The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
复制标题
DOI：
10.4049/jimmunol.2300406
复制
发表时间：
2023-11-01
期刊：
影响因子：
--
通讯作者：
Malmberg KJ
中科院分区：
文献类型：
--
作者：
Clement D;Szabo EK;Krokeide SZ;Wiiger MT;Vincenti M;Palacios D;Chang YT;Grimm C;Patel S;Stenmark H;Brech A;Majhi RK;Malmberg KJ
TRPML1衍生的溶酶体钙调节线粒体的组织和适合性。溶酶体钙通道TRPML1的缺失导致线粒体功能障碍。TRPML1活性调节自噬诱导，这是有丝分裂的先决条件。细胞毒性淋巴细胞通过释放裂解颗粒来清除癌细胞，裂解颗粒是一种特殊形式的分泌型溶酶体。这个隔室是多形性内溶酶体系统的一部分，其特点是具有高度动态的钙信号机制。几种瞬时受体电位(Trp)钙通道在内溶酶体内钙信号转导中起着重要作用，并保证这些细胞器的正常功能。在这项研究中，我们研究了TRPML1(Trp阳离子通道，粘脂亚家族，成员1)在调节人NK细胞分泌溶酶体的动态平衡及其与线粒体的相互作用中的作用。我们发现，定位于NK细胞溶酶体的TRPML1基因缺失导致线粒体碎裂，并有线粒体脊塌陷的证据。因此，TRPML1ATPNK92(NK92ML1−/−−/−)表现为线粒体膜电位丧失，活性氧应激增加，三磷酸腺苷生成减少，呼吸能力降低。使用敏感的细胞器特异性探针，我们观察到NK92ML1−/−细胞的线粒体表现出钙超载的证据。此外，药物激活原代NK细胞的TRPML1通道导致了LC3-II的上调，而基因缺失阻碍了自噬流量和功能障碍的线粒体的积累。因此，TRPML1影响自噬和受损线粒体的清除。综上所述，这些结果表明，NK细胞中的一种紧密的细胞器间通讯是由溶酶体钙通道TRPML1协调的。
TRPML1-derived lysosomal calcium regulates mitochondrial organization and fitness. Loss of the lysosomal calcium channel TRPML1 leads to mitochondrial dysfunction. TRPML1 activity modulates autophagy induction, a prerequisite for mitophagy. Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1−/− NK92 (NK92ML1−/−) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1−/− cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.