Biochemistry (Moscow)最新文献

The naked mole rat is considered a unique non-aging mammalian species and is widely used in laboratories to study the biology of longevity. Previously, our group was the first to describe a new fatal disease in the naked mole rat, termed “idiopathic cachexia.” A detailed study of pathological changes in the organs of affected animals, combined with the data on gene expression changes, allows us to interpret this disease as a highly specific variant of accelerated aging (progeroid syndrome or progeria) in these animals. Symptoms of the disease include cachexia, cataracts, lipofuscinosis, and appearance of amyloid bodies (corpora amylacea) in the brain, severe degeneration of cardiomyocytes, fatty degeneration, and generalized lipofuscinosis of the liver and kidneys, with signs of autophagy dysfunction in these organs. Further research is needed to elucidate the mechanism of this disease in animals with negligible aging, such as naked mole rats, which may provide insights into the mechanisms of aging and lifespan extension.

Being among the most metabolically active organs, brain and kidneys critically depend on efficient energy metabolism, which primarily relies on oxidative phosphorylation. Acute pathological conditions associated with a lack of metabolic substrates or their impaired utilization trigger signaling cascades that initiate cell death and lead to poorly reversible organ dysfunction. One of the therapeutic approaches to correct the energy deficit is administration of exogenous metabolites of the tricarboxylic acid cycle, such as succinate. In this study, we investigated the effects of exogenous succinate on astrocytes and renal epithelial cells under normal conditions and in serum deprivation-induced injury. Incubation with succinate increased the viability of both cell types under normal and pathological conditions, but a more pronounced cytoprotective effect was observed in renal cells. In injured renal epithelial cells, succinate increased mitochondrial membrane potential, a critical parameter for the maintenance of mitochondrial function and ATP generation. Comparison of respiration and oxidative phosphorylation parameters in astrocytes and renal epithelial cells in the presence of exogenous succinate revealed that epithelial cells exhibited a significantly higher respiratory control and lower proton leak compared to astrocytes, which correlated with the higher cytoprotective activity of succinate for kidney cells. Therefore, succinate showed a noticeable positive effect in the renal epithelium both under normal conditions and after serum deprivation; however, in astrocytes, its effect was less pronounced. This discrepancy might be related to a more efficient succinate utilization by the mitochondria in renal cells and intrinsic bioenergetic differences between astrocytes and epithelial cells. Despite the clinical use of succinate-containing drugs, the determination of optimal dosages and development of effective therapeutic regimens require further investigation. Our results demonstrate cell type-dependent differences in the efficacy of succinate, suggesting that its therapeutic potential may differ significantly depending on the organ-specific bioenergetic and metabolic properties.

Acquired drug resistance reduces the effectiveness of anticancer therapy and leads to cancer progression. Selective inhibition of anti-apoptotic proteins of the Bcl-2 family using BH3-mimetics is a promising treatment strategy for cancer patients. Recently, antagonists of the anti-apoptotic protein Mcl-1 have been actively studied in clinical trials. However, like other BH3-mimetics, they can lose their effectiveness due to the development of acquired resistance. We have found that cancer cells develop resistance to Mcl-1 inhibition through increased gene expression of other anti-apoptotic proteins, such as Bcl-2 or Bcl-xL, thereby becoming less Mcl-1-dependent. Alterations in cellular metabolism have also accompanied the development of this resistance. We have shown that combining the Mcl-1 antagonist S63845 with various anticancer compounds can overcome the resistance of malignant cells to its action.

Mitochondria play a central role in cell physiology, and in addition to performing their primary function as an energy source, they are involved in processes such as regulating intracellular calcium levels, generating reactive oxygen species, synthesizing many critical compounds, regulating apoptosis, and more. In this regard, maintaining them in a normal state is of great importance, ensuring their transport, intracellular distribution, timely biogenesis, and removal of damaged mitochondria from the cells. All of this is defined as cellular mitostasis, maintenance of which involves many cellular structures and, primarily, the cytoskeleton. This review summarizes the data on the role of one component of cytoskeleton, vimentin intermediate filaments, in these processes.

Activation of lipid peroxidation (LPO) in the mitochondria of rat H9c2 cardiomyoblasts and human fibroblasts by the cystine transport inhibitor erastin or glutathione peroxidase 4 inhibitor RSL3 was accompanied by rapid (18 h) accumulation of lipofuscin. The mitochondria-targeted antioxidant SkQ1 and redox mediator methylene blue, which prevents the formation of reactive oxygen species (ROS) in the mitochondrial respiratory chain complex I, blocked both mitochondrial LPO and lipofuscin accumulation. These data indicate that mitochondrial LPO serves as a driving force for the accelerated accumulation of lipofuscin in cells. Rapid (24 h) lipofuscin formation was observed in isolated heart mitochondria in the presence of iron ions. It was significantly accelerated by ROS generated in the respiratory chain complex I and blocked by SkQ1. The question of whether oxidized components of mitochondria serve as a source for lipofuscin formation in cells remains open. The results obtained suggest possible application of mitochondria-targeted compounds in the treatment of diseases associated with excessive lipofuscin accumulation.

I discuss the therapeutic potential of site-specific suppressors of the production of mitochondrial reactive oxygen species (ROS). The best-defined suppressors are S1QELs (targeting site I_Q in complex I) and S3QELs (targeting site III_Qo in complex III). They prevent ROS formation at source without affecting oxidative phosphorylation. The antidiabetic drug imeglimin and the anti-xerostomia and antischistosomal anethole dithiolethiones also have S1QEL activity, although how much this contributes to their clinical effects needs further study. Suppressing mitochondrial ROS production has therapeutic potential in many diseases. S1QELs and imeglimin improve glucose tolerance, insulin sensitivity, and decrease hepatic steatosis in models of diabetes and obesity. S1QELs and S3QELs protect against age-related cardiac decline, atrial fibrillation and hypertension. They reduce inflammatory cytokines and oxidative stress in macrophages and other cells. They inhibit cancer cell proliferation and tumour growth. In neurological diseases, S1QELs protect against noise-induced hearing loss. S1QELs protect against cardiac and hepatic damage during ischemia-reperfusion. S1QELs and S3QELs extend lifespan in model organisms and S3QELs protect against aging-related intestinal barrier dysfunction. Suppressors mitigate drug-induced toxicities (e.g., acetaminophen, cisplatin) and the effects of environmental stressors. In exocrinopathy, anethole dithiolethione alleviates symptoms of dry mouth and dry eye. Suppressors of mitochondrial ROS production show promise in treating a wide range of diseases driven by mitochondrial oxidative stress. Their mechanism-based specificity offers advantages over traditional antioxidants, with potential applications in metabolic, cardiovascular, inflammatory, neurological, and aging-related diseases. Further research is needed to fully explore their clinical efficacy.

The mitochondrial reticulum of skeletal muscles has been characterized in the 1970-80s. It has been suggested and then proven its role is delivering energy in a form of transmembrane potential on the mitochondrial inner membrane throughout the cell volume, followed by ATP synthesis by the mitochondrial ATP synthase. However, the data on the mitochondrial ultrastructure still remains a subject to criticism. To exclude the possibility of artifacts caused by the sample preparation for electron microscopy, we compared the structure of mitochondria in the ultrathin sections of muscle fibers observed by electron microscopy and in intact fibers stained with a membrane potential-dependent dye and visualized by confocal microscopy. The comparison was carried out for mice and naked mole rats known for their superior longevity. The obtained results confirmed previous findings regarding the structure of mitochondrial reticulum. A model suggesting the functioning of giant mitochondria as intracellular structures preventing tissue hypoxia was proposed.

Eukaryotic cells contain multiple mitochondrial DNA (mtDNA) molecules. Heteroplasmy is coexistence in the same cell of different mtDNA variants competing for cellular resources required for their replication. Here, we review documented cases of emergence and spread of selfish mtDNA (i.e., mtDNA that has a selective advantage in a cell but decreases cell fitness) in eukaryotic species, from humans to baker’s yeast. The review discusses hypothetical mechanisms enabling preferential proliferation of certain mtDNA variants in heteroplasmy. We propose that selfish mtDNAs have significantly influenced the evolution of eukaryotes and may be responsible for the emergence of uniparental inheritance and constraints on the mtDNA copy number in germline cells.

It has been proven that the preclinical period of the sporadic (>95% of cases) form of Alzheimer’s disease (AD) can last for decades, but the question of when the disease begins to develop and what contributes to it remains open. It is hypothesized that vulnerabilities to AD may be influenced by anatomical and functional brain parameters formed early in life. This is supported by our research on the senescence-accelerated OXYS rats – a unique model of AD. The delayed brain maturation observed in these rats is associated with insufficient glial support, a key regulator of neural network function, and the development of AD signs in the OXYS rats is preceded and accompanied by the mitochondrial dysfunction. This raises the question of whether the structural and functional features of mitochondria could influence brain maturation and thus determine predisposition to the later development of AD signs. In this study, we compared mitochondrial biogenesis, their trafficking, and structural state in the neuronal cell bodies, axonal and dendritic processes, as well as activity of the mitochondrial dynamics processes in the prefrontal cortex and hippocampus of OXYS and Wistar rats (control) during the period of brain maturation completion (from birth to 20 days of age). Changes in the number and ultrastructural parameters of mitochondria were compared with the parameters of dynamics processes, assessed by the frequency of mitochondria undergoing fusion or fission, the content of the key biogenesis protein PGC-1α, and proteins mediating mitochondrial dynamics (mitofusins Mfn1 and Mfn2, dynamin-1-like protein DRP1). In OXYS rats, deviations in formation of the mitochondrial apparatus in the early postnatal period were identified, which may contribute to the delayed brain maturation of these rats, promote mitochondrial dysfunction, reduce synaptic density, and ultimately lead to the neuronal death and development of the early neurodegenerative changes.

Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are prosthetic groups of many enzymes and can be attached to proteins either covalently or non-covalently. Covalent attachment of FMN to Thr or Ser residues via a phosphate group is catalyzed by the recently discovered enzyme flavin transferase. Among the enzymes containing phosphoester-linked FMN, the most widely represented ones are various microbial 2-enoate reductases catalyzing reduction of unsaturated carboxylic acids (fumaric, acrylic, cinnamic, urocanic, etc.). The review is focused on microbial 2-enoate reductases and discusses their classification by domain organization and intracellular location, structural basis of substrate specificity, catalytic mechanism, and function, as well as the significance and evolutionary origin of the covalent attachment of FMN as a prosthetic group.