Acyl CoA Dehydrogenase 9 (ACAD9) is a member of the family of flavoenzymes that catalyze the dehydrogenation of acyl-CoAs to 2,3 enoyl-CoAs in mitochondrial fatty acid oxidation (FAO). Inborn errors of metabolism of all family members, including ACAD9, have been described in humans, and represent significant causes of morbidity and mortality particularly in children. ACAD9 deficiency leads to a combined defect in fatty acid oxidation and oxidative phosphorylation (OXPHOS) due to a dual role in the pathways. In addition to its function in mitochondrial FAO, ACAD9 has a second function as one of 14 factors responsible for assembly of complex I of the electron transport chain (ETC). Considerable controversy remains over the relative role of these two functions in normal physiology and the disparate clinical findings described in patients with ACAD9 deficiency. To better understand the normal function of ACAD9 and the pathophysiology of its deficiency, several knock out mouse models were developed. Homozygous total body knock out appeared to be lethal as no ACAD9 animals were obtained. Cre-lox technology was then used to generate tissue-specific deletion of the gene. Cardiac-specific ACAD9 deficient animals had severe neonatal cardiomyopathy and died by 17 days of age. They had severe mitochondrial dysfunction in vitro. Muscle-specific mutants were viable but exhibited muscle weakness. Additional studies of heart muscle from the cardiac specific deficient animals were used to examine the evolutionarily conserved signaling Intermediate in toll pathway (ECSIT) protein, a known binding partner of ACAD9 in the electron chain complex I assembly pathway. As expected, ECSIT levels were significantly reduced in the absence of ACAD9 protein, consistent with the demonstrated impairment of the complex I assembly. The various ACAD9 deficient animals should serve as useful models for development of novel therapeutics for this disorder.

酰基辅酶A 脱氢酶 9 (ACAD9) 是黄素酶家族的成员，可在线粒体脂肪酸氧化 (FAO) 中催化酰基辅酶A 脱氢为 2,3 烯酰辅酶 A。包括 ACAD9 在内的所有家庭成员的先天性新陈代谢错误已在人类中进行了描述，并且是导致发病率和死亡率的重要原因，尤其是在儿童中。由于在这些途径中的双重作用，ACAD9 缺乏导致脂肪酸氧化和氧化磷酸化 (OXPHOS) 的组合缺陷。除了在线粒体 FAO 中的功能外，ACAD9 还具有第二个功能，即负责组装电子传递链 (ETC) 复合物 I 的 14 个因子之一。关于这两种功能在正常生理学中的相对作用以及在 ACAD9 缺乏症患者中描述的不同临床发现仍存在相当大的争议。为了更好地了解 ACAD9 的正常功能及其缺陷的病理生理学，开发了几种敲除小鼠模型。由于没有获得 ACAD9 动物，纯合子全身敲除似乎是致命的。然后使用Cre-lox技术产生基因的组织特异性缺失。心脏特异性 ACAD9 缺陷动物患有严重的新生儿心肌病，并在 17 天大时死亡。他们在体外有严重的线粒体功能障碍. 肌肉特异性突变体是可行的，但表现出肌肉无力。对来自心脏特异性缺陷动物的心肌的其他研究用于检查进化上保守的信号通路中间体 (ECSIT) 蛋白，它是电子链复合物 I 组装通路中 ACAD9 的已知结合伙伴。正如预期的那样，在没有 ACAD9 蛋白的情况下，ECSIT 水平显着降低，这与复合物 I 组装的受损情况一致。各种 ACAD9 缺陷动物应作为开发这种疾病的新疗法的有用模型。