Regulation of Mitochondrial Fission/Fusion by PP2A and PKA in Neurons

神经元中 PP2A 和 PKA 对线粒体裂变/融合的调节

基本信息

批准号：
7426845
负责人：
STEFAN STRACK
金额：
$ 15万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426845
关键词：
A kinase anchoring protein Address Affect Apoptosis Behavioral Biolistics Biological Assay Brain Brain Injuries Buffers Calcium Cell Death Chromosome Pairing Condition Cultured Cells Cyclic AMP-Dependent Protein Kinases Data Dendritic Spines Development Dynamin Enzymes Equilibrium Figs - dietary Free Radicals Functional disorder Galactosidase Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Holoenzymes Homeostasis Hydrolysis Hypoglycemia Hypoglycemic Agents Hypoxia In Vitro Inherited Injury Ischemia Knockout Mice Label Lead Link Localized Mediating Metabolic Mitochondria Modeling Molecular Target Monoclonal Antibodies Morphology Mus Mutagenesis Mutate Mutation Natural regeneration Nervous System Trauma Neurodegenerative Disorders Neurons Organelles Outer Mitochondrial Membrane Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiology Predisposition Process Protein Kinase Proteins Proteomics RNA Splicing Rattus Regulation Reporter Research Personnel Resistance Role Shapes Side Signal Transduction Spinocerebellar Ataxias Stable Isotope Labeling Structure Surface Synapses System Transfection Transient Cerebral Ischemia follow-up in vivo inhibitor/antagonist mitochondrial dysfunction mossy fiber nervous system disorder neuron loss neuronal survival neuropathology novel programs protein phosphatase 2A regulatory subunit 65 kDa response stroke therapy synaptic function synaptogenesis tandem mass spectrometry trafficking

项目摘要

DESCRIPTION (provided by applicant): Mitochondria provide energy, buffer calcium, and sequester cell death-inducing molecules, and mitochondrial dysfunction is implicated in various neuropathologies. Especially in neurons, mitochondria are highly dynamic organelles that constantly move, divide, and fuse. This proposal investigates the regulation of mitochondrial fission and fusion in neurons, which are antagonistic processes carried out by large GTPases similar to dynamin. Mutations in two of these enzymes, Opal and Mfn2, are responsible for hereditary neurological diseases. While a proper balance of mitochondrial fusion and fragmentation is clearly important for neuronal survival, some fragmentation is necessary for axonal and dendritic transport of mitochondria, and consequently for the development and function of synapses. We have found that shape changes of mitochondria are controlled by an opposing protein kinase and phosphatase that are localized to the outer mitochondrial membrane via specific targeting/regulatory subunits. On the phosphatase side, Bp2 is a neuron-specific, postnatally induced protein phosphatase 2A (PP2A) regulatory subunit mutated in spinocerebellar ataxia type 12. The alternatively spliced N terminus of Bp2 mediates translocation of the PP2A holoenzyme to the mitochondrial surface, where PP2A accelerates cell death, apparently by fragmenting mitochondria. The kinase opposing PP2A/Bp2's effect on mitochondrial morphology and survival is cAMP-dependent protein kinase (PKA) anchored to the OMM via A kinase anchoring protein (AKAP)121. Aim 1 investigates the mechanism by which outer-mitochondrial PP2A and PKA control neuronal survival. In Aim 2, we will identify the relevant substrates and phosphorylation sites among mitochondrial fission/fusion enzymes. Aim 3 addresses the role of PP2A/PKA-dependent mitochondrial restructuring in the delivery of mitochondria to and development of dendritic spines. Finally, Aim 4 characterizes PP2A/Bp2 knockout mice in terms of mitochondria and synapse morphology and resistance to ischemic injury. These studies will advance our understanding of how shape transitions of mitochondria are regulated, and how this affects vulnerability of neurons and the establishment of functional connections between them. Our studies may ultimately lead to better therapies for stroke and neurodegenerative disorders.

描述（由申请人提供）：线粒体提供能量，缓冲钙和隔离细胞死亡诱导分子，以及线粒体功能障碍与各种神经病理有关。尤其是在神经元中，线粒体是高度动态的细胞器，不断移动，分裂和融合。该提案研究了神经元中线粒体裂变和融合的调节，这是类似于Dynamin的大型GTP酶进行的拮抗过程。这些酶中的两个蛋白石和MFN2的突变是遗传神经系统疾病的原因。虽然线粒体融合和碎片化的适当平衡对于神经元的存活显然很重要，但对于线粒体的轴突和树突转运是必要的，因此对于突触的发展和功能是必不可少的。我们发现，线粒体的形状变化受相反的蛋白激酶和磷酸酶的控制，该蛋白激酶和磷酸酶通过特定的靶向/调节亚基局部位于线粒体外膜。 On the phosphatase side, Bp2 is a neuron-specific, postnatally induced protein phosphatase 2A (PP2A) regulatory subunit mutated in spinocerebellar ataxia type 12. The alternatively spliced N terminus of Bp2 mediates translocation of the PP2A holoenzyme to the mitochondrial surface, where PP2A accelerates cell death, apparently by线粒体破碎。激酶反对PP2A/BP2对线粒体形态和生存的影响是cAMP依赖性蛋白激酶（PKA）通过激酶锚定蛋白（AKAP）121固定在OMM上的cAMP依赖性蛋白激酶（PKA）。 AIM 1研究了线粒体PP2A和PKA控制神经元存活的机制。在AIM 2中，我们将确定线粒体裂变/融合酶之间相关的底物和磷酸化位点。 AIM 3解决了PP2A/PKA依赖性线粒体重组在线粒体向树突棘的发育和发育中的作用。最后，AIM 4在线粒体和突触形态和对缺血性损伤的耐药性方面表征了PP2A/BP2基因敲除小鼠。这些研究将促进我们对线粒体的形状转变的理解，以及这如何影响神经元的脆弱性以及它们之间的功能联系。我们的研究最终可能导致对中风和神经退行性疾病的更好疗法。