Manganese Toxicity, Mitochondrial Dysfunction, and the Potential Therapeutic Value of p‐Aminosalicylic Acid, Taurine and Carnosine

Abstract

Manganese (Mn) is an essential metal but toxic exposure causes accumulation in human brain and extrapyramidal symptoms called manganism, which is clinically similar to Parkinson's disease. Mn disrupts dopamine (DA) neurotransmission. The neurotoxic mechanism of Mn is not fully understood. Currently there are no effective treatments. Proposed mechanisms of Mn toxicity include elevated oxidative stress and mitochondrial (MITO) dysfunction. Using the Eastern Oyster, Crassostrea virginica, as a model to study Mn toxicity on the animal and its DA system, we previously showed Mn interferes with DA's cilio-inhibitory effect in oyster gill cells, and reduces gill MITO O2 consumption and MITO membrane potential. We also showed the toxic effects were reduced or prevented by p-aminosalicylic acid (PAS), taurine (TAU) and carnosine (CAR). We hypothesize PAS, TAU and CAR are protective against Mn induced MITO dysfunction in other animals including mammals. To study this we analyzed published data of other labs to qualify and quantify the MITO dysfunction reported in animals exposed to toxic levels of Mn and determine if PAS, TAU or CAR were effective in alleviating the damage. We found in invertebrates and vertebrates, including mice and rats, Mn caused MITO dysfunction. The damage included: inhibition of MITO electron transport chain, decreased O2 consumption, oxidative phosphorylation interference of ATP synthase, decreased MITO dehydrogenases and glutathione peroxidase, decreased MITO membrane potential, altered MITO permeability and disruption of MITO Ca2+ homeostasis with resulting MITO swelling. While less data was available on the use of PAS, TAU and CAR against Mn induced MITO dysfunction, there were significant number of reports these agents showed various degrees of efficacy against Mn toxicity in other animals. PAS, which generally is thought to work by chelating Mn, was reported to reduce neuro-inflammation, oxidative stress and intracellular reactive O2 species (ROS) generation. It also prevented Mn induced loss of MITO membrane potential and reduced O2 consumption. TAU preserved MITO ATP as well as membrane potential, prevented swelling and increased MITO dehydrogenases activity. CAR was reported to regulate MITO matrix pH, preserve membrane potential, increase respiratory chain complexes activity and enhance MITO energy production. These findings concur with our previous work on Mn toxicity in oyster mitochondria, and support our hypothesis PAS, TAU and CAR show protective actions against Mn induced MITO dysfunction in other animals. They further support our use of C. virginica as a model animal to study the mechanisms underlying Mn toxicity and generate new information to assist in the design of future experiments, the results of which should be of interest to those exploring possible agents in the prevention or therapeutic treatment of manganism.