丙酸血症小鼠模型中 CoA 隔离的缓解和线粒体功能的恢复,Journal of Inherited Metabolic Disease

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丙酸血症小鼠模型中 CoA 隔离的缓解和线粒体功能的恢复
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2022-10-17 , DOI: 10.1002/jimd.12570
Chitra Subramanian ₁ , Matthew W Frank ₁ , Rajendra Tangallapally ₂ , Mi-Kyung Yun ₃ , Stephen W White _{3,

4,

5} , Richard E Lee ₂ , Charles O Rock _{1,

5} , Suzanne Jackowski ₁

Affiliation

丙酸血症 (PA, OMIM 606054) 是一种破坏性的先天性代谢错误，由降低线粒体酶丙酰辅酶 A 羧化酶 (PCC) 活性的突变引起。PCC 中的缺陷会降低非酯化辅酶 A (CoASH) 的浓度，从而损害线粒体功能并破坏中间代谢。在这里，我们使用亚形态 PA 小鼠模型来测试 BBP-671 在纠正 PA 代谢失衡方面的有效性。BBP-671 是一种高亲和力变构泛酸激酶激活剂，可抵消酶的反馈抑制以增加 CoA 的细胞内浓度。PA 小鼠的肝脏 CoASH 和乙酰辅酶 A 受到抑制，BBP-671 治疗使这两种关键辅因子的细胞浓度正常化。肝丙酰辅酶 A 也被 BBP-671 减少，导致细胞内 C3:C2-CoA 比率提高。BBP-671 显着降低了升高的血浆 C3:C2-肉碱比率和柠檬酸甲酯（PA 的标志性生物标志物）。PA 小鼠尿液中苹果酸和 α-酮戊二酸的大量升高是三羧酸循环活性受损的生物标志物，BBP-671 疗法减少了这两种代谢物的量。此外，BBP-671 使 PA 小鼠的低存活率恢复正常。这些数据表明，BBP-671 可减轻 CoA 隔离，改善线粒体功能，减少血浆 PA 生物标志物，并延长 PA 小鼠的寿命，为 BBP-671 的治疗潜力提供临床前基础。BBP-671 显着减少。PA 小鼠尿液中苹果酸和 α-酮戊二酸的大量升高是三羧酸循环活性受损的生物标志物，BBP-671 疗法减少了这两种代谢物的量。此外，BBP-671 使 PA 小鼠的低存活率恢复正常。这些数据表明，BBP-671 可减轻 CoA 隔离，改善线粒体功能，减少血浆 PA 生物标志物，并延长 PA 小鼠的寿命，为 BBP-671 的治疗潜力提供临床前基础。BBP-671 显着减少。PA 小鼠尿液中苹果酸和 α-酮戊二酸的大量升高是三羧酸循环活性受损的生物标志物，BBP-671 疗法减少了这两种代谢物的量。此外，BBP-671 使 PA 小鼠的低存活率恢复正常。这些数据表明，BBP-671 可减轻 CoA 隔离，改善线粒体功能，减少血浆 PA 生物标志物，并延长 PA 小鼠的寿命，为 BBP-671 的治疗潜力提供临床前基础。

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Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers, and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671.

更新日期：2022-10-17

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