Abstract 432: MCUB Regulates Mitochondrial Calcium Uniporter Channel Gating and Modulates Bioenergetics and Cell Death

Uniporter公司 线粒体通透性转换孔 线粒体 细胞生物学 生物能学 线粒体内膜 去极化 膜电位 钌红 化学 电压依赖性钙通道 生物 钙信号传导 程序性细胞死亡 生物物理学 生物化学 信号转导 细胞凋亡 胞浆 有机化学
作者
Jonathan P Lambert,Timothy S. Luongo,Pooja Jadiya,Erhe Gao,Xueqian Zhang,Anna Maria Lucchesee,John W. Elrod
出处
期刊:Circulation Research [Lippincott Williams & Wilkins]
卷期号:121 (suppl_1)
标识
DOI:10.1161/res.121.suppl_1.432
摘要

The mitochondrial calcium uniporter (MCU) is a high-capacity, inward-rectifying channel in the inner mitochondrial membrane and is required for mitochondrial Ca 2+ ( m Ca 2+ ) uptake. m Ca 2+ signaling regulates bioenergetics and activates the mitochondrial permeability transition pore (MPTP) which are cellular processes implicated in cardiac pathophysiology warranting further research into the molecular regulation of the MCU. Recently, a MCU gene paralog, MCUB , was identified as a possible component of the channel. To investigate MCUB’s contribution to uniporter regulation we created a MCUB -/- HeLa cell line using CRISPR-Cas9n. Here, we report that loss of MCUB increased m Ca 2+ transient amplitude after IP3R stimulation (52% vs. con) suggesting MCUB negatively regulates m Ca 2+ uptake. Mitoplast patch-clamping confirmed that loss of MCUB increases MCU current density, suggesting MCUb modulates channel capacitance. Permeabilized MCUB -/- and WT cells exposed to various levels of Ca 2+ (0.5-20μM) revealed that MCUB -/- cells exhibited m Ca 2+ uptake at lower Ca 2+ concentrations than controls, suggesting MCUB contributes to channel gating. In m Ca 2+ retention capacity experiments MCUB -/- cells required ~30% less bath Ca 2+ to induce depolarization, suggesting a predisposition to m Ca 2+ overload. Next, we generated a cardiac-specific, tamoxifen-inducible MCUB overexpression mouse model ( MCUB -Tg). Cardiomyocytes isolated from MCUB -Tg hearts exhibited decreased m Ca 2+ uptake at low-Ca 2+ (59% vs. con) and isolated mitochondria exhibited a reduction in Ca 2+ -induced swelling (37% vs. con), suggesting a resistance to permeability transition. MCUB -Tg mice displayed a significant impairment in isoproterenol-induced contractile reserve and this correlated with a loss of isoproterenol-mediated activation of pyruvate dehydrogenase. In summary, our results suggest that MCUB limits m Ca 2+ uptake by altering channel-gating and thereby regulates bioenergetics and MPTP opening.

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