Toxic effects of microbial phenolic acids on the functions of mitochondria.
Low-molecular-weight phenolic acids (PhAs) phenylacetate, phenyllactate, phenylpropionate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate are essentially the products of the degradation of aromatic amino acids and polyphenols by the intestinal microflora. In sepsis, the concentrations of some of these acids in the blood increase tens of times. Assuming that these compounds can cause the mitochondrial dysfunction in sepsis, we examined their effects on respiration, the induction of pore opening, and the production of reactive oxygen species (ROS) in mitochondria. It was found that phenylpropionate and phenylacetate produce a more toxic effect on mitochondria than the other phenolic acids. At concentrations 0.01-0.1 mM they decreased the rate of oxidation of NAD-dependent substrates and activated the Ca2+- and menadione-induced opening of the cyclosporin A-sensitive pore and the production of ROS. The disturbances caused by these PhAs are similar to those observed in mitochondria in sepsis, and hence the rise in their level may be one of the causes of mitochondrial dysfunctions. Phenyllactate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate inhibited the production of ROS and pore opening, acting as antioxidants. Thus, the ability of PhAs to affect the mitochondrial functions, as well as an increase in their concentrations in sepsis (the total concentration of these PhAs in the blood is close to 0.1 mM), suggests that PhAs can be directly involved in the development of mitochondrial failure.
Fedotcheva
N I
NI
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region, 142290 Russia. nfedotcheva@mail.ru
Kazakov
R E
RE
Kondrashova
M N
MN
Beloborodova
N V
NV
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects; D062385:Hydroxybenzoates / Q000737:chemistry / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship; D024483:Vitamin K 3 / Q000494:pharmacology
D062385:Hydroxybenzoates; D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; D024483:Vitamin K 3; D016572:Cyclosporine; C017616:phenolic acid