Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments.

In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation.

Neuroprotective effect of mildronate and L-carnitine on the cognitive parameters of aged mice and mice with LPS-induced inflammation.

Mildronate (MD) is a cardioprotective drug used for the treatment of cardiovascular diseases by switching metabolism from the fatty acids to glucose oxidation. This effect is achieved via inhibition of synthesis of L-carnitine (L-car), a common supplement, which is used for improving of fatty acid metabolism. Both MD and L-car have similar neuroprotective effect.

Effect of l-carnitine and mildronate on the mitochondrial metabolism of heart and bacterial composition of the gut microbiome in ageing mice.

Ageing is the most significant risk factor for cardiovascular diseases. l-Carnitine has a potent cardioprotective effect and its synthesis decreases during ageing. At the same time, there are pharmaceuticals, such as mildronate which, on the contrary, are aimed at reducing the concentration of l-carnitine in the heart and lead to slows down the oxidation of fatty acids in mitochondria.

Mildronate protects heart mtDNA from oxidative stress toxicity induced by exhaustive physical exercise.

Exhaustive physical exercises are potentially dangerous for human's physical health and may lead to chronic heart disease. Therefore, individuals involved in such activity require effective and safe cardioprotectors. The goal of this research was to study Mildronate (a cardioprotective drug) effect on the level of oxidative stress markers in hearts of mice under conditions of exhausting physical exercise, such as forced swimming for 1 h per day for 7 days.

The effect of pesticides on the mtDNA integrity and bioenergetic properties of potato mitochondria.

Potato (Solanum tuberosum L.) is one of the most common crops in the world, and it is very susceptible to a wide range of pests such as insects and fungi. The use of pesticides often results in the suppression of seed germination and plant growth, in particular, due to their effect on the respiratory chain of mitochondria.

Long-term mildronate treatment increased Proteobacteria level in gut microbiome, and caused behavioral deviations and transcriptome change in liver, heart and brain of healthy mice.

Mildronate is a cardiac and neuroprotective drug that is widely used in some countries. By inhibiting carnitine biosynthesis, mildronate impairs the fatty acids transport into mitochondria, thereby decreasing the β-oxidation intensity. Since 2016, it has been prohibited by the World Anti-Doping Agency (WADA).

Methylene blue elicits non-genotoxic HO production and protects brain mitochondria from rotenone toxicity.

Methylene blue (MB) is a promising compound with a broad range of neuroprotective activity. One of therapeutic effects is the activation of mitochondrial biogenesis via Nrf2/ARE signaling cascade. Probably, mild oxidative stress caused by MB-depended H2O2 production is a trigger for activation of this signaling cascade.

Regulation of Mitochondrial Biogenesis as a Way for Active Longevity: Interaction Between the Nrf2 and PGC-1α Signaling Pathways.

Aging is a general degenerative process related to deterioration of cell functions in the entire organism. Mitochondria, which play a key role in energy homeostasis and metabolism of reactive oxygen species (ROS), require lifetime control and constant renewal. This explains recently peaked interest in the processes of mitochondrial biogenesis and mitophagy.

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria.

Methylene blue (MB) is a promising prodrug to treat mitochondrial dysfunctions that is currently being used in clinical trials for Alzheimer's disease. MB can penetrate the blood brain barrier, accumulating in brain mitochondria where it acts as a redox mediator in the electron transfer chain (ETC). Mitochondrial flavins are thought to reduce MB, which is then oxidized by cytochrome c, thereby bypassing inhibited Complex I of ETC.

β-Guanidinopropionic Acid Stimulates Brain Mitochondria Biogenesis and Alters Cognitive Behavior in Nondiseased Mid-Age Mice.

β-guanidinopropionic acid (β-GPA) has been used as a nutritional supplement for increasing physical strength and endurance with positive and predictable results. In muscles, it works as a nonadaptive stimulator of mitochondria biogenesis; it also increases lipid metabolism. There are data indicating that β-GPA can be also neuroprotective, but its mechanisms of action in the brain are less understood.

Simplified qPCR method for detecting excessive mtDNA damage induced by exogenous factors.

Damage to mitochondrial DNA (mtDNA) is a meaningful biomarker for evaluating genotoxicity of drugs and environmental toxins. Existing PCR methods utilize long mtDNA fragments (∼8-10kb), which complicates detecting exact sites of mtDNA damage. To identify the mtDNA regions most susceptible to damage, we have developed and validated a set of primers to amplify ∼2kb long fragments, while covering over 95% of mouse mtDNA.