Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering

• Published in: International journal of molecular sciences 2022-01, Vol.23 (3), p.1124
• Main Authors: Suzuki-Karasaki, Manami, Ando, Takashi, Ochiai, Yushi, Kawahara, Kenta, Suzuki-Karasaki, Miki, Nakayama, Hideki, Suzuki-Karasaki, Yoshihiro
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Air plasma; Animals; Antioxidants; Apoptosis; Autophagy; Biomedical materials; Bone cancer; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Cancer therapies; Cell activation; Cell Death; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cluster Analysis; Clustering; Cytotoxicity; Humans; Hypoxia; Lipid Peroxides - metabolism; Lipids; Male; Medical prognosis; Metastases; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Dynamics - drug effects; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Nocodazole; Oral cancer; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Oxidative stress; Plasma; Plasma Gases - administration & dosage; Plasma Gases - pharmacology; Reactive Oxygen Species - metabolism; Sarcoma; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031124

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as -acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity.