RESUMEN
Arterial cord blood (CB) acid-base status and gas values, such as pH, PCO2, PO2, HCO3(-)and base excess, provide useful information on the fetal and neonatal condition. However, it remains unknown whether these values affect the radiosensitivity of fetal/neonatal hematopoiesis. The present study evaluated the relationship between arterial CB acid-base status, gas values, and the radiosensitivity of CB hematopoietic stem/progenitor cells (HSPCs). A total of 25 CB units were collected. The arterial CB acid-base status and gas values were measured within 30 min of delivery. The CD34(+)HSPCs obtained from CB were exposed to 2 Gy X-irradiation, and then assayed for colony-forming unit-granulocyte-macrophage, burst-forming unit-erythroid (BFU-E), and colony-forming unit-granulocyte erythroid, macrophage and megakaryocyte cells. Acid-base status and gas values for PCO2and HCO3(-)showed a statistically significant negative correlation with the surviving fraction of BFU-E. In addition, a significant positive correlation was observed between gestational age and PCO2. Moreover, the surviving fraction of BFU-E showed a significant negative correlation with gestational age. Thus, HSPCs obtained from CB with high PCO2/HCO3(-)levels were sensitive to X-irradiation, which suggests that the status of arterial PCO2/HCO3(-)influences the radiosensitivity of fetal/neonatal hematopoiesis, especially erythropoiesis.
Asunto(s)
Sangre Fetal/química , Células Madre Fetales/química , Células Madre Fetales/efectos de la radiación , Células Madre Hematopoyéticas/química , Células Madre Hematopoyéticas/efectos de la radiación , Tolerancia a Radiación/fisiología , Adulto , Análisis de los Gases de la Sangre , Dióxido de Carbono/sangre , Carbonatos/sangre , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Concentración de Iones de Hidrógeno , Recién Nacido , Placenta/irrigación sanguínea , Placenta/química , Embarazo , Adulto JovenRESUMEN
Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na(+)/Ca(2+) exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.
