Compromised mitochondrial fatty acid synthesis in transgenic mice results in defective protein lipoylation and energy disequilibrium.
Compromised mitochondrial fatty acid synthesis in transgenic mice results in defective protein lipoylation and energy disequilibrium.
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DOI：
10.1371/journal.pone.0047196
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pasta S
中科院分区：
文献类型：
--
作者：
Smith S;Witkowski A;Moghul A;Yoshinaga Y;Nefedov M;de Jong P;Feng D;Fong L;Tu Y;Hu Y;Young SG;Pham T;Cheung C;Katzman SM;Brand MD;Quinlan CL;Fens M;Kuypers F;Misquitta S;Griffey SM;Tran S;Gharib A;Knudsen J;Hannibal-Bach HK;Wang G;Larkin S;Thweatt J;Pasta S
已经设计了线粒体脂肪酸合成受损的小鼠模型，以评估该途径在线粒体功能和整体健康中的作用。减少线粒体丙二酰辅酶A-酰基载体蛋白转酰酶的表达，核Mcat基因编码的途径中的关键酶，在不同程度上实现在所有检查的组织采用他莫昔芬诱导的Cre-lox技术。虽然受影响的小鼠比对照组动物消耗更多的食物，但它们没有增加体重，身体活动较少，遭受白色脂肪组织损失，肌肉力量下降，脊柱后凸，脱发，体温过低和寿命缩短。Mcat缺陷表型主要归因于几种组织中丙酮酸和α-酮戊二酸脱氢酶复合物翻译后脂酰化所需的辛酰前体合成减少，导致柠檬酸循环能力降低和能量代谢中断。利用外源性游离硫辛酸的替代性脂酰化途径的存在似乎仅限于肝脏，并且单独不足以保存正常的能量代谢。因此，蛋白质脂酰化途径前体的从头合成在维持线粒体功能和整体活力中起着至关重要的作用。
A mouse model with compromised mitochondrial fatty acid synthesis has been engineered in order to assess the role of this pathway in mitochondrial function and overall health. Reduction in the expression of mitochondrial malonyl CoA-acyl carrier protein transacylase, a key enzyme in the pathway encoded by the nuclear Mcat gene, was achieved to varying extents in all examined tissues employing tamoxifen-inducible Cre-lox technology. Although affected mice consumed more food than control animals, they failed to gain weight, were less physically active, suffered from loss of white adipose tissue, reduced muscle strength, kyphosis, alopecia, hypothermia and shortened lifespan. The Mcat-deficient phenotype is attributed primarily to reduced synthesis, in several tissues, of the octanoyl precursors required for the posttranslational lipoylation of pyruvate and α-ketoglutarate dehydrogenase complexes, resulting in diminished capacity of the citric acid cycle and disruption of energy metabolism. The presence of an alternative lipoylation pathway that utilizes exogenous free lipoate appears restricted to liver and alone is insufficient for preservation of normal energy metabolism. Thus, de novo synthesis of precursors for the protein lipoylation pathway plays a vital role in maintenance of mitochondrial function and overall vigor.
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影响因子：
--
作者：
Patel, Kushang V.;Ferrucci, Luigi;Ershler, William B.;Longo, Dan L.;Guralnik, Jack M.
通讯作者：
Guralnik, Jack M.
影响因子：
3.6
作者：
Kastaniotis, AJ;Autio, KJ;Hiltunen, JK
通讯作者：
Hiltunen, JK
影响因子：
1.5
作者：
Haines, DC;Chattopadhyay, S;Ward, JM
通讯作者：
Ward, JM
影响因子：
2.5
作者：
Paul, Erin;Cronan, Rachel;Klysik, Jan E.
通讯作者：
Klysik, Jan E.
影响因子：
64.5
作者：
Festa E;Fretz J;Berry R;Schmidt B;Rodeheffer M;Horowitz M;Horsley V
通讯作者：
Horsley V