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Plasma - Activated medium engages redox signaling to activate a VDAC1-TRPML1 lysosomal-mitochondrial Ca2+ death

Pengpeng Huang1, Yan Zheng2, Chuanzan Zhou3

  • 1School of Nuclear Science and Technology, University of Science and Technology of China, Hefei, Anhui, China; Institute of Advanced Technology, University of Science and Technology of China, Hefei, Anhui, China.

Free Radical Biology & Medicine
|June 4, 2026
PubMed

Insights

Plasma-activated medium (PAM) triggers cancer cell death by disrupting calcium flow between lysosomes and mitochondria. This involves the VDAC1-TRPML1 axis, offering a potential therapeutic target and biomarker for cancer treatment.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Plasma-activated medium (PAM) is a redox-based anticancer therapy with unclear mechanisms of tumor cell death.
  • Understanding PAM's action is crucial for optimizing its therapeutic potential.

Purpose of the Study:

  • To elucidate the molecular mechanisms of PAM-induced tumor cell death.
  • To identify key molecular players and pathways involved in PAM cytotoxicity.
  • To explore the VDAC1-TRPML1 axis as a potential therapeutic target and biomarker.

Main Methods:

  • Utilized A549 lung cancer cells and other tumor models.
  • Investigated organelle contact sites and calcium (Ca2+) flux between lysosomes and mitochondria.
  • Analyzed signaling pathways including mTORC2-SGK1 and VDAC1 phosphorylation.
  • Performed in vivo studies and pan-cancer analyses.

Main Results:

  • Identified a lysosome-mitochondria Ca2+ circuit critical for PAM-induced cell death.
  • PAM promotes VDAC1-TRPML1 coupling, leading to lysosomal Ca2+ release and mitochondrial Ca2+ overload.
  • PAM suppresses mTORC2-SGK1 signaling, stabilizing VDAC1 and enhancing pathological Ca2+ transfer.
  • Disrupting the VDAC1-TRPML1 interaction or VDAC1 phosphorylation attenuated PAM's antitumor effects.
  • High VDAC1 expression may predict tumor response to PAM.

Conclusions:

  • The VDAC1-TRPML1 axis is a key mediator of PAM-induced, lysosome-mitochondria Ca2+-dependent tumor cell death.
  • This pathway represents a novel therapeutic target and a potential biomarker for stratifying tumors for PAM therapy.
  • Findings advance the understanding of redox-based cancer therapies and cell death mechanisms.
Keywords:
Lysosome crosstalkMitochondriaMitochondrial calcium overloadPlasma activated mediumUbiquitinationVDAC1-TRPML1 interaction sites

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