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首页> 外文期刊>American Journal of Physiology >Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase.
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Abnormal mitochondrial bioenergetics and heart rate dysfunction in mice lacking very-long-chain acyl-CoA dehydrogenase.

机译：缺乏非常长链的酰基辅酶A脱氢酶的小鼠的线粒体生物能异常和心律失常。

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Mitochondrial very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is associated with severe hypoglycemia, cardiac dysfunction, and sudden death in neonates and children. Sudden death is common, but the underlying mechanisms are not fully understood. We report on a mouse model of VLCAD deficiency with a phenotype induced by the stresses of fasting and cold, which includes hypoglycemia, hypothermia, and severe bradycardia. The administration of glucose did not rescue the mice under stress conditions, but rewarming alone consistently led to heart rate recovery. Brown adipose tissue (BAT) from the VLCAD-/- mice showed elevated levels of the uncoupling protein isoforms and peroxisome proliferator-activated receptor-alpha. Biochemical assessment of the VLCAD(/- mice BAT showed increased oxygen consumption, attributed to uncoupled respiration in the absence of stress. ADP-stimulated respiration was 23.05 (SD 4.17) and 68.24 (SD 6.3) nmol O2.min(-1).mg mitochondrial protein(-1) for VLCAD+/+ and VLCAD-/- mice, respectively (P < 0.001), and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated respiration was 35.9 (SD 3.6) and 49.3 (SD 9) nmol O2.min(-1).mg mitochondrial protein(-1) for VLCAD+/+ and VLCAD-/- mice, respectively (P < 0.20), but these rates were insufficient to protect them in the cold. We conclude that disturbed mitochondrial bioenergetics in BAT is a critical contributing factor for the cold sensitivity in VLCAD deficiency. Our observations provide insights into the possible mechanisms of stress-induced death in human newborns with abnormal fat metabolism and elucidate targeting of specific substrates for particular metabolic needs.
机译：线粒体超长链酰基辅酶A脱氢酶（VLCAD）缺乏与新生儿和儿童中的严重低血糖症，心脏功能障碍和猝死有关。猝死是很普遍的现象，但其潜在机制尚未得到充分了解。我们报告了一种小鼠的VLCAD缺乏症模型，其表型由禁食和感冒（包括低血糖，体温过低和严重的心动过缓）引起。葡萄糖的施用不能在压力条件下拯救小鼠，但是单独的变暖始终导致心率恢复。 VLCAD-/-小鼠的棕色脂肪组织（BAT）显示出较高水平的解偶联蛋白同工型和过氧化物酶体增殖物激活的受体α。对VLCAD（/-小鼠BAT）的生化评估显示，氧气消耗增加，这归因于在没有压力的情况下无呼吸作用，ADP刺激的呼吸作用分别为23.05（SD 4.17）和68.24（SD 6.3）nmol O2.min（-1）。分别用于VLCAD + / +和VLCAD-/-小鼠的线粒体蛋白（-1）（P <0.001），以及由氰化物对三氟甲氧基苯基hydr刺激的呼吸作用为35.9（SD 3.6）和49.3（SD 9）nmol O2.min （-1）.VLCAD + / +和VLCAD-/-小鼠的线粒体蛋白（-1）分别（P <0.20），但这些比率不足以在寒冷中保护它们。我们得出结论，BAT中线粒体的生物能受到干扰。是导致VLCAD缺乏症对寒冷敏感的关键因素，我们的观察结果为人们揭示了脂肪代谢异常的新生儿应激性死亡的可能机制，并阐明了针对特定代谢需求的特定底物的靶向作用。

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