Biological trace element research · 2026
Realgar Transforming Solution as a Novel Arsenic Agent Triggers PINK1/Parkin-Dependent Mitophagy and Apoptosis in the Molm-13 Acute Myeloid Leukemia Cell Line.
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Wang Teng, Lyu Chunyi, Luo Yunxiao, Liu Weilin, Han Chen, Tang Xinyu, Xu Ruirong
Аннотация
BACKGROUND: Acute myeloid leukemia (AML) remains challenging to treat due to frequent relapse and therapeutic resistance. Mitochondrial stress responses and mitophagy have emerged as critical regulators of leukemic cell fate. Realgar Transforming Solution (RTS) is a highly soluble arsenic preparation bioleached from realgar via Acidithiobacillus ferrooxidans; however, its impact on mitochondrial quality control in AML is poorly defined.
METHODS: Human AML cell lines Molm-13 and THP-1, as well as normal human bone marrow stromal cells HS-5, were treated with RTS. Cell viability, apoptosis, oxidative stress, mitochondrial membrane potential, and mitophagy were assessed using CCK-8 assays, Annexin V-FITC/PI flow cytometry, DCFH-DA and JC-1 staining, Western blotting, RT-qPCR, monodansylcadaverine staining, immunofluorescence, and transmission electron microscopy. Mitophagy involvement was evaluated using the Drp1/mitophagy inhibitor Mdivi-1, while mitochondrial ROS contribution was examined using the mitochondrial-targeted antioxidant mitoTEMPO.
RESULTS: After 24 h treatment, RTS selectively reduced viability and induced apoptosis in Molm-13 and THP-1 cells, while HS-5 cells were less sensitive. RTS provoked mitochondrial ROS accumulation, MMP loss, Bax/Cyt-c upregulation and Bcl-2 downregulation. Concomitantly, markers of PINK1/Parkin-dependent mitophagy (characterized by increased LC3-II/LC3-I ratio, PINK1/Parkin upregulation, and p62 degradation), increased MDC/TEM autophagic structures, and mitochondrial ultrastructural damage were observed. Pharmacologic inhibition with Mdivi-1 or mitochondrial ROS scavenging with mitoTEMPO significantly attenuated RTS-induced ROS, mitophagy activation, mitochondrial dysfunction and apoptosis.
CONCLUSION: In vitro, RTS induces mitochondrial ROS-dependent activation of PINK1/Parkin-mediated mitophagy that converges on intrinsic mitochondrial apoptosis in AML cells. These data nominate RTS as a mitochondria-targeting candidate for further preclinical evaluation.
METHODS: Human AML cell lines Molm-13 and THP-1, as well as normal human bone marrow stromal cells HS-5, were treated with RTS. Cell viability, apoptosis, oxidative stress, mitochondrial membrane potential, and mitophagy were assessed using CCK-8 assays, Annexin V-FITC/PI flow cytometry, DCFH-DA and JC-1 staining, Western blotting, RT-qPCR, monodansylcadaverine staining, immunofluorescence, and transmission electron microscopy. Mitophagy involvement was evaluated using the Drp1/mitophagy inhibitor Mdivi-1, while mitochondrial ROS contribution was examined using the mitochondrial-targeted antioxidant mitoTEMPO.
RESULTS: After 24 h treatment, RTS selectively reduced viability and induced apoptosis in Molm-13 and THP-1 cells, while HS-5 cells were less sensitive. RTS provoked mitochondrial ROS accumulation, MMP loss, Bax/Cyt-c upregulation and Bcl-2 downregulation. Concomitantly, markers of PINK1/Parkin-dependent mitophagy (characterized by increased LC3-II/LC3-I ratio, PINK1/Parkin upregulation, and p62 degradation), increased MDC/TEM autophagic structures, and mitochondrial ultrastructural damage were observed. Pharmacologic inhibition with Mdivi-1 or mitochondrial ROS scavenging with mitoTEMPO significantly attenuated RTS-induced ROS, mitophagy activation, mitochondrial dysfunction and apoptosis.
CONCLUSION: In vitro, RTS induces mitochondrial ROS-dependent activation of PINK1/Parkin-mediated mitophagy that converges on intrinsic mitochondrial apoptosis in AML cells. These data nominate RTS as a mitochondria-targeting candidate for further preclinical evaluation.