REVISIÓNDisfunción mitocondrial en sepsis, impacto y posible papel regulador del factor inducible por hipoxia (HIF-1α)Mitochondrial dysfunction during sepsis, impact and possible regulating role of hypoxia-inducible factor -1α
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Daño y disfunción mitocondrial tienen un papel en la sepsis
A pesar de todos los esfuerzos y recursos empleados en investigación, la mortalidad por sepsis continúa siendo elevada1, 2. Existe una relación directa entre el desarrollo del síndrome de disfunción de órganos (SDOM) y la mortalidad; así, pacientes sépticos con disfunción de 4 o más sistemas alcanzan mortalidades de un 65%2. Los mecanismos causantes del desarrollo de SDOM durante la sepsis permanecen aún en estudio3, 4, 5, pero parece claro que las alteraciones macrohemodinámicas y
Breve repaso de la función mitocondrial
La producción de ATP por parte de la célula depende de procesos metabólicos interconectados. Entre éstos figuran la glucólisis en el citoplasma, el ciclo de Krebs, la betaoxidación de ácidos grasos y la FO en la mitocondria (fig. 1).
Las mitocondrias son estructuras dinámicos en constante movimiento y fusión-división. Están constituidas por un sistema de doble membrana; ambas membranas son diferentes: la externa es altamente permeable (presencia de poros) y sólo contiene un 50% de proteínas,
Mecanismo de daño mitocondrial durante la sepsis
Estudios en animales así como estudios clínicos confirman que la presencia de daño celular (necrosis o apoptosis), a excepción del sistema inmunitario y el epitelio gastrointestinal, es de escasa cuantía en órganos sólidos durante la sepsis con falla multiorgánica. Hotchkiss et al8 estudiaron 20 pacientes que fallecieron a causa de sepsis con SDOM. Sólo encontraron una grave depleción de linfocitos y focos de apoptosis en células intestinales; el resto de los órganos presentaba mínimos signos
Posible papel regulador del factor inducible por hipoxia-1α
El HIF-1α es un factor de trascripción que actúa como un regulador clave en la homeostasis del oxígeno celular. Cientos de genes están regulados por HIF-1α28. El HIF-1α es un heterodímero que consiste en 2 subunidades (α y β). Ambas subunidades se expresan constitutivamente, pero la subunidad α es constantemente degradada en presencia de oxígeno. Para ser funcionales, las 2 subunidades de HIF-1 deben translocarse dentro del núcleo, dimerizarse y unirse a las secuencias de ADN conocidas como HRE
Inflamación y factor inducible por hipoxia-1α
Publicaciones recientes han demostrado que el HIF-1α puede estabilizarse y translocarse efectivamente al núcleo no sólo en condiciones de hipoxia tisular, sino también en condiciones de inflamación. Se ha demostrado que el HIF-1α se encuentra en concentraciones aumentadas en macrófagos y monocitos estimulados con lipopolisacáridos (LPS) bajo condiciones de normoxia37. Esta activación es funcionalmente relevante en cuanto se asocia a translocación al núcleo y unión en el ADN a los HRE37.
El LPS
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Melatonin's role in preventing toxin-related and sepsis-mediated hepatic damage: A review
2016, Pharmacological ResearchCitation Excerpt :This causes a reduction of ATP production due to a massive consumption of NADH and loss of enzyme function in the electron transport chain with peroxidation of cardiolipin and dissociation of cytochrome c [184,185]. Furthermore, proinflammatory cytokines generated during sepsis inhibit pyruvate dehydrogenase (PDH) expression, which reduces the substrates for oxidative phosphorylation, increasing ROS production with an additional drop in ATP production [186,187]. In addition, during sepsis, iNOS causes a significant elevation of NO· levels and reversibly inhibits complex IV of the electronic transport chain.
Tissue hypoxia during ischemic stroke: Adaptive clues from hypoxia-tolerant animal models
2015, Brain Research BulletinCitation Excerpt :An important question relevant to the current discussion is: “how does the manipulation of brain-proteins lead to protection of anoxic tolerant neurons?” Several lines of evidence indicate that parallel responses to energetic stress occur in cells during extreme hypoxia (Ge et al., 2010; Regueira et al., 2009; Rowley and Patel, 2013; Van Ginneken et al., 1999). An extremely balanced suppression of ATP demand and supply pathways is known to allow ATP levels to remain relatively constant, despite the fact that ATP turnover rates significantly decline (Brown and Squier, 1996; Hochachka, 1997; Hochachka et al., 1997), events coinciding with the downregulation of ATP demands of protein synthesis.
Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry
2015, Life SciencesCitation Excerpt :Then, poly (A) polymerase 1 (PARP-1) activation leads to a massive consumption of NAD+, decreasing its mitochondrial availability and reducing ATP production [38]. Later, proinflammatory cytokines generated during sepsis participate in the inhibition of pyruvate dehydrogenase (PDH), which reduces the substrates of OXPHOS, favoring an additional drop in ATP production [62,73]. In parallel, the induction of inducible nitric oxide synthase (iNOS) during sepsis results in a significant elevation of nitric oxide (NO•) levels.
Physiopathology of acute renal failure during sepsis
2011, Medicina IntensivaSerum concentrations of apoptosis-associated molecules in septic children with leukemia, neutropenia and fever
2017, International Journal of Hematology