Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca2+ Influx and Mitochondrial Permeability Transition

Kang, Myung-Ji; Ryu, Hyung Won; Oh, Eun Sol; Song, Yu Na; Huh, Yang Hoon; Park, Ji-Yoon; Oh, Seon Min; Lee, Su-Yeon; Park, Yhun Jung; Kim, Doo-Young; Ro, Hyunju; Hong, Sung-Tae; Lee, Su Ui; Moon, Dong-Oh; Kim, Mun-Ock

doi:10.3390/ijms24087057

Open AccessArticle

Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition

by

Myung-Ji Kang

^1,†,

Hyung Won Ryu

^1,†

,

Eun Sol Oh

^1,2,

Yu Na Song

^1,2,

Yang Hoon Huh

³,

Ji-Yoon Park

^1,4,

Seon Min Oh

¹,

Su-Yeon Lee

¹,

Yhun Jung Park

¹,

Doo-Young Kim

¹,

Hyunju Ro

²,

Sung-Tae Hong

⁴

,

Su Ui Lee

¹

,

Dong-Oh Moon

^5,* and

Mun-Ock Kim

^1,*

¹

Natural Product Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju 28116, Republic of Korea

²

Department of Biological Sciences, College of Bioscience and Biotechnology, Chungnam National University, Daejeon 34134, Republic of Korea

³

Korea Basic Science Institute, Cheongju 28119, Republic of Korea

⁴

Departments of Anatomy & Cell Biology, Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea

⁵

Department of Biology Education, Daegu University, 201 Daegudae-ro, Gyeongsan-si 38453, Republic of Korea

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2023, 24(8), 7057; https://doi.org/10.3390/ijms24087057

Submission received: 15 March 2023 / Revised: 2 April 2023 / Accepted: 6 April 2023 / Published: 11 April 2023

(This article belongs to the Special Issue Advances in Natural Products for Application in Biomedicine and Pharmacotherapy 3.0)

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Abstract

The recently defined type of cell death ferroptosis has garnered significant attention as a potential new approach to cancer treatment owing to its more immunogenic nature when compared with apoptosis. Ferroptosis is characterized by the depletion of glutathione (GSH)/glutathione peroxidase-4 (GPx4) and iron-dependent lipid peroxidation. Diplacone (DP), a geranylated flavonoid compound found in Paulownia tomentosa fruit, has been identified to have anti-inflammatory and anti-radical activity. In this study, the potential anticancer activity of DP was explored against A549 human lung cancer cells. It was found that DP induced a form of cytotoxicity distinct from apoptosis, which was accompanied by extensive mitochondrial-derived cytoplasmic vacuoles. DP was also shown to increase mitochondrial Ca²⁺ influx, reactive oxygen species (ROS) production, and mitochondrial permeability transition (MPT) pore-opening. These changes led to decreases in mitochondrial membrane potential and DP-induced cell death. DP also induced lipid peroxidation and ATF3 expression, which are hallmarks of ferroptosis. The ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 were effective in counteracting the DP-mediated ferroptosis-related features. Our results could contribute to the use of DP as a ferroptosis-inducing agent, enabling studies focusing on the relationship between ferroptosis and the immunogenic cell death of cancer cells.

Keywords: diplacone (DP); mitochondria permeability transition (MPT); ferroptosis; vacuolation

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MDPI and ACS Style

Kang, M.-J.; Ryu, H.W.; Oh, E.S.; Song, Y.N.; Huh, Y.H.; Park, J.-Y.; Oh, S.M.; Lee, S.-Y.; Park, Y.J.; Kim, D.-Y.; et al. Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition. Int. J. Mol. Sci. 2023, 24, 7057. https://doi.org/10.3390/ijms24087057

AMA Style

Kang M-J, Ryu HW, Oh ES, Song YN, Huh YH, Park J-Y, Oh SM, Lee S-Y, Park YJ, Kim D-Y, et al. Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition. International Journal of Molecular Sciences. 2023; 24(8):7057. https://doi.org/10.3390/ijms24087057

Chicago/Turabian Style

Kang, Myung-Ji, Hyung Won Ryu, Eun Sol Oh, Yu Na Song, Yang Hoon Huh, Ji-Yoon Park, Seon Min Oh, Su-Yeon Lee, Yhun Jung Park, Doo-Young Kim, and et al. 2023. "Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition" International Journal of Molecular Sciences 24, no. 8: 7057. https://doi.org/10.3390/ijms24087057

APA Style

Kang, M.-J., Ryu, H. W., Oh, E. S., Song, Y. N., Huh, Y. H., Park, J.-Y., Oh, S. M., Lee, S.-Y., Park, Y. J., Kim, D.-Y., Ro, H., Hong, S.-T., Lee, S. U., Moon, D.-O., & Kim, M.-O. (2023). Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition. International Journal of Molecular Sciences, 24(8), 7057. https://doi.org/10.3390/ijms24087057

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Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca²⁺ Influx and Mitochondrial Permeability Transition

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