β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.
β-carotene oxygenase 2 deficiency-triggered mitochondrial oxidative stress promotes low-grade inflammation and metabolic dysfunction.
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DOI：
10.1016/j.freeradbiomed.2021.01.003
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发表时间：
2021-02-20
影响因子：
7.4
通讯作者：
Lin D
中科院分区：
文献类型：
--
作者：
Wu L;Lu P;Guo X;Song K;Lyu Y;Bothwell J;Wu J;Hawkins O;Clarke SL;Lucas EA;Smith BJ;Chowanadisai W;Hartson SD;Ritchey JW;Wang W;Medeiros DM;Li S;Lin D
低度炎症是导致代谢紊乱的重要病理因素。β-胡萝卜素加氧酶2 （BCO2）最初被确定为线粒体内膜中催化类胡萝卜素的酶。BCO2突变与人类炎症和代谢紊乱有关，但其潜在机制尚不清楚。在这里，我们在小鼠和细胞培养模型中使用功能丧失方法来研究BCO2在炎症和代谢功能障碍中的作用。我们发现，在2型糖尿病患者的肝脏中，BCO2 mRNA和蛋白水平降低，线粒体呼吸复合体I蛋白和线粒体超氧化物歧化酶水平受到抑制。BCO2缺乏导致线粒体呼吸超复合体的组装中断，如小鼠体内的超复合体III2+IV，以及小鼠胚胎成纤维细胞中超氧自由基的过量产生。此外，BCO2的缺乏增加了蛋白质羰基化和自然杀伤细胞和M1巨噬细胞的数量，减少了骨髓和白色脂肪组织中T细胞（包括CD4+和/或CD8+）的数量。血浆炎症细胞因子升高，脂肪组织肥大和炎症也在BCO2缺乏小鼠中表现出来。此外，BCO2缺乏的小鼠更容易发生高脂肪饮食引起的肥胖和高血糖症。与年龄和性别匹配的瘦素受体基因敲除相比，双敲除BCO2和瘦素受体基因导致小鼠在4周龄时空腹血糖水平显著升高。最后，给予线粒体特异性抗氧化剂Mito-TEMPO可减轻BCO2缺乏引起的全身低级别炎症。总的来说，这些发现表明BCO2对哺乳动物的线粒体呼吸和代谢稳态至关重要。BCO2表达缺失或减少导致线粒体氧化应激、低度炎症和随后的代谢紊乱。
Low-grade inflammation is a critical pathological factor contributing to the development of metabolic disorders. β-carotene oxygenase 2 (BCO2) was initially identified as an enzyme catalyzing carotenoids in the inner mitochondrial membrane. Mutations in BCO2 are associated with inflammation and metabolic disorders in humans, yet the underlying mechanisms remain unknown. Here, we used loss-of-function approaches in mice and cell culture models to investigate the role of BCO2 in inflammation and metabolic dysfunction. We demonstrated decreases in BCO2 mRNA and protein levels and suppression of mitochondrial respiratory complex I proteins and mitochondrial superoxide dismutase levels in the liver of type 2 diabetic human subjects. Deficiency of BCO2 caused disruption of assembly of the mitochondrial respiratory supercomplexes, such as supercomplex III2+IV in mice, and overproduction of superoxide radicals in primary mouse embryonic fibroblasts. Further, deficiency of BCO2 increased protein carbonylation and populations of natural killer cells and M1 macrophages, and decreased populations of T cells, including CD4+ and/or CD8+ in the bone marrow and white adipose tissues. Elevation of plasma inflammatory cytokines and adipose tissue hypertrophy and inflammation were also characterized in BCO2 deficient mice. Moreover, BCO2 deficient mice were more susceptible to high-fat diet-induced obesity and hyperglycemia. Double knockout of BCO2 and leptin receptor genes caused a significantly greater elevation of the fasting blood glucose level in mice at 4 weeks of age, compared to the age- and sex-matched leptin receptor knockout. Finally, administration of Mito-TEMPO, a mitochondrial specific antioxidant attenuated systemic low-grade inflammation induced by BCO2 deficiency. Collectively, these findings suggest that BCO2 is essential for mitochondrial respiration and metabolic homeostasis in mammals. Loss or decreased expression of BCO2 leads to mitochondrial oxidative stress, low-grade inflammation, and the subsequent development of metabolic disorders.
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影响因子：
7.7
作者：
Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
通讯作者：
Sztalryd, Carole
DOI：
10.1161/atvbaha.109.199422
发表时间：
2010-04
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
He M;Cornelis MC;Kraft P;van Dam RM;Sun Q;Laurie CC;Mirel DB;Chasman DI;Ridker PM;Hunter DJ;Hu FB;Qi L
通讯作者：
Qi L
影响因子：
2.4
作者：
Indo HP;Yen HC;Nakanishi I;Matsumoto K;Tamura M;Nagano Y;Matsui H;Gusev O;Cornette R;Okuda T;Minamiyama Y;Ichikawa H;Suenaga S;Oki M;Sato T;Ozawa T;Clair DK;Majima HJ
通讯作者：
Majima HJ
影响因子：
10.7
作者：
Gazda, Malgorzata Anna;Toomey, Matthew B.;Carneiro, Miguel
通讯作者：
Carneiro, Miguel
影响因子：
5.2
作者：
Gong, Xiaoming;Marisiddaiah, Raju;Rubin, Lewis P.
通讯作者：
Rubin, Lewis P.