Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes
Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes
复制标题
PHB 复合物的缺乏会损害呼吸超复合物的形成并激活线粒体闪光
DOI：
10.1242/jcs.198523
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Wang, Xianhua
中科院分区：
文献类型：
--
作者：
Jian, Chongshu;Xu, Fengli;Wang, Xianhua
中文摘要：抑制剂（PHBs;抑制素1，PHB 1或PHB 2，和抑制素2，PHB 2）是进化上保守的和普遍表达的线粒体蛋白。PHB形成多聚环复合物，作为线粒体内膜中的支架。线粒体闪光（mitoflashes）是新近发现的反映细胞器电和化学激发的线粒体信号事件。在这里，我们调查的可能作用的聚羟基丁酸酯在调节mitoflash信号。由于线粒体中基础活性氧（ROS）产生升高，PHBs的下调使线粒体闪光频率增加高达5.4倍。从机制上讲，PHB缺乏会损害线粒体呼吸超复合物（RSC）的形成，而不会改变单个呼吸复合物亚基的丰度。这些损伤诱导的PHB缺陷被有效地拯救的PHB 1和PHB 2的共表达，表明多聚体的PHB复合物作为功能单元。此外，下调其他RSC组装因子，包括SCAFI（也称为COX 7A 2L），RCF 1a（HIGD 1A），RCF 1b（HIGD 2A），UQCC 3和SLP 2（STOML 2），都通过提高线粒体ROS的产生来激活线粒体闪光。我们的研究结果确定了聚羟基丁酸复合物作为一种新的调节RSC的形成和mitoflash信号，并描绘了RSC的形成，基础活性氧产生和mitoflash生物发生之间的一般关系。总结：抑制素复合物通过影响呼吸超复合物的形成和基础线粒体活性氧的产生而在调节线粒体闪光活性中发挥新的作用。
ABSTRACT Prohibitins (PHBs; prohibitin 1, PHB1 or PHB, and prohibitin 2, PHB2) are evolutionarily conserved and ubiquitously expressed mitochondrial proteins. PHBs form multimeric ring complexes acting as scaffolds in the inner mitochondrial membrane. Mitochondrial flashes (mitoflashes) are newly discovered mitochondrial signaling events that reflect electrical and chemical excitations of the organelle. Here, we investigate the possible roles of PHBs in the regulation of mitoflash signaling. Downregulation of PHBs increases mitoflash frequency by up to 5.4-fold due to elevated basal reactive oxygen species (ROS) production in the mitochondria. Mechanistically, PHB deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits. These impairments induced by PHB deficiency are effectively rescued by co-expression of PHB1 and PHB2, indicating that the multimeric PHB complex acts as the functional unit. Furthermore, downregulating other RSC assembly factors, including SCAFI (also known as COX7A2L), RCF1a (HIGD1A), RCF1b (HIGD2A), UQCC3 and SLP2 (STOML2), all activate mitoflashes through elevating mitochondrial ROS production. Our findings identify the PHB complex as a new regulator of RSC formation and mitoflash signaling, and delineate a general relationship among RSC formation, basal ROS production and mitoflash biogenesis. Summary: The prohibitin (PHB) complex has a novel role in regulating mitoflash activity by affecting respiratory supercomplex formation and, thus, basal mitochondrial ROS production.