Beta-Hydroxybutyrate Mitigates Sensorimotor and Cognitive Impairments in a Photothrombosis-Induced Ischemic Stroke in Mice.

The consequences of stroke include cognitive deficits and sensorimotor disturbances, which are largely related to mitochondrial impairments in the brain. In this work, we have shown that the mimetic of the ketogenic diet beta-hydroxybutyrate (ßHB) can improve neurological brain function in stroke. At 3 weeks after photothrombotic stroke, mice receiving ßHB with drinking water before and after surgery recovered faster in terms of sensorimotor functions assessed by the string test and static rods and cognitive functions assessed by the Morris water maze. At the same time, the ßHB-treated mice had lower expression of some markers of astrocyte activation and inflammation (Gfap, Il-1b, Tnf). We hypothesize that long-term administration of ßHB promotes the activation of the nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway, which leads to increased expression of antioxidant genes targeting mitochondria and genes involved in signaling pathways necessary for the maintenance of synaptic plasticity. ßHB partially maintained mitochondrial DNA (mtDNA) integrity during the first days after photothrombosis. However, in the following three weeks, the number of mtDNA damages increased in all experimental groups, which coincided with a decrease in Ogg1 expression, which plays an important role in mtDNA repair. Thus, we can assume that ßHB is not only an important metabolite that provides additional energy to brain tissue during recovery from stroke under conditions of mitochondrial damage but also an important signaling molecule that supports neuronal plasticity and reduces neuroinflammation.

Role of the Nrf2/ARE Pathway in the mtDNA Reparation.

Mitochondrial DNA (mtDNA) is located in the mitochondrial matrix, in close proximity to major sources of reactive oxygen species (ROS) in the cell. This makes mtDNA one of the most susceptible components to damage in the cell. The nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is an important cytoprotective mechanism. It is well-studied and described that Nrf2 can regulate the expression of mitochondrial-targeted antioxidant systems in the cell, indirectly protecting mtDNA from damage. However, the Nrf2/ARE pathway can also directly impact on the mtDNA repair processes. In this review, we summarize the existing data on the impact of Nrf2 on mtDNA repair, primarily base excision repair (BER), as it is considered the main repair pathway for the mitochondrial genome. We explore the crosstalk between Nrf2/ARE, BRCA1, and p53 signaling pathways in their involvement in maintaining mtDNA integrity. The role of other repair mechanisms in correcting mismatched bases and double-strand breaks is discussed. Additionally, the review addresses the role of Nrf2 in the repair of noncanonical bases, which contribute to an increased number of mutations in mtDNA and can contaminate the nucleotide pool.

The Ketogenic Diet but not Hydroxycitric Acid Keeps Brain Mitochondria Quality Control and mtDNA Integrity Under Focal Stroke.

Mitochondrial dysfunction in the ischemic brain is one of the hallmarks of stroke. Dietary interventions such as the ketogenic diet and hydroxycitric acid supplementation (a caloric restriction mimetic) may potentially protect neurons from mitochondrial damage induced by focal stroke in mice. We showed that in control mice, the ketogenic diet and the hydroxycitric acid did not impact significantly on the mtDNA integrity and expression of genes involved in the maintenance of mitochondrial quality control in the brain, liver, and kidney. The ketogenic diet changed the bacterial composition of the gut microbiome, which via the gut-brain axis may affect the increase in anxiety behavior and reduce mice mobility. The hydroxycitric acid causes mortality and suppresses mitochondrial biogenesis in the liver. Focal stroke modelling caused a significant decrease in the mtDNA copy number in both ipsilateral and contralateral brain cortex and increased the levels of mtDNA damage in the ipsilateral hemisphere. These alterations were accompanied by a decrease in the expression of some of the genes involved in maintaining mitochondrial quality control. The ketogenic diet consumption before stroke protects mtDNA in the ipsilateral cortex, probably via activation of the Nrf2 signaling. The hydroxycitric acid, on the contrary, increased stroke-induced injury. Thus, the ketogenic diet is the most preferred variant of dietetic intervention for stroke protection compared with the hydroxycitric acid supplementation. Our data confirm some reports about hydroxycitric acid toxicity, not only for the liver but also for the brain under stroke condition.

Dietary restriction modulates mitochondrial DNA damage and oxylipin profile in aged rats.

Age-related impairment of coordination of the processes of maintaining mitochondrial homeostasis is associated with a decrease in the functionality of cells and leads to degenerative processes. mtDNA can be a marker of oxidative stress and tissue degeneration. However, the mechanism of accumulation of age-related damage in mtDNA remains unclear. In the present study, we analyzed the accumulation of mtDNA damage in several organs of rats during aging and the possibility of reversing these alterations by dietary restriction (DR). We showed that mtDNA of brain compartments (with the exception of the cerebellum), along with kidney mtDNA, was the most susceptible to accumulation of age-related damage, whereas liver, testis, and lung were the least susceptible organs. DR prevented age-related accumulation of mtDNA damage in the cortex and led to its decrease in the lung and testis. Changes in mtDNA copy number and expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy were also tissue-specific. There was a tendency for an age-related decrease in the copy number of mtDNA in the striatum and its increase in the kidney. DR promoted an increase in the amount of mtDNA in the cerebellum and hippocampus. mtDNA damage may be associated not only with the metabolic activity of organs, but also with the lipid composition and activity of processes associated with the isoprostanes pathway of lipid peroxidation. The comparison of polyunsaturated fatty acids and oxylipin profiles in old rats showed that DR decreased the synthesis of arachidonic acid and its metabolites synthesized by the cyclooxygenase, cytochrome P450 monooxygenases and lipoxygenase metabolic pathways.

Nrf2/ARE Activators Improve Memory in Aged Mice via Maintaining of Mitochondrial Quality Control of Brain and the Modulation of Gut Microbiome.

Aging is one of the most serious factors for central nervous dysfunctions, which lead to cognitive impairment. New highly effective drugs are required to slow the development of cognitive dysfunction. This research studied the effect of dimethyl fumarate (DMF), methylene blue (MB), and resveratrol (RSV) on the cognitive functions of 15-month-old mice and their relationship to the maintenance of mitochondrial quality control in the brain and the bacterial composition of the gut microbiome. We have shown that studied compounds enhance mitochondrial biogenesis, mitophagy, and antioxidant defense in the hippocampus of 15-month-old mice via Nrf2/ARE pathway activation, which reduces the degree of oxidative damage to mtDNA. It is manifested in the improvement of short-term and long-term memory. We have also shown that memory improvement correlates with levels of Roseburia, Oscillibacter, ChristensenellaceaeR-7, Negativibacillus, and Faecalibaculum genera of bacteria. At the same time, long-term treatment by MB induced a decrease in gut microbiome diversity, but the other markers of dysbiosis were not observed. Thus, Nrf2/ARE activators have an impact on mitochondrial quality control and are associated with a positive change in the composition of the gut microbiome, which together lead to an improvement in memory in aged mice.

Gene- and Disease-Based Expansion of the Knowledge on Inborn Errors of Immunity.

The recent report of the International Union of Immunological Societies (IUIS) has provided the categorized list of 354 inborn errors of immunity. We performed a systematic analysis of genes and diseases from the IUIS report with the use of the OMIM, ORPHANET, and HPO resources. To measure phenotypic similarity we applied the Jaccard/Tanimoto (J/T) coefficient for HPO terms and top-level categories. Low J/T coefficients for HPO terms for OMIM or ORPHANET disease pairs associated with the same genes indicated high pleiotropy of these genes. Gene ORGANizer enrichment analysis demonstrated that gene sets related to HPO top-level categories were most often enriched in immune, lymphatic, and corresponding body systems (for example, genes from the category "Cardiovascular" were enriched in cardiovascular system). We presented available data on frequent and very frequent clinical signs and symptoms in inborn errors of immunity. With the use of DisGeNET, we generated the list of 25 IUIS/OMIM diseases with two or more relatively high score gene-disease associations, found for unrelated genes and/or for clusters of genes coding for interacting proteins. Our study showed the enrichment of gene sets related to several IUIS categories with neoplastic and autoimmune diseases from the GWAS Catalog and reported individual genes with phenotypic overlap between inborn errors of immunity and GWAS diseases/traits. We concluded that genetic background may play a role in phenotypic diversity of inborn errors of immunity.