Glycerol kinase-like proteins cooperate with Pld6 in regulating sperm mitochondrial sheath formation and male fertility.
Glycerol kinase-like proteins cooperate with Pld6 in regulating sperm mitochondrial sheath formation and male fertility.
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甘油激酶样蛋白与 Pld6 协同调节精子线粒体鞘形成和男性生育力
DOI：
10.1038/celldisc.2017.30
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Chen Y;Liang P;Huang Y;Li M;Zhang X;Ding C;Feng J;Zhang Z;Zhang X;Gao Y;Zhang Q;Cao S;Zheng H;Liu D;Songyang Z;Huang J
精子细胞在精子发生过程中经历最后的成熟阶段，这一过程需要线粒体等细胞器的广泛重排。男性不育与线粒体紊乱有关，例如，精子发育不全和弱精子症。然而，在精子发生过程中调控线粒体动力学的机制在很大程度上仍不清楚。我们发现甘油蛋白(Gyk)样蛋白甘油蛋白1(Gyk1)和甘油蛋白2(GK2)特异性地定位于精子细胞的线粒体。GykL1或GK2基因缺失的雄性小鼠由于精子功能障碍而不育，表现为ATP合成紊乱，线粒体鞘形成紊乱，线粒体形态异常，精子尾部有缺陷。我们证明了在GykL1和GK2中发现的独特的C-末端序列介导了它们对线粒体外膜的靶向。此外，GykL1和GK2都能与Pld6(MitoPLD)相互作用，诱导细胞内依赖Pld6和磷脂酸(PA)的线粒体聚集。综上所述，我们的研究揭示了Gyk样蛋白在精子发生中先前未知的功能，为导致精子功能障碍和男性不育的潜在机制提供了新的见解。
Spermatids undergo the final steps of maturation during spermiogenesis, a process that necessitates extensive rearrangement of organelles such as the mitochondria. Male infertility has been linked to mitochondrial disorder, for example, hypospermatogenesis and asthenozoospermia. However, the mechanisms that regulate mitochondrial dynamics during spermiogenesis remain largely unknown. We found the glycerol kinase (Gyk)-like proteins glycerol kinase-like 1 (Gykl1) and glycerol kinase 2 (Gk2) were specifically localized to the mitochondria in spermatids. Male mice deficient in either Gykl1 or Gk2 were infertile due to dysfunctional spermatozoa, which exhibited unregulated ATP production, disordered mitochondrial sheath formation, abnormal mitochondrial morphology, and defective sperm tail. We demonstrated that the unique C-terminal sequences found in Gykl1 and Gk2 mediated their targeting to the mitochondrial outer membrane. Furthermore, both Gykl1 and Gk2 could interact with Pld6 (MitoPLD) and induce Pld6 and phosphatidic acid (PA)-dependent mitochondrial clustering in cells. Taken together, our study has revealed previously unsuspected functions of Gyk-like proteins in spermiogenesis, providing new insight into the potential mechanisms that lead to spermatozoa dysfunction and male infertility.
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