Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK, 74078, USA.
Department of Microbiology and Immunology, Tulane University, New Orleans, LA, 70112, USA.
Free Radic Biol Med. 2021 Feb 20;164:271-284. doi: 10.1016/j.freeradbiomed.2021.01.003. Epub 2021 Jan 13.
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 III+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.
低度炎症是导致代谢紊乱发展的关键病理因素。β-胡萝卜素加氧酶 2（BCO2）最初被鉴定为一种在线粒体内膜中催化类胡萝卜素的酶。BCO2 的突变与人类的炎症和代谢紊乱有关，但潜在的机制尚不清楚。在这里，我们使用小鼠和细胞培养模型中的功能丧失方法来研究 BCO2 在炎症和代谢功能障碍中的作用。我们在 2 型糖尿病患者的肝脏中证明了 BCO2 mRNA 和蛋白水平降低，以及线粒体呼吸复合物 I 蛋白和线粒体超氧化物歧化酶水平降低。BCO2 缺乏导致线粒体呼吸超复合体（如小鼠中的超复合体 III+IV）的组装破坏，以及原发性小鼠胚胎成纤维细胞中超氧自由基的过度产生。此外，BCO2 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，并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。BCO2 缺乏的小鼠还表现出血浆炎症细胞因子升高、脂肪组织肥大和炎症。此外，BCO2 缺乏的小鼠更容易发生高脂肪饮食诱导的肥胖和高血糖。BCO2 和瘦素受体基因的双重敲除导致 4 周龄时小鼠空腹血糖水平显著升高，与年龄和性别匹配的瘦素受体敲除小鼠相比。最后，施用线粒体特异性抗氧化剂 Mito-TEMPO 可减轻 BCO2 缺乏引起的全身低度炎症。总之，这些发现表明 BCO2 是哺乳动物线粒体呼吸和代谢稳态所必需的。BCO2 的缺失或表达降低会导致线粒体氧化应激、低度炎症，进而导致代谢紊乱的发生。
