Pan Chen, Shimada Keisuke, Chang Hsin-Yi, Wang Haoting, Ikawa Masahito
Department of Experimental Genome Research, Research Institute for Microbial Diseases, The University of Osaka, Osaka 5650871, Japan.
Department of Experimental Genome Research, Graduate School of Pharmaceutical Sciences, The University of Osaka, Osaka 5650871, Japan.
Development. 2025 Aug 1;152(15). doi: 10.1242/dev.204683. Epub 2025 Aug 7.
It is known that various testis-specific mitochondrial proteins are associated with energy metabolism and male meiosis. PDHA2 is a testis-specific mitochondrial protein, and its encoding gene is speculated to be an autosomal retrogene of the progenitor X-linked Pdha1. Here, we show that Pdha2 knockout (KO) mice exhibit azoospermia due to failure at the late pachytene-diplotene transition. We found that PDHA2 interacts with PDHB and PDHA1. PDHA2 absence leads to decreased PDHB amounts and ATP levels in male germ cells. ATP reduction impairs the function of the ATPase recombination proteins RAD51 and DMC1, causing crossover formation deficiency, further resulting in double-strand break repair failure at the pachytene stage. Pdha1 expression by transgenes in Pdha2 KO germ cells rescues fertility and PDHB expression in Pdha2 KO males, confirming the functional equivalence of PDHA1 and PDHA2. Because X-linked Pdha1 expression is silenced during meiotic sex chromosome inactivation, our findings also support the hypothesis that Pdha2 was transposed from Pdha1. In summary, PDHA2 compensates for silenced PDHA1 in male germ cells, and plays a crucial role in maintaining efficient double-strand break repair for proper meiotic progression.
已知多种睾丸特异性线粒体蛋白与能量代谢和雄性减数分裂相关。PDHA2是一种睾丸特异性线粒体蛋白，其编码基因据推测是祖先X连锁的Pdha1的常染色体反转录基因。在此，我们表明Pdha2基因敲除（KO）小鼠由于在粗线期-双线期转换后期失败而表现出无精子症。我们发现PDHA2与PDHB和PDHA1相互作用。PDHA2的缺失导致雄性生殖细胞中PDHB含量和ATP水平降低。ATP减少会损害ATP酶重组蛋白RAD51和DMC1的功能，导致交叉形成缺陷，进而导致粗线期双链断裂修复失败。通过转基因在Pdha2 KO生殖细胞中表达Pdha1可挽救Pdha2 KO雄性小鼠的生育能力和PDHB表达，证实了PDHA1和PDHA2的功能等效性。由于X连锁的Pdha1表达在减数分裂性染色体失活期间被沉默，我们的发现也支持Pdha2是从Pdha1转座而来的假说。总之，PDHA2在雄性生殖细胞中补偿沉默的PDHA1，并在维持有效的双链断裂修复以实现正常减数分裂进程中起关键作用。
