Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
Development. 2010 Aug 1;137(15):2587-96. doi: 10.1242/dev.043745.
Costeff Syndrome, which is caused by mutations in the OPTIC ATROPHY 3 (OPA3) gene, is an early-onset syndrome characterized by urinary excretion of 3-methylglutaconic acid (MGC), optic atrophy and movement disorders, including ataxia and extrapyramidal dysfunction. The OPA3 protein is enriched in the inner mitochondrial membrane and has mitochondrial targeting signals, but a requirement for mitochondrial localization has not been demonstrated. We find zebrafish opa3 mRNA to be expressed in the optic nerve and retinal layers, the counterparts of which in humans have high mitochondrial activity. Transcripts of zebrafish opa3 are also expressed in the embryonic brain, inner ear, heart, liver, intestine and swim bladder. We isolated a zebrafish opa3 null allele for which homozygous mutants display increased MGC levels, optic nerve deficits, ataxia and an extrapyramidal movement disorder. This correspondence of metabolic, ophthalmologic and movement abnormalities between humans and zebrafish demonstrates a phylogenetic conservation of OPA3 function. We also find that delivery of exogenous Opa3 can reduce increased MGC levels in opa3 mutants, and this reduction requires the mitochondrial localization signals of Opa3. By manipulating MGC precursor availability, we infer that elevated MGC in opa3 mutants derives from extra-mitochondrial HMG-CoA through a non-canonical pathway. The opa3 mutants have normal mitochondrial oxidative phosphorylation profiles, but are nonetheless sensitive to inhibitors of the electron transport chain, which supports clinical recommendations that individuals with Costeff Syndrome avoid mitochondria-damaging agents. In summary, this paper introduces a faithful Costeff Syndrome model and demonstrates a requirement for mitochondrial OPA3 to limit HMG-CoA-derived MGC and protect the electron transport chain against inhibitory compounds.
Costeff 综合征是由 OPTIC ATROPHY 3（OPA3）基因突变引起的一种早发性综合征，其特征为 3-甲基戊烯二酸（MGC）尿排泄、视神经萎缩和运动障碍，包括共济失调和锥体外系功能障碍。OPA3 蛋白在内线粒体膜中丰富，并具有线粒体靶向信号，但尚未证明其需要线粒体定位。我们发现斑马鱼 opa3 mRNA 在视神经和视网膜层中表达，人类的对应物具有高线粒体活性。斑马鱼 opa3 的转录本也在胚胎大脑、内耳、心脏、肝脏、肠道和鳔中表达。我们分离出一个斑马鱼 opa3 缺失等位基因，纯合突变体显示 MGC 水平升高、视神经缺陷、共济失调和锥体外系运动障碍。人类和斑马鱼之间代谢、眼科和运动异常的这种对应关系表明 OPA3 功能在进化上是保守的。我们还发现，外源性 Opa3 的传递可以减少 opa3 突变体中增加的 MGC 水平，而这种减少需要 Opa3 的线粒体定位信号。通过操纵 MGC 前体的可用性，我们推断 opa3 突变体中升高的 MGC 来自线粒体外的 HMG-CoA 通过非典型途径。opa3 突变体具有正常的线粒体氧化磷酸化谱，但对电子传递链抑制剂敏感，这支持 Costeff 综合征患者避免线粒体损伤剂的临床建议。总之，本文介绍了一个忠实的 Costeff 综合征模型，并证明了线粒体 OPA3 限制 HMG-CoA 衍生的 MGC 和保护电子传递链免受抑制化合物的必要性。
