Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.
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DOI：
10.1371/journal.pbio.1000612
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发表时间：
2011-04
期刊：
影响因子：
9.8
通讯作者：
Strack S
中科院分区：
文献类型：
--
作者：
Merrill RA;Dagda RK;Dickey AS;Cribbs JT;Green SH;Usachev YM;Strack S
线粒体信号复合体PKA/AKAP1通过磷酸化和失活线粒体裂变酶Drp1来保护神经元免受线粒体断裂和细胞死亡。线粒体形状由动力蛋白家族的大gtpase催化的裂变和融合反应决定，其突变可导致神经功能障碍。虽然已经确定了诱导裂变的蛋白磷酸酶，但相对的激酶信号复合物的身份仍然难以捉摸。我们在这里报道，在神经元和非神经元细胞中，cAMP的升高和蛋白激酶A （PKA）催化亚基的外线粒体膜（OMM）靶向形式的表达将线粒体重塑成一个相互连接的网络。相反，omm靶向PKA抑制剂PKI可促进神经元死亡上游的线粒体断裂。RNAi和过表达方法在体外和体内均发现线粒体定位的A激酶锚定蛋白1 （AKAP1）是一种神经保护和线粒体稳定因子。根据磷酸化位点突变的动力蛋白相关蛋白1 （Drp1）的上位性研究，通过保守的PKA位点抑制线粒体裂变酶是cAMP和PKA/AKAP1促进线粒体延长和神经元存活的主要机制。通过减缓GTP水解的突变，Drp1磷酸化抑制了其催化循环的分解步骤，在OMM积累了大量缓慢回收的Drp1低聚物。无对抗融合促进线粒体网的形成，从而保护神经元免受各种损伤。线粒体，细胞动力源，是高度动态的细胞器，由相反的裂变和融合事件形成。过去十年的研究已经确定了线粒体裂变/融合机制的许多组成部分，并导致发现编码这些蛋白质的基因突变可导致人类神经系统疾病。虽然线粒体形状的变化与细胞对环境压力的反应密切相关，但我们对细胞动态调节线粒体形状和功能的机制知之甚少。在本报告中，我们发现支架蛋白AKAP1将camp依赖性蛋白激酶PKA带到线粒体外膜，以保护神经元免受损伤。PKA/AKAP1复合物通过抑制Drp1起作用，Drp1是一种机械收缩并最终切断线粒体的酶。而活性的、去磷酸化的Drp1在细胞质和线粒体之间快速循环，磷酸化的Drp1在无活性的线粒体复合体中积累，使线粒体融合成神经保护网。我们的研究结果表明，改变线粒体外膜激酶和磷酸酶活性的平衡可能为新的神经保护疗法提供基础。
The mitochondrial signaling complex PKA/AKAP1 protects neurons against mitochondrial fragmentation and cell death by phosphorylating and inactivating the mitochondrial fission enzyme Drp1. Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM) targeted form of the protein kinase A (PKA) catalytic subunit reshapes mitochondria into an interconnected network. Conversely, OMM-targeting of the PKA inhibitor PKI promotes mitochondrial fragmentation upstream of neuronal death. RNAi and overexpression approaches identify mitochondria-localized A kinase anchoring protein 1 (AKAP1) as a neuroprotective and mitochondria-stabilizing factor in vitro and in vivo. According to epistasis studies with phosphorylation site-mutant dynamin-related protein 1 (Drp1), inhibition of the mitochondrial fission enzyme through a conserved PKA site is the principal mechanism by which cAMP and PKA/AKAP1 promote both mitochondrial elongation and neuronal survival. Phenocopied by a mutation that slows GTP hydrolysis, Drp1 phosphorylation inhibits the disassembly step of its catalytic cycle, accumulating large, slowly recycling Drp1 oligomers at the OMM. Unopposed fusion then promotes formation of a mitochondrial reticulum, which protects neurons from diverse insults. Mitochondria, the cellular powerhouse, are highly dynamic organelles shaped by opposing fission and fusion events. Research over the past decade has identified many components of the mitochondrial fission/fusion machinery and led to the discovery that mutations in genes coding for these proteins can cause human neurological diseases. While it is well established that mitochondrial shape changes are intimately involved in cellular responses to environmental stressors, we know very little about the mechanisms by which cells dynamically adjust mitochondrial form and function. In this report, we show that the scaffold protein AKAP1 brings the cAMP-dependent protein kinase PKA to the outer mitochondrial membrane to protect neurons from injury. The PKA/AKAP1 complex functions by inhibiting Drp1, an enzyme that mechanically constricts and eventually severs mitochondria. Whereas active, dephosphorylated Drp1 rapidly cycles between cytosol and mitochondria, phosphorylated Drp1 builds up in inactive mitochondrial complexes, allowing mitochondria to fuse into a neuroprotective reticulum. Our results suggest that altering the balance of kinase and phosphatase activities at the outer mitochondrial membrane may provide the basis for novel neuroprotective therapies.
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作者：
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DOI：
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期刊：
The Journal of cell biology
影响因子：
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