Activity

Any theory suggesting an adaptive meaning for aging implicitly postulates the existence of specific mechanisms, genetically determined and modulated, causing progressive decline of an organism. According to the subtelomere-telomere theory, each telomere is covered by a hood formed in the first cell of an organism having a size preserved at each subsequent duplication. Telomere shortening, which is quantitatively different for each cell type according to the telomerase regulation, causes the hood to slide on the subtelomere repressing it by the telomeric position effect. At this point, the theory postulates existence of subtelomeric regulatory sequences, whose progressive transcriptional repression by the hood should cause cellular alterations that would be the likely determinant of aging manifestations. However, sequences with characteristics of these hypothetical sequences have already been described and documented. They are the [sub]TElomeric Repeat-containing RNA (TERRA) sequences. The repression of TERRA sequences causes progressively (i) down- or up-regulation of many other regulatory sequences; (ii) increase in the probability of activation of cell senescence program (blockage of the ability to replicate and very significant alterations of the cellular functions). When cell senescence program has not been triggered and the repression is partial, there is a partial alteration of the cellular functions that is easily reversible by telomerase activation. Location of the extremely important sequences in chromosomal parts that are most vulnerable to repression by the telomeric hood is evolutionarily unjustifiable if aging is not considered adaptive this location must be necessarily adaptive with the specific function of determining aging of the cell and consequently of the whole organism.Promising ideas and directions for further research into biology of aging are discussed using analysis of the age-related kinetics of organisms’ mortality. It is shown that the traditional evolutionary theory explaining aging by decreasing force of natural selection with age is not consistent with the data on age-related mortality kinetics. The hypothesis of multistage destruction of organisms with age, including the rate-limiting stage of transition to a state of non-specific vulnerability (“non-survivor”), is discussed. It is found that the effect of the COVID-19 coronavirus infection on mortality is not additive (as it was the case with the Spanish flu epidemic in 1918), but multiplicative (proportional) for ages over 65 years.In 1999 V. P. Skulachev proposed the term “mitoptosis” to refer to the programmed elimination of mitochondria in living cells. According to the initial thought, mitoptosis serves to protect cells from malfunctioning of the damaged mitochondria. At the same time, a new mechanism of the complete mitochondria elimination was found under the conditions of massive mitochondrial damage associated with oxidative stress. In this experimental model, mitochondrial cluster formation in the perinuclear region leads to the formation of “mitoptotic body” surrounded by a single-layer membrane and subsequent release of mitochondria from the cell. Later, it was found that mitoptosis plays an important role in various normal and pathological processes that are not necessarily associated with the mitochondrial damage. It was found that mitoptosis takes place during cell differentiation, self-maintenance of hematopoietic stem cells, metabolic remodelling, and elimination of the paternal mitochondria in organisms with the maternaortant both for understanding the processes of development and aging, and for designing therapeutic approaches for inflammatory, neurodegenerative and other diseases.Dr. Vladimir Skulachev was my mentor, and his pioneering work in the field of bioenergetics inspired the discoveries described in this review, written in the form of a personal account of events. Examining basic mechanisms of chemiosmotic coupling unexpectedly led us to transenvelope multidrug resistance pumps (MDR pumps) that severely limit development of novel antibiotics. One of the major advances of Skulachev and his group was the discovery of the mitochondrial membrane potential with the use of permeant cations such as TPP+, which served as electric probes. We describe our finding of their natural counterparts in plants, where they act as antimicrobials. read more The most challenging problems in antimicrobial drug discovery are antibiotic tolerance of chronic infections caused by dormant persister cells; antibiotic resistance, responsible for the current antimicrobial resistance crisis (AMR); and finding novel compounds acting against Gram-negative bacteria, protected by their powerful multidrug resistance pumps. Our study of persisters shows that these are rare cells formed by stochastic fluctuation in expression of Krebs cycle enzymes, leading to a drop in ATP, target shutdown, and antibiotic tolerance. Searching for compounds that can corrupt targets in the absence of ATP, we identified acyldepsipeptide (ADEP) that activates the ClpP protease, forcing cells to self-digest. Growing previously uncultured bacteria led us to teixobactin, a novel cell wall acting antibiotic. Teixobactin avoids efflux by targeting lipid II and lipid III, precursors of peptidoglycan and wall teichoic acid, located on the surface. The targets are immutable, and teixobactin is the first antibiotic with no detectable resistance. Our search for compounds acting against Gram-negative bacteria led to the discovery of darobactins, which also hit a surface target, the essential chaperone BamA.The effect of Zn2+ on the P-side of proteoliposomes containing membrane-incorporated Rhodobacter sphaeroides cytochrome c oxidase was investigated by the time-resolved electrometrics following a single electron injection into the enzyme prepared in the F state. The wild-type enzyme was examined along with the two mutants, N139D and D132N. All obtained data indicate that the primary effect of Zn2+ added from the P-side of the membrane is slowing of the pumped proton release from the proton loading site (PLS) to the bulk aqueous phase on the P-side of the membrane. The results strongly suggest the presence of two pathways by which the pumped proton can exit the protein from the PLS and of two separate binding sites for Zn2+. A model is presented to explain the influence of Zn2+ on the kinetics of membrane-potential generation by the wild-type COX, as well as by the N139D and D132N mutants.