ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.
ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility.
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DOI：
10.1073/pnas.2018355118
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发表时间：
2021-02-09
影响因子：
11.1
通讯作者：
Ikawa M
中科院分区：
文献类型：
--
作者：
Shimada K;Park S;Miyata H;Yu Z;Morohoshi A;Oura S;Matzuk MM;Ikawa M
虽然线粒体鞘的形成是成熟精子形成的关键过程，但线粒体鞘发生的分子机制仍不清楚。使用基因操作的小鼠，我们发现ARMC 12通过与线粒体蛋白MIC 60，VDAC 2和VDAC 3以及睾丸特异性蛋白TBC 1D 21和GK 2的相互作用，在线粒体鞘形成过程中调节时空“精子线粒体动力学”。此外，我们证明了ARMC 12相互作用蛋白TBC 1D 21和GK 2也是线粒体鞘形成所必需的。我们的论文揭示了线粒体鞘形成的分子机制和精子线粒体动力学的调节，使我们能够进一步了解精子发生的生物学和男性不育的病因。哺乳动物精子中段有一个独特的双螺旋结构，称为线粒体鞘，紧紧地包裹在轴丝周围。尽管线粒体鞘的显著组织，但线粒体鞘形成的分子机制尚不清楚。在筛选小鼠睾丸富集基因的过程中，我们确定了Armadillo repeat-containing 12（ARMC 12）作为线粒体鞘形成的必需蛋白。在这里，我们设计了Armc 12-null小鼠，FLAG标记的Armc 12敲入小鼠和TBC 1结构域家族成员21（Tbc 1d 21）-null小鼠，以确定ARMC 12在体内线粒体鞘形成中的功能。我们发现，ARMC 12的缺乏导致线粒体沿着鞭毛沿着卷曲，导致精子活力降低和雄性不育。在精子发生过程中，Armc 12基因敲除小鼠的精子线粒体在线粒体互锁步骤不能正确伸长，这破坏了异常的线粒体卷曲。ARMC 12是线粒体外周膜蛋白，在培养的细胞中作为线粒体之间的粘附因子发挥作用。睾丸生殖细胞中的ARMC 12与线粒体蛋白MIC 60、VDAC 2和VDAC 3以及TBC 1D 21和GK 2相互作用，这是线粒体鞘形成所必需的。我们还观察到TBC 1D 21对于ARMC 12和VDAC蛋白在体内的相互作用是必需的。这些结果表明，ARMC 12使用完整的线粒体膜蛋白VDAC 2和VDAC 3作为支架连接线粒体，并与TBC 1D 21协同工作。因此，我们的研究表明，ARMC 12通过与精子线粒体表面上的几种蛋白质的协同相互作用来调节时空线粒体动力学以形成线粒体鞘。
Although formation of the mitochondrial sheath is a critical process in the formation of mature spermatozoa, the molecular mechanisms involved in mitochondrial sheath genesis remain unclear. Using gene-manipulated mice, we discovered that ARMC12 regulates spatiotemporal “sperm mitochondrial dynamics” during mitochondrial sheath formation through interactions with mitochondrial proteins MIC60, VDAC2, and VDAC3 as well as testis-specific proteins TBC1D21 and GK2. In addition, we demonstrated that ARMC12-interacting proteins TBC1D21 and GK2 are also essential for mitochondrial sheath formation. Our paper sheds light on the molecular mechanisms of mitochondrial sheath formation and the regulation of sperm mitochondrial dynamics, allowing us to further understand the biology of spermatogenesis and the etiology of infertility in men. The mammalian sperm midpiece has a unique double-helical structure called the mitochondrial sheath that wraps tightly around the axoneme. Despite the remarkable organization of the mitochondrial sheath, the molecular mechanisms involved in mitochondrial sheath formation are unclear. In the process of screening testis-enriched genes for functions in mice, we identified armadillo repeat-containing 12 (ARMC12) as an essential protein for mitochondrial sheath formation. Here, we engineered Armc12-null mice, FLAG-tagged Armc12 knock-in mice, and TBC1 domain family member 21 (Tbc1d21)-null mice to define the functions of ARMC12 in mitochondrial sheath formation in vivo. We discovered that absence of ARMC12 causes abnormal mitochondrial coiling along the flagellum, resulting in reduced sperm motility and male sterility. During spermiogenesis, sperm mitochondria in Armc12-null mice cannot elongate properly at the mitochondrial interlocking step which disrupts abnormal mitochondrial coiling. ARMC12 is a mitochondrial peripheral membrane protein and functions as an adherence factor between mitochondria in cultured cells. ARMC12 in testicular germ cells interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3 as well as TBC1D21 and GK2, which are required for mitochondrial sheath formation. We also observed that TBC1D21 is essential for the interaction between ARMC12 and VDAC proteins in vivo. These results indicate that ARMC12 uses integral mitochondrial membrane proteins VDAC2 and VDAC3 as scaffolds to link mitochondria and works cooperatively with TBC1D21. Thus, our studies have revealed that ARMC12 regulates spatiotemporal mitochondrial dynamics to form the mitochondrial sheath through cooperative interactions with several proteins on the sperm mitochondrial surface.
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影响因子：
3.6
作者：
Goodson, Summer G.;Zhang, Zhaojun;O'Brien, Deborah A.
通讯作者：
O'Brien, Deborah A.
影响因子：
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3.3
作者：
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通讯作者：
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影响因子：
16.6
作者：
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通讯作者：
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