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The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk

Dennis Clement1,2, Edina K Szabo1, Silje Zandstra Krokeide1

  • 1Precision Immunotherapy Alliance, Institute for Cancer Research, University of Oslo, Norway.

Journal of Immunology (Baltimore, Md. : 1950)
|September 22, 2023
PubMed

Insights

The lysosomal calcium channel TRPML1 is crucial for maintaining healthy mitochondria and proper autophagy in natural killer (NK) cells. Its absence impairs mitochondrial function and hinders the clearance of damaged organelles.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Cytotoxic lymphocytes, such as NK cells, eliminate cancer cells via secretory lysosomes.
  • Endolysosomal system calcium (Ca2+) signaling is vital for organelle function.
  • TRPML1 is a lysosomal Ca2+ channel implicated in endolysosomal signaling.

Purpose of the Study:

  • To investigate the role of TRPML1 in secretory lysosome homeostasis and mitochondrial communication in human NK cells.

Main Methods:

  • Genetic deletion of TRPML1 in NK92 cells (NK92ML1-/-).
  • Assessment of mitochondrial morphology, membrane potential, and reactive oxygen species (ROS).
  • Measurement of ATP production, respiratory capacity, and Ca2+ levels.
  • Pharmacological activation of TRPML1 and analysis of autophagic flux (LC3-II).

Main Results:

  • TRPML1 deletion caused mitochondrial fragmentation and cristae collapse in NK cells.
  • TRPML1 deficiency led to mitochondrial Ca2+ overload, loss of membrane potential, increased ROS, and reduced ATP production.
  • TRPML1 activation upregulated LC3-II, while its deletion impaired autophagic flux and increased dysfunctional mitochondria.

Conclusions:

  • TRPML1 is essential for maintaining mitochondrial integrity and function within NK cells.
  • TRPML1 regulates autophagy and the clearance of damaged mitochondria.
  • Lysosomal TRPML1 orchestrates interorganelle communication critical for NK cell function.

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