Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan.
Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume, 830-0011, Japan.
Proc Natl Acad Sci U S A. 2022 Nov 22;119(47):e2210730119. doi: 10.1073/pnas.2210730119. Epub 2022 Nov 16.
Mitochondria have their own DNA (mtDNA), which encodes essential respiratory subunits. Under live imaging, mitochondrial nucleoids, composed of several copies of mtDNA and DNA-binding proteins, such as mitochondrial transcription factor A (TFAM), actively move inside mitochondria and change the morphology, in concert with mitochondrial membrane fission. Here we found the mitochondrial inner membrane-anchored AAA-ATPase protein ATAD3A mediates the nucleoid dynamics. Its ATPase domain exposed to the matrix binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also required ATAD3A oligomerization via an interaction between the coiled-coil domains in intermembrane space. In ATAD3A deficiency, impaired nucleoid trafficking repressed the clustered and enlarged nucleoids observed in mitochondrial fission-deficient cells resulted in dispersed distribution of small nucleoids observed throughout the mitochondrial network, and this enhanced respiratory complex formation. Thus, mitochondrial fission and nucleoid trafficking cooperatively determine the size, number, and distribution of nucleoids in mitochondrial network, which should modulate respiratory complex formation.
线粒体拥有自己的 DNA（mtDNA），其编码重要的呼吸亚基。在活体成像下，由多个 mtDNA 拷贝和 DNA 结合蛋白（如线粒体转录因子 A [TFAM]）组成的线粒体核体在线粒体内部活跃移动，并与线粒体膜分裂协调改变形态。在这里，我们发现线粒体内膜锚定的 AAA-ATP 酶蛋白 ATAD3A 介导核体动力学。其暴露在基质中的 ATP 酶结构域与 TFAM 直接结合，并通过 ATP 水解介导核体沿着线粒体的运输。核体运输还需要通过膜间空间卷曲螺旋域之间的相互作用进行 ATAD3A 寡聚化。在 ATAD3A 缺乏的情况下，核体运输受损会抑制线粒体分裂缺陷细胞中观察到的簇状和增大的核体，导致小核体在整个线粒体网络中呈弥散分布，从而增强呼吸复合物的形成。因此，线粒体分裂和核体运输协同决定线粒体网络中核体的大小、数量和分布，这应该调节呼吸复合物的形成。
