Magnesium flux compendium: Discover ligands, channels, and metabolic signals
Magnesium flux compendium: Discover ligands, channels, and metabolic signals
批准号:
10791996
负责人:
MADESH MUNISWAMY
金额:
$25.0万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-06-01 至 2027-05-31
关键词:
Acinar CellBindingBiochemical ReactionBioenergeticsBiologicalBiophysicsBuffersCRISPR/Cas technologyCationsCell membraneCell modelCell physiologyCellsCellular biologyComplexCytosolDeficiency DiseasesDissociationEndosomesEnzymesEquilibriumEventFunctional disorderFundingFutureHomeostasisHormonalIon ChannelLaboratoriesLigandsLinkLysosomesMagnesiumMembraneMetabolicMetabolismMgATPMitochondriaMitochondrial MatrixMolecularNucleic AcidsNucleotidesOrganellesPhenotypePhysiologicalProteinsRNA interference screenRestRoleRouteShapesSignal PathwaySignal TransductionStimulusTestingWorkcofactorionizationmouse modelprogramsuptake
中文摘要
摘要/摘要
游离的胞内电离镁(IMG2)估计在0.5-1.2毫米范围内。一般来说,它是被接受的。
在静息状态下,细胞内游离镁的浓度被磷代谢产物“抑制”,
核酸和蛋白质。例如,三磷酸腺苷与Kd值50M-70μM结合,因此在
胞浆和线粒体基质主要与三磷酸腺苷(mg-ATP2-)络合。因为它的丰度(~5
(Mm),ATP被认为是iMG2最大的‘商店’。激素性激素对游离胞浆(CMG2)的影响
刺激被吹捧为从旺盛的镁-三磷酸腺苷状态中分离出来的镁的被动调整
以及其他有缓冲的镁2池。除了IMG2的“缓冲”机制,镁离子通道和转运体
控制质膜上镁的进入和流出被认为是维持细胞内镁离子的平衡。
免费CMG2。目前,有几个候选者与mg2进入机制(TRPM6、TRPM7、MagT1)相关,但
仍在等待这种作用的令人信服的生物物理和生理证据。镁钠交换器
Slc41a1被认为有助于镁从细胞外流,而mrs2被认为是线粒体。
MG2传送器。关于镁离子转运进出细胞器的分子细节还知之甚少。
如内质网、线粒体、内切体和溶酶体。一些研究推测,内质网中的游离[Mg2]
线粒体很可能类似于[CMG2]。然而,时间和空间动态,更不用说
IMg2动员的生物学意义,在细胞生物学中仍然是一个谜。尽管如此,mg2是一种必不可少的
控制许多生化反应的阳离子。我们最近的工作表明,L-乳酸作为激活剂,
触发内质网和线粒体之间的镁动态转移,以形成生物能量学和细胞
代谢(细胞2020)。L乳酸盐促进内质网镁离子释放和镁摄取的作用机制
通过线粒体。线粒体定位的mrs2转运蛋白被发现是导致这种积累的原因。
线粒体中的镁含量。然而,L-乳酸诱导内质网释放的分子机制尚不清楚。
我建议鉴定内质网mg2释放组分、质膜进入机制以及由此产生的
分子信号通路。我将利用无偏见的RNAi屏幕和有针对性的CRISPR/Cas9编辑
在MG2信令领域,解答这些谜团的方法。这些分子机制的鉴定
将有助于我们理解iMg2的动力学以及iMg2通量之间存在的因果关系
和细胞过程。此外,我将测试和定义依赖于MG2的信号事件
细胞和小鼠模型表型。这是令人兴奋的定义之间的分子联系细胞镁
动态平衡和生理功能。我们对镁熔剂组分的鉴定和表征将
进一步研究这些信号通路如何以及是否会影响越来越多的
人类中的镁缺乏疾病。总体而言,R35/Mira的资金将支持这一测试
非常规假说和我的实验室将在不久的将来解开这些重大谜团。
英文摘要
ABSTRACT/SUMMARY
Free ionized intracellular Mg2+ (iMg2+) is estimated to be in the range of 0.5–1.2 mM. In general, it is accepted
that under resting conditions, the concentration of ionized cytosolic Mg2+ is `muffled' by phosphometabolites,
nucleic acids and proteins. For example, ATP binds with a Kd value of 50 M-70 μM and therefore Mg2+ in the
cytosol and the mitochondrial matrix is primarily complexed with ATP (Mg-ATP2-). Because of its abundance (~5
mM), ATP is considered to be the largest iMg2+ `store'. Fluctuations in free cytosolic (cMg2+) following hormonal
stimuli have been touted as passive adjustments of Mg2+ dissociating from the exuberant Mg-ATP contingent
and other `buffered' pools of Mg2+. Apart from iMg2+ `buffering' mechanism, Mg2+ ion channels and transporters
controlling Mg2+ entry as well as efflux across the plasma membrane are thought to maintain the equilibrium of
free cMg2+. Currently, several candidates are correlated to Mg2+ entry machinery (TRPM6, TRPM7, MagT1), but
are still awaiting convincing biophysical and physiological evidence for such roles. The Mg2+/Na+ exchanger
SLC41A1 was proposed to contribute Mg2+ efflux from the cell, whereas Mrs2 was proposed as a mitochondrial
Mg2+ transporter. Very little is known about the molecular details of Mg2+ transport into/from cellular organelles
like the ER, mitochondria, endosomes and lysosomes. A few studies have speculated that free [Mg2+] in the ER
and mitochondria are likely to be similar to [cMg2+]. However, the temporal and spatial dynamics, let alone the
biological relevance of iMg2+ mobilization, remain a mystery in cell biology. Nevertheless, Mg2+ is an essential
cation controlling many biochemical reactions. Our recent work has shown that L-lactate acts as an activator that
triggers a dynamic transfer of Mg2+ between the ER and mitochondria to shape bioenergetics and cellular
metabolism (Cell 2020). Mechanistically, L-lactate stimulates Mg2+ release from the ER followed by Mg2+ uptake
by mitochondria. The mitochondrial localized Mrs2 transporter was found to be responsible for the accumulation
of Mg2+ in mitochondria. However, the L-lactate-induced ER release molecular machinery remains unidentified.
I propose to identify ER Mg2+ release component, plasma membrane entry machinery and the resultant
molecular signaling pathways. I will take advantage of unbiased RNAi screen and targeted CRISPR/Cas9 editing
approaches to answer these mysteries in the Mg2+ signaling field. Identification of these molecular machineries
would aid in our understanding of iMg2+ dynamics and the cause-effect relationships that exist between iMg2+ flux
and cellular processes. Additionally, I will test and define the Mg2+-dependent signaling events based on the
cellular and mouse model phenotypes. It is thrilling to define the molecular link between cellular Mg2+
homeostasis and physiological function. Our identification and characterization of the Mg2+ flux components will
further investigate how, and if, these signaling routes impinge on the pathophysiology of a growing number of
Mg2+ deficiency diseases in humankind. Overall, the R35/MIRA funding will support the testing of this
unconventional hypothesis and my laboratory will address these major mysteries in the near future.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.
DOI:
10.1038/s41419-023-06290-1
发表时间:
2023-11-25
期刊:
CELL DEATH & DISEASE
影响因子:
9
作者:
[Marmolejo-Garza, Alejandro, Krabbendam, Inge E., Luu, Minh Danh Anh, Brouwer, Famke, Trombetta-Lima, Marina, Unal, Osman, O'Connor, Shane J., Majernikova, Nad'a, Elzinga, Carolina R. S., Mammucari, Cristina, Schmidt, Martina, Madesh, Muniswamy, Boddeke, Erik, Dolga, Amalia M.]
通讯作者:
Dolga, Amalia M.
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