Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1
Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1
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DOI：
10.1073/pnas.2003236117
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发表时间：
2020-08-11
影响因子：
11.1
通讯作者：
Krainc, Dimitri
中科院分区：
文献类型：
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作者：
Peng, Wesley;Wong, Yvette C.;Krainc, Dimitri
线粒体和溶酶体对于细胞稳态至关重要，这两种细胞器的功能障碍与许多疾病有关。最近，线粒体和溶酶体之间的细胞器间接触被鉴定并发现可以调节线粒体动力学。然而，线粒体-溶酶体接触是否通过促进两个细胞器之间代谢物或离子的直接转移来提供额外的功能尚未阐明。在这里，使用高空间和时间分辨率活细胞显微镜，我们确定了线粒体-溶酶体接触通过溶酶体钙流出通道瞬时受体电位粘脂蛋白 1 (TRPML1) 调节线粒体钙动力学的作用。 TRPML1 释放的溶酶体钙促进钙转移到线粒体，这是通过线粒体-溶酶体接触位点的束缚介导的。此外，线粒体-溶酶体接触位点的线粒体钙摄取分别受到线粒体外膜通道和线粒体内膜通道、电压依赖性阴离子通道1和线粒体钙单向转运蛋白的调节。由于 TRPML1 功能丧失会导致 IV 型溶酶体贮积症粘脂沉积症 (MLIV)，因此我们检查了 MLIV 患者的成纤维细胞，发现线粒体-溶酶体接触动力学发生了改变，接触依赖性线粒体钙吸收也发生了缺陷。因此，我们的工作强调线粒体-溶酶体接触是细胞器间钙动力学的关键贡献者，及其在以线粒体或溶酶体功能障碍为特征的疾病的病理生理学中的潜在作用。
Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contactdependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.