Human Mpv17-like protein with a mitigating effect on mtDNA damage is involved in cAMP/PKA signaling in the mitochondrial matrix
Human Mpv17-like protein with a mitigating effect on mtDNA damage is involved in cAMP/PKA signaling in the mitochondrial matrix
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DOI：
10.1016/j.bbamcr.2020.118792
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发表时间：
2020-10-01
影响因子：
5.1
通讯作者：
Yasuda, Toshihiro
中科院分区：
文献类型：
--
作者：
Iida, Reiko;Ueki, Misuzu;Yasuda, Toshihiro
人Mpv 17样蛋白（M-LPH/Mpv 17 L）被认为在最小化由线粒体DNA（mtDNA）损伤引起的线粒体功能障碍中发挥作用。我们最近证明，除了增加线粒体DNA损伤外，HepG 2细胞中的M-LPH-敲除（M-LPH-KO）导致线粒体转录因子A（TFAM）蛋白显著减少，TFAM蛋白是线粒体DNA维持的重要因子，沿着其磷酸化的增加。这些细胞内变化表明M-LPH与cAMP/PKA信号通路相关，因为线粒体蛋白酶选择性降解TFAM是由蛋白激酶A（PKA）依赖性磷酸化驱动的。在本研究中，我们观察到M-LPH-KO在HepG 2细胞中引起线粒体cAMP水平的增加和总细胞环核苷酸磷酸二酯酶（PDE）活性的降低。体外合成的M-LPH具有PDE活性，可被PDE的非选择性抑制剂IBMX抑制。此外，M-LPH-KO促进了一些线粒体蛋白的PKA依赖性磷酸化。总之，目前的研究结果表明，M-LPH，它具有PDE家族成员的非典型结构特征，可能是一种新的人类PDE参与cAMP/PKA信号在线粒体基质。
Human Mpv17-like protein (M-LPH/Mpv17L) is thought to play a role in minimizing mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) damage. We have recently demonstrated that, in addition to an increase of mtDNA damage, M-LPH-knockout (M-LPH-KO) in HepG2 cells causes a significant reduction of mitochondrial transcription factor A (TFAM) protein, an essential factor for mtDNA maintenance, along with an increase in its phosphorylation. These intracellular changes suggested an association of M-LPH with the cAMP/PKA signaling pathway, as selective degradation of TFAM by mitochondrial protease is driven by protein kinase A (PKA)-dependent phosphorylation. In the present study, we observed that M-LPH-KO in HepG2 cells caused an increase in the level of mitochondrial cAMP and a reduction of total cellular cyclic nucleotide phosphodiesterase (PDE) activity. In vitro-synthesized M-LPH showed PDE activity, which was inhibited by IBMX, a non-selective inhibitor of PDE. Furthermore, M-LPH-KO promoted PKA-dependent phosphorylation of some mitochondrial proteins. Taken together, the present findings suggest that M-LPH, which has structural features atypical of PDE family members, might be a novel human PDE involved in cAMP/PKA signaling in the mitochondrial matrix.