Transcriptomics study on the effect of alternative oxidase expression in Bcs1l mutant (S78G) mice (Mus musculus)

We crossed a Ciona intestinalis AOX transgene into RC complex III (cIII) deficient Bcs1lp.S78G knock-in mice, displaying multiple visceral manifestations and premature death. The homozygotes expressing AOX were viable and their median survival was extended from 210 to 590 days due to permanent prevention of lethal cardiomyopathy. AOX also prevented renal tubular atrophy and cerebral astrogliosis, but not liver disease, growth restriction, or lipodystrophy, suggesting distinct tissue-specific pathogenetic mechanisms. Cardiac mitochondrial ultrastructure, mitochondrial respiration, and pathological transcriptome and metabolome alterations were essentially normalized by AOX, showing that the restored electron flow upstream of cIII was sufficient to prevent cardiac energetic crisis and detrimental decompensation.我们将肠海鞘（Ciona intestinalis）来源的交替氧化酶（AOX）转基因品系，与呼吸链复合物III（RC complex III，简称cIII）缺陷型Bcs1样蛋白S78G位点敲入小鼠进行杂交，获得了同时携带该转基因与缺陷基因型的小鼠，这类小鼠表现出多种内脏表型并伴随过早死亡。表达AOX的纯合子小鼠可正常存活，其中位生存期从210天延长至590天，这是因为AOX永久阻断了致死性心肌病的发生。AOX同时可抑制肾小管萎缩与大脑星形胶质细胞增生，但无法改善肝脏病变、生长受限及脂肪营养不良，这提示不同组织存在特异性的致病机制。AOX可使心脏线粒体超微结构、线粒体呼吸功能以及病理性转录组和代谢组改变基本恢复正常，表明恢复复合物III上游的电子流动足以阻止心脏能量危机及有害的失代偿进程。