In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They ...participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control.
Mitochondrial oxidant damage, including damage to mitochondrial DNA (mtDNA) is a feature of both severe microbial infections and inflammation arising from sterile (non-infectious) sources such as ...tissue trauma. Damaged mitochondria release intact or oxidized fragments of mtDNA into the cytoplasm, which represent oxidant injury, and the fragments promote a spontaneous innate immune response, exemplifying a modern frontier of immunological research. MtDNA and mitochondrial-derived oxidants are central factors in activating at least three innate immune pathways involving the TLR9 (Toll-like receptor 9), the NLRP3 (NACHT, LRR and PYD domains-containing protein-3) inflammasome, and the cGAS (cyclic AMP-GMP synthase) pathway. The events that allow mtDNA to escape from damaged mitochondria and from damaged cells are incompletely known, but the presence of cytoplasmic mtDNA and cell-free mtDNA as immune regulators are important for understanding the cell's capacity for protecting mitochondrial quality control (MQC) and cell viability during inflammatory states.
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•Mitochondrial oxidant damage, including mitochondrial DNA (mtDNA) damage, accompanies microbial infections and sterile inflammation.•Fragmented mtDNA escaping from mitochondria activates three innate immune pathways.•Oxidation of mtDNA produces cell-free mtDNA, which may amplify inflammation.
Here, I discuss the role and impact of net-baryon number conservation in measurements of net-proton fluctuations in heavy-ion collisions. I show that the magnitude of the fluctuations is entirely ...determined by the strength of two particle correlations. At LHC and top RHIC energy, this implies the fluctuations are proportional to the integral of the balance function (BF), Bpp¯ of protons and antiprotons, while in the context of the RHIC beam energy scan (BES), one must also account for correlations of stopped protons. The integral of Bpp¯ measured in a 4π detector depends on the relative cross sections of processes yielding pp¯ and those balancing the proton baryon number via the production of other antibaryons. The accepted integral of Bpp¯ further depends on the shape and width of the BF relative to the width of the acceptance. The magnitude of the measured second-order cumulant of net-proton fluctuations thus has much less to do with QCD susceptibilities than with the creation/transport of baryons and antibaryons in heavy-ion collisions, and most particularly the impact of radial flow on the width of the BF. I thus advocate that net-proton fluctuations should be studied by means of differential BF measurements rather than with integral correlators. I also derive an expression of net-baryon fluctuations in terms of integrals of balance functions of identified baryon pairs and argue that measurements of such balance functions would enable a better understanding of the collision system expansion dynamics, the hadronization chemistry, and an experimental assessment of the strength of net-baryon fluctuations.
The Ecology of Sandy Shores provides the students and researchers with a one- volume resource for understanding the conservation and management of the sandy shore ecosystem. Covering all beach types, ...and addressing issues from the behavioral and physiological adaptations of the biota to exploring the effects of pollution and the impact of man's activities, this book should become the standard reference for those interested in Sandy Shore study, management and preservation. * More than 25% expanded from the previous edition * Three entirely new chapters: Energetics and Nutrient Cycling, Turtles and Terrestrial Vertebrates, and Benthic Macrofauna Populations * New sections on the interstitial environment, seagrasses, human impacts and coastal zone management * Examples drawn from virtually all parts of the world, considering all beach types from the most exposed to the most sheltered
The ubiquitous gas, carbon monoxide (CO), is of substantial biological importance, but apart from its affinity for reduced transition metals, particularly heme-iron, it is surprisingly nonreactive—as ...is the ferrous-carbonyl—in living systems. CO does form strong complexes with heme proteins for which molecular O
2 is the preferred ligand and to which are attributed diverse physiological, adaptive, and toxic effects. Lately, it has become apparent that both exogenous and endogenous CO produced by heme oxygenase engender a prooxidant milieu in aerobic mammalian cells which initiates signaling related to reactive oxygen species (ROS) generation. ROS signaling contingent on CO can be segregated by CO concentration-time effects on cellular function, by the location of heme proteins, e.g., mitochondrial or nonmitochondrial sites, or by specific oxidation-reduction (redox) reactions. The fundamental responses to CO involve overt physiological regulatory events, such as activation of redox-sensitive transcription factors or stress-activated kinases, which institute compensatory expression of antioxidant enzymes and other adaptations to oxidative stress. In contrast, responses originating from highly elevated or protracted CO exposures tend to be nonspecific, produce untoward biological oxidations, and interfere with homeostasis. This brief overview provides a conceptual framework for understanding CO biology in terms of this physiological-pathological hierarchy.
Nitric oxide (NO) exerts powerful physiological effects through guanylate cyclase (GC), a non-mitochondrial enzyme, and through the generation of protein cysteinyl-NO (SNO) adducts—a ...post-translational modification relevant to mitochondrial biology. A small number of SNO proteins, generated by various mechanisms, are characteristically found in mammalian mitochondria and influence the regulation of oxidative phosphorylation and other aspects of mitochondrial function.
The principles by which mitochondrial SNO proteins are formed and their actions, independently or collectively with NO binding to heme, iron–sulfur centers, or to glutathione (GSH) are reviewed on a molecular background of SNO-based signal transduction.
Mitochondrial SNO-proteins have been demonstrated to inhibit Complex I of the electron transport chain, to modulate mitochondrial reactive oxygen species (ROS) production, influence calcium-dependent opening of the mitochondrial permeability transition pore (MPTP), promote selective importation of mitochondrial protein, and stimulate mitochondrial fission. The ease of reversibility and the affirmation of regulated S-nitros(yl)ating and denitros(yl)ating enzymatic reactions support hypotheses that SNO regulates the mitochondrion through redox mechanisms. SNO modification of mitochondrial proteins, whether homeostatic or adaptive (physiological), or pathogenic, is an area of active investigation.
Mitochondrial SNO proteins are associated with mainly protective, bur some pathological effects; the former mainly in inflammatory and ischemia/reperfusion syndromes and the latter in neurodegenerative diseases. Experimentally, mitochondrial SNO delivery is also emerging as a potential new area of therapeutics. This article is part of a Special Issue entitled: Regulation of cellular processes by S-nitrosylation.
► Mitochondria contain both S-nitrosylating and denitrosylating mechanisms. ► Reversible protein S-nitrosylation supports redox regulation in mitochondria. ► SNO inhibits Complex I and steps in intermediary and fatty acid metabolism. ► SNO activates mitochondrial protein importation and regulates mitochondrial fission. ► Mitochondrial SNO proteins are involved in both cell protection and cell damage.
Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be ...simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. These processes participate in disease pathogenesis in all lung regions mainly when interference with mitochondrial quality control mechanisms impedes their roles in maintenance of lung health. Sharper identification of mitochondrial-driven signaling mechanisms in specific lung cell types will better refine our understanding of respiratory disease pathogenesis and lead to new diagnostic and therapeutic measures to support mitochondrial quality.
Sexual assault on college campuses is a public health issue. However varying research methodologies (e.g., different sexual assault definitions, measures, assessment timeframes) and low response ...rates hamper efforts to define the scope of the problem. To illuminate the complexity of campus sexual assault, we collected survey data from a large population-based random sample of undergraduate students from Columbia University and Barnard College in New York City, using evidence based methods to maximize response rates and sample representativeness, and behaviorally specific measures of sexual assault to accurately capture victimization rates. This paper focuses on student experiences of different types of sexual assault victimization, as well as sociodemographic, social, and risk environment correlates. Descriptive statistics, chi-square tests, and logistic regression were used to estimate prevalences and test associations. Since college entry, 22% of students reported experiencing at least one incident of sexual assault (defined as sexualized touching, attempted penetration oral, anal, vaginal, other, or completed penetration). Women and gender nonconforming students reported the highest rates (28% and 38%, respectively), although men also reported sexual assault (12.5%). Across types of assault and gender groups, incapacitation due to alcohol and drug use and/or other factors was the perpetration method reported most frequently (> 50%); physical force (particularly for completed penetration in women) and verbal coercion were also commonly reported. Factors associated with increased risk for sexual assault included non-heterosexual identity, difficulty paying for basic necessities, fraternity/sorority membership, participation in more casual sexual encounters ("hook ups") vs. exclusive/monogamous or no sexual relationships, binge drinking, and experiencing sexual assault before college. High rates of re-victimization during college were reported across gender groups. Our study is consistent with prevalence findings previously reported. Variation in types of assault and methods of perpetration experienced across gender groups highlight the need to develop prevention strategies tailored to specific risk groups.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tremendous biomedical advancements in HIV prevention and treatment have led to aspirational efforts to end the HIV epidemic. However, this goal will not be achieved without addressing the significant ...mental health and substance use problems among people living with HIV (PLWH) and people vulnerable to acquiring HIV. These problems exacerbate the many social and economic barriers to accessing adequate and sustained healthcare, and are among the most challenging barriers to achieving the end of the HIV epidemic. Rates of mental health problems are higher among both people vulnerable to acquiring HIV and PLWH, compared with the general population. Mental health impairments increase risk for HIV acquisition and for negative health outcomes among PLWH at each step in the HIV care continuum. We have the necessary screening tools and efficacious treatments to treat mental health problems among people living with and at risk for HIV. However, we need to prioritize mental health treatment with appropriate resources to address the current mental health screening and treatment gaps. Integration of mental health screening and care into all HIV testing and treatment settings would not only strengthen HIV prevention and care outcomes, but it would additionally improve global access to mental healthcare.
Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 ...protection mechanism by demonstrating that HO-1 activity in mouse heart stimulates the bigenomic mitochondrial biogenesis program via induction of NF-E2–related factor (Nrf)2 gene expression and nuclear translocation. Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3β, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis, which opposes apoptosis and necrosis caused by the cardio-toxic anthracycline chemotherapeutic agent, doxorubicin. In cardiac cells, Akt silencing exacerbates doxorubicin-induced apoptosis, and in vivo CO rescues wild-type but not Akt1 mice from doxorubicin cardiomyopathy. These findings consign HO-1/CO signaling through Nrf2 and Akt to the myocardial transcriptional program for mitochondrial biogenesis, provide a rationale for targeted mitochondrial CO therapy, and connect cardiac mitochondrial volume expansion with the inducible network of xenobiotic and antioxidant cellular defenses.
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