Lucienne Marie, Mathis Déborah, Perkins Nathan, Fingerhut Ralph, Baumgartner Matthias R, Froese D Sean
Division of Metabolism and Children's Research Center University Children's Hospital Zurich Zurich Switzerland.
radiz - Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases University of Zurich Zurich Switzerland.
JIMD Rep. 2020 Nov 8;58(1):44-51. doi: 10.1002/jmd2.12182. eCollection 2021 Mar.
Methylmalonyl-CoA mutase (MMUT) is part of the propionyl-CoA catabolic pathway, responsible for the breakdown of branched-chain amino acids, odd-chain fatty acids and the side-chain of cholesterol. Patients with deficient activity of MMUT suffer from isolated methylmalonic aciduria (MMAuria), frequently presenting in the newborn period with failure to thrive and metabolic crisis. Even well managed patients remain at risk for metabolic crises, of which one known trigger is acute illness, which may lead to poor feeding and vomiting, putting the patient in a catabolic state. This situation is believed to result in increased breakdown of propionyl-CoA catabolic pathway precursors, producing massively elevated levels of disease related metabolites, including methylmalonic acid and propionylcarnitine. Here, we used fasting of a hemizygous mouse model (-ko/ki) of MMUT deficiency to study the role of induced catabolism on metabolite production. Although mice lost weight and displayed markers consistent with a catabolic state, contrary to expectation, we found strongly reduced levels of methylmalonic acid and propionylcarnitine in fasted conditions. Switching -ko/ki mice from a high-protein diet to fasted conditions, or from a standard diet to a no-protein diet, resulted in similar reductions of methylmalonic acid and propionylcarnitine levels. These results suggest, in our mouse model at least, induction of a catabolic state on its own may not be sufficient to trigger elevated metabolite levels.
甲基丙二酰辅酶A变位酶（MMUT）是丙酰辅酶A分解代谢途径的一部分，负责分解支链氨基酸、奇数链脂肪酸和胆固醇的侧链。MMUT活性不足的患者患有孤立性甲基丙二酸尿症（MMAuria），常在新生儿期出现生长发育迟缓及代谢危机。即使病情得到良好控制的患者仍有代谢危机风险，其中一个已知诱因是急性疾病，这可能导致喂养困难和呕吐，使患者处于分解代谢状态。据信这种情况会导致丙酰辅酶A分解代谢途径前体的分解增加，产生大量与疾病相关的代谢产物，包括甲基丙二酸和丙酰肉碱。在此，我们利用MMUT缺陷的半合子小鼠模型（-ko/ki）禁食来研究诱导分解代谢对代谢产物产生的作用。尽管小鼠体重减轻并表现出与分解代谢状态一致的指标，但与预期相反，我们发现在禁食条件下甲基丙二酸和丙酰肉碱水平大幅降低。将-ko/ki小鼠从高蛋白饮食改为禁食条件，或从标准饮食改为无蛋白饮食，都会导致甲基丙二酸和丙酰肉碱水平出现类似程度的降低。这些结果表明，至少在我们的小鼠模型中，单纯诱导分解代谢状态可能不足以引发代谢产物水平升高。
