes in the parameters of the calcium-induced opening of the mitochondrial permeability transition pore (MPTP) and iron-activated swelling of rat liver mitochondria were evaluated. The most active metabolites were indole-3-carboxylic acid (ICA) and benzoic acid (BA), which activated MPTP opening and swelling under all conditions. AcP showed the opposite effect on the induction of MPTP opening, increasing the threshold concentration of calcium by 1.5 times, while TMAO activated swelling only under acidification. All the redox-dependent effects of metabolites were suppressed by the lipid radical scavenger butyl-hydroxytoluene (BHT), which indicates the participation of these microbial metabolites in the activation of membrane lipid peroxidation. Thus, microbial metabolites can directly affect the nonspecific permeability of mitochondrial membranes, if conditions of acidosis, an imbalance of calcium ions and an excess of free iron are created in the pathological state.

Highlights

Introduction published maps and institutional affilMitochondria play a key role in cellular metabolism, survival and homeostasis by participating in energy production, intracellular signaling and cell death regulation.Dysfunction of mitochondria has been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disorders, inflammation and other.Mitochondrial dysfunction is of special interest in the case of the development of a lifethreatening pathological process associated with an inadequate response of the body to excessive bacterial load, which is called “sepsis”
We investigated the influence of microbial metabolites of various groups, including indolic and phenolic acids, TMAO and acetyl phosphate (AcP), on the nonspecific permeability of mitochondrial membranes activated by calcium and iron ions as well as by acidification of medium
mitochondrial permeability transition pore (MPTP) opening was accompanied by a decrease in the membrane potential and a release of calcium ions from mitochondria, as shown in the experiment with the addition of indole-3-carboxylic acid (ICA) (Figure 1b)

Summary

Introduction

Introduction published maps and institutional affilMitochondria play a key role in cellular metabolism, survival and homeostasis by participating in energy production, intracellular signaling and cell death regulation.Dysfunction of mitochondria has been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disorders, inflammation and other.Mitochondrial dysfunction is of special interest in the case of the development of a lifethreatening pathological process associated with an inadequate response of the body to excessive bacterial load, which is called “sepsis”. Mitochondria play a key role in cellular metabolism, survival and homeostasis by participating in energy production, intracellular signaling and cell death regulation. Dysfunction of mitochondria has been associated with several pathologies, including neurodegenerative diseases, cancer, cardiovascular disorders, inflammation and other. Mitochondrial dysfunction is of special interest in the case of the development of a lifethreatening pathological process associated with an inadequate response of the body to excessive bacterial load, which is called “sepsis”. The progression of multiple organ failure in sepsis is inevitably accompanied by a high frequency of deaths; at the same time, studies have confirmed the important role of mitochondrial disorders in the violation of the function of organs and systems in sepsis, which remains a keen interest in the search for mechanisms of this process [1,2]. Bioenergetic failure, up to metabolic reprogramming, decreased activity of some mitochondrial enzymes and respiratory chain complexes are iations.

Methods

Results

Discussion

Conclusion