Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics.
Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics.
复制标题
DOI：
10.1016/j.bbamcr.2017.01.015
复制
发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Duchen MR
中科院分区：
文献类型：
--
作者：
Bhosale G;Sharpe JA;Koh A;Kouli A;Szabadkai G;Duchen MR
蛋白质MICU 1（线粒体Ca 2+摄取的调节剂）的功能缺失突变导致神经元和肌肉疾病，其特征在于认知受损、肌无力和锥体外系运动障碍。我们以前已经表明，MICU 1突变导致静息线粒体Ca 2+浓度（[Ca 2 +]m）增加。我们现在探讨MICU 1突变在患者来源的成纤维细胞中的功能后果，以澄清这种疾病的潜在病理生理学。我们认为，由于MICU 1的丧失而导致线粒体Ca 2+吸收失调，从而增加了静息[Ca 2 +]m，启动了无效的Ca 2+循环，从而通过钠钙交换剂（NLCXm）的Ca 2+流出来平衡连续的线粒体Ca 2+内流。因此，CGP-37157对NCLXm的抑制导致患者细胞而非对照细胞中线粒体Ca 2+的快速积累。我们认为，增加NCLX活性将增加钠/质子交换，可能破坏氧化磷酸化，虽然这是平衡的去磷酸化和激活丙酮酸脱氢酶（PDH）响应增加[Ca 2 +]m。与该模型一致，虽然患者来源的或对照成纤维细胞中的ATP含量没有差异，但患者细胞中的ATP响应于CGP-37157而显著增加，而对照细胞中则没有。此外，与对照组相比，MICU 1患者细胞中的EMRE表达水平发生了改变。MICU 1突变与线粒体片段化有关，我们发现线粒体片段化与DRP 1磷酸化改变有关。因此，MICU 1在线粒体钙信号传导中充当信号噪声抑制剂，限制线粒体Ca 2+信号传导的能量成本，这可能破坏氧化磷酸化，特别是在具有高度动态能量需求的组织中。本文是由Claus Heizmann、Joachim Krebs和Jacques Haiech编辑的题为：ECS会议的特刊的一部分。人成纤维细胞中MICU 1蛋白表达的缺失增加静息线粒体钙浓度（[Ca 2 +]m）。增加的线粒体Ca 2+摄取导致MICU 1缺陷细胞中无效的Ca 2+循环。[Ca 2 +]增加通过激活丙酮酸脱氢酶（PDH）磷酸酶而使PDH失活，从而使PDH去磷酸化。MICU 1的缺失导致MCU复合物组成的改变和线粒体片段化。
Loss of function mutations of the protein MICU1, a regulator of mitochondrial Ca2 + uptake, cause a neuronal and muscular disorder characterised by impaired cognition, muscle weakness and an extrapyramidal motor disorder. We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca2+ concentration ([Ca2 +]m). We now explore the functional consequences of MICU1 mutations in patient derived fibroblasts in order to clarify the underlying pathophysiology of this disorder. We propose that deregulation of mitochondrial Ca2+ uptake through loss of MICU1 raises resting [Ca2+]m, initiating a futile Ca2+ cycle, whereby continuous mitochondrial Ca2+ influx is balanced by Ca2+ efflux through the sodium calcium exchanger (NLCXm). Thus, inhibition of NCLXm by CGP-37157 caused rapid mitochondrial Ca2+ accumulation in patient but not control cells. We suggest that increased NCLX activity will increase sodium/proton exchange, potentially undermining oxidative phosphorylation, although this is balanced by dephosphorylation and activation of pyruvate dehydrogenase (PDH) in response to the increased [Ca2+]m. Consistent with this model, while ATP content in patient derived or control fibroblasts was not different, ATP increased significantly in response to CGP-37157 in the patient but not the control cells. In addition, EMRE expression levels were altered in MICU1 patient cells compared to the controls. The MICU1 mutations were associated with mitochondrial fragmentation which we show is related to altered DRP1 phosphorylation. Thus, MICU1 serves as a signal–noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca2+ signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. Loss of MICU1 protein expression in human fibroblasts increases resting mitochondrial calcium concentration ([Ca2+]m). The increased mitochondrial Ca2+ uptake causes a futile Ca2+ cycle in MICU1 deficient cells. Increased [Ca2+]mactivates pyruvate dehydrogenase (PDH) by activating PDH phosphatase, consequently dephosphorylating PDH. Loss of MICU1 leads to modifications of the MCU complex composition and mitochondrial fragmentation.