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1.
Arch Biochem Biophys ; 705: 108900, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33964247

RESUMO

Mitochondria play an essential role in inflammatory processes such as sepsis or endotoxemia, contributing to organ-cellular redox metabolism, emerging as the energy hub of the cell, and as an important center of action of second messengers. In this work, we aimed to elucidate the energy state, redox balance, and mitochondrial remodeling status in cerebral cortex in an experimental model of endotoxemia. Female Sprague-Dawley rats were subjected to a single dose of LPS (ip 8 mg kg-1 body weight) for 6 h. State 3 O2 consumption was observed increased, ATP production and P/O ratio were observed decreased, probably indicating an inefficient oxidative phosphorylation process. O2- production and both systemic and tissue NO markers were observed increased in treated animals. The existence of nitrated proteins suggests an alteration in the local redox balance and possible harmful effects over energetic processes. Increases in PGC-1α and mtTFA expression, and in OPA-1 expression, suggest an increase in de novo formation of mitochondria and fusion of pre-existing mitochondria. The observed elongation of mitochondria correlates with the occurrence of mild mitochondrial dysfunction and increased levels of systemic NO. Our work presents novel results that contribute to unravel the mechanism by which the triad endotoxemia-redox homeostasis-energy management interact in the cerebral cortex, leading to propose a relevant mechanism for future developing therapeutics with the aim of preserving this organ from inflammatory and oxidative damage.


Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Endotoxemia/metabolismo , Endotoxemia/patologia , Metabolismo Energético , Dinâmica Mitocondrial , Animais , Feminino , Fosforilação Oxidativa , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
2.
Basic Res Cardiol ; 114(5): 38, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31428876

RESUMO

There is current awareness about the central role of mitochondrial dysfunction in the development of cardiac dysfunction in systemic inflammatory syndromes, especially in sepsis and endotoxemia. The aim of this work was to elucidate the mechanism that governs the link between the severity of the systemic inflammatory insult and mitochondrial function, analysing the consequences on heart function, particularly in cardiac contractile state. Female Sprague-Dawley rats were subjected to low-grade endotoxemia (i.p. injection LPS 0.5 mg kg-1 body weight) and severe endotoxemia (i.p. injection LPS 8 mg kg-1 body weight) for 6 h. Blood NO, as well as cardiac TNF-α and IL-1ß mRNA, were found increased as the severity of the endotoxemia increases. Cardiac relaxation was altered only in severe endotoxemia, although contractile and lusitropic reserves were found impaired in both treatments in response to work-overload. Cardiac ultrastructure showed disorientation of myofibrillar structure in both endotoxemia degrees, but mitochondrial swelling and cristae disruption were only observed in severe endotoxemia. Mitochondrial ATP production, O2 consumption and mitochondrial inner membrane potential decreases were related to blood NO levels and mitochondrial protein nitration, leading to diminished ATP availability and impairment of contractile state. Co-treatment with the NOS inhibitor L-NAME or the administration of the NO scavenger c-PTIO leads to the observation that mitochondrial bioenergetics status depends on the degree of the inflammatory insult mainly determined by blood NO levels. Unravelling the mechanisms involved in the onset of sepsis and endotoxemia improves the interpretation of the pathology, and provides new horizons for novel therapeutic targets.


Assuntos
Endotoxemia/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Inflamação/fisiopatologia , Mitocôndrias Cardíacas/fisiologia , Contração Miocárdica/fisiologia , Animais , Endotoxemia/complicações , Metabolismo Energético , Feminino , Insuficiência Cardíaca/etiologia , Mitocôndrias Cardíacas/patologia , Ratos , Ratos Sprague-Dawley
3.
Artigo em Inglês | MEDLINE | ID: mdl-38062738

RESUMO

Significance: The growing importance of mitochondria in the immune response and inflammation is multifaceted. Unraveling the different mechanisms by which mitochondria have a relevant role in the inflammatory response beyond the energy management of the process is necessary for improving our understanding of the host immune defense and the pathogenesis of various inflammatory diseases and syndromes. Critical Issues: Mitochondria are relevant in the immune response at different levels, including releasing activation molecules, changing its structure and function to accompany the immune response, and serving as a structural base for activating intermediates as NLRP3 inflammasome. In this scientific journey of dissecting mitochondrial mechanisms, new questions and interesting aspects arise, such as the involvement of mitochondrial-derived vesicles in the immune response with the putative role of preventing uncontrolled situations. Recent Advances: Researchers are continuously rethinking the role of mitochondria in acute and chronic inflammation and related disorders. As such, mitochondria have important roles as centrally positioned signaling hubs in regulating inflammatory and immune responses. In this review, we present the current understanding of mitochondrial mechanisms involved, beyond the largely known mitochondrial dysfunction, in the onset and development of inflammatory situations. Future Directions: Mitochondria emerge as an interesting and multifaceted platform for studying and developing pharmaceutical and therapeutic approaches. There are many ongoing studies aimed to describe the effects of specific mitochondrial targeted molecules and treatments to ameliorate the consequences of exacerbated inflammatory components of pathologies and syndromes, resulting in an open area of increasing research interest.

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