Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability.
Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability.
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DOI：
10.1038/srep13989
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发表时间：
2015-09-14
影响因子：
4.6
通讯作者：
Khalimonchuk O
中科院分区：
文献类型：
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作者：
Bohovych I;Fernandez MR;Rahn JJ;Stackley KD;Bestman JE;Anandhan A;Franco R;Claypool SM;Lewis RE;Chan SS;Khalimonchuk O
线粒体参与关键的细胞功能，包括能量产生、代谢稳态和细胞凋亡。正常的线粒体功能由几种相互关联的机制维持。其中一种机制——线粒体内质量控制（IMQC）——以分布在线粒体区室中的保守蛋白酶为代表。 IMQC 成分的许多方面和生理作用仍不清楚。在这里，我们证明 IMQC 蛋白酶 Oma1 是呼吸超复合物的稳定性所必需的，从而实现平衡和可调节的生物能功能。 Oma1 活性的丧失会导致呼吸超复合物的特定不稳定，从而导致酵母呼吸不平衡和进行性呼吸衰退。同样，在培养的 Oma1 缺陷型小鼠胚胎成纤维细胞中进行的实验，连接在一起会阻碍超复合物的稳定性，并且无法在需要最大生物能输出的条件下维持适当的呼吸。最后，斑马鱼中 OMA1 的短暂敲低会导致生物能障碍以及心脏和眼睛的形态缺陷。我们对酵母、斑马鱼和哺乳动物细胞的生化和遗传学研究共同确定了 Oma1 蛋白酶在呼吸功能微调中的新颖且保守的生理作用。我们认为这种意想不到的生理作用对于细胞生物能量可塑性很重要，并且可能导致人类 Oma1 相关疾病表型。
Mitochondria are involved in key cellular functions including energy production, metabolic homeostasis, and apoptosis. Normal mitochondrial function is preserved by several interrelated mechanisms. One mechanism – intramitochondrial quality control (IMQC) – is represented by conserved proteases distributed across mitochondrial compartments. Many aspects and physiological roles of IMQC components remain unclear. Here, we show that the IMQC protease Oma1 is required for the stability of the respiratory supercomplexes and thus balanced and tunable bioenergetic function. Loss of Oma1 activity leads to a specific destabilization of respiratory supercomplexes and consequently to unbalanced respiration and progressive respiratory decline in yeast. Similarly, experiments in cultured Oma1-deficient mouse embryonic fibroblasts link together impeded supercomplex stability and inability to maintain proper respiration under conditions that require maximal bioenergetic output. Finally, transient knockdown of OMA1 in zebrafish leads to impeded bioenergetics and morphological defects of the heart and eyes. Together, our biochemical and genetic studies in yeast, zebrafish and mammalian cells identify a novel and conserved physiological role for Oma1 protease in fine-tuning of respiratory function. We suggest that this unexpected physiological role is important for cellular bioenergetic plasticity and may contribute to Oma1-associated disease phenotypes in humans.