The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk
Year: 2023
Type: article
Abstract: 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.
Source: The Journal of Immunology
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,500
Funders: Kreftforeningen, European Commission, Stiftelsen för Strategisk Forskning, Cancerfonden, Helse- og Omsorgsdepartementet, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Norges Forskningsråd, Barncancerfonden, HORIZON EUROPE Framework Programme, Biotechnology and Biological Sciences Research Council, Helse Sør-Øst RHF, National Cancer Institute, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: G1041968903, G1361880963, Membrane contact sites between endolysosomes and the ER as novel hubs in Ca2+ signalling., G1548982775, G1985722182, G2146638502, G2721544364, G3266172733, Understanding polymodal gating of a lysosomal ion channel, G4614614772, G4906268028, G5718969220, G5789738556, G5953125828, Switching the ion selectivity of an ion channel on demand, G6259914438, G6956744914, G7605698675, G7690631208, SCIENTIA-FELLOWS II: International Postdoctoral Fellowship Programme, G8758535662, NK cells, their receptors and cancer therapy
OpenAlex ID: W4386944903