Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup

INTRODUCTION: We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival. METHODS: A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints. RESULTS: Patients with the JT mtDNA haplogroup (n = 15) showed higher COXq/CSa ratio at day 4 (P = 0.04) and day 8 (P = 0.02) than those with other haplogroups (n = 81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio = 0.18; 95% confidence interval = 0.04 to 0.94; P = 0.04) and COXq/CSa ratio (odds ratio = 0.53; 95% confidence interval = 0.30 to 0.93; P = 0.03) were associated with 1-month survival after controlling for age and lactic acid levels. CONCLUSIONS: The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups

Caracterización del transportador de serotonina humano en células Caco-2: Estudio de los mecanismos de regulación fisiológica

El transportador de serotonina (SERT) realiza la recaptación de 5-HT al interior celular, regulando así su disponibilidad y unión a receptores. La 5-HT es producida en un 99% en el tracto gastrointestinal donde actúa como regulador. El objetivo de este trabajo ha sido caracterizar la expresión de SERT en la línea celular humana de tipo enterocitario Caco-2 y estudiar su regulación fisiológica y farmacológica y los mecanismos implicados. Los resultados obtenidos muestran que las células Caco-2 expresan endógenamente SERT, que es idéntico a la proteína cerebral humana y que se encuentra regulado por las vías intracelulares mediadas por AMPc y PKC. Asimismo, tanto el tratamiento de las células con fluoxetina como con 5-HT redujo la función de SERT, debido en el caso de la fluoxetina a una internalización de SERT, independiente de PKC y PKA, y en el caso de la 5-HT a una inhibición de tipo alostérico

Severe Septic Patients with Mitochondrial DNA Haplogroup JT Show Higher Survival Rates: A Prospective, Multicenter, Observational Study

<div><p>Objective</p><p>In a previous cohort study (n=96), we found an association between mitochondrial (mt) DNA haplogroup JT and increased survival of severe septic patients, after controlling for age and serum lactic acid levels. The aim of this research was to increase the predictive accuracy and to control for more confounder variables in a larger cohort (n=196) of severe septic patients, to confirm whether mtDNA haplogroup JT influences short and medium-term survival in these patients.</p> <p>Methods</p><p>We conducted a prospective, multicenter, observational study in six Spanish Intensive Care Units. We determined 30-day and 6-month survival and mtDNA haplogroup in this second cohort of 196 patients and in the global cohort (first and second cohorts combined) with 292 severe septic patients. Multiple logistic regression and Cox regression analyses were used to test for the association of mtDNA haplogroups JT with survival at 30-days and 6-months, controlling for age, sex, serum interleukin-6 levels and SOFA score.</p> <p>Results</p><p>Logistic and Cox regression analyses showed no differences in 30-day and 6-month survival between patients with mtDNA haplogroup JT and other haplogroups in the first cohort (n=96). In the second cohort (n=196), these analyses showed a trend to higher 30-day and 6-month survival in those with haplogroup JT. In the global cohort (n=292), logistic and Cox regression analyses showed higher 30-day and 6-month survival for haplogroup JT. There were no significant differences between J and T sub-haplogroups in 30-day and 6-month survival.</p> <p>Conclusions</p><p>The global cohort study (first and second cohorts combined), the largest to date reporting on mtDNA haplogroups in septic patients, confirmed that haplogroup JT patients showed increased 30-day and 6-month survival. This finding may be due to single nucleotide polymorphism defining the whole haplogroup JT and not separately for J or T sub-haplogroups.</p> </div

Cumulative proportion of patients' survival at 30 days and 6 months according to mtDNA haplogroup JT versus no JT.

<p>Cumulative proportion of patients' survival at 30 days and 6 months according to mtDNA haplogroup JT versus no JT.</p

Mitochondrial DNA haplogroups.

<p>Haplogroup nomenclature is denoted in bold. N* defines those N non HV, JT or U individuals. HV* defines HV non H individuals. H* defines H non H1, H2 or H5 individuals. U5a* defines U5a non U5a1 individuals. U1811* defines U1811 non U4 or UK individuals. U* defines U non U4, UK, U1811* or U5 individuals. J1* defines J1 non J1c individuals. A) Haplogrouping strategy. The three numbers in brackets indicate the number of patients from each haplogroup and the number of one- and six-months survivors. B) Phylogeny summarizing the relationship between different mtDNA haplogroups.</p