2. Academic Validation
  3. Inhibition of VDAC1 oligomerization blocks cysteine deprivation-induced ferroptosis via mitochondrial ROS suppression

Inhibition of VDAC1 oligomerization blocks cysteine deprivation-induced ferroptosis via mitochondrial ROS suppression

  • Cell Death Dis. 2024 Nov 9;15(11):811. doi: 10.1038/s41419-024-07216-1.
Se-Kyeong Jang # 1 2,  Se Hee Ahn # 1 3,  Gyeongmi Kim 1,  Selim Kim 1,  Jungil Hong 2,  Ki Soo Park 3,  In-Chul Park 4,  Hyeon-Ok Jin 5
Affiliations

Affiliations

  • 1 Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
  • 2 Department of Food Science and Technology, College of Science and Convergence Technology, Seoul Women's University, Seoul, Republic of Korea.
  • 3 Department of Biological Engineering, Konkuk University, Seoul, Republic of Korea.
  • 4 Division of Fusion Radiology Research, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea. parkic@kirams.re.kr.
  • 5 KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. hyeonok@kirams.re.kr.
  • # Contributed equally.
PMID: 39521767 DOI: 10.1038/s41419-024-07216-1
Abstract

Ferroptosis, a regulated form of cell death dependent on Reactive Oxygen Species (ROS), is characterized by iron accumulation and lethal lipid peroxidation. Mitochondria serve as the primary source of ROS and thus play a crucial role in Ferroptosis initiation and execution. This study highlights the role of mitochondrial ROS and the significance of voltage-dependent anion channel 1 (VDAC1) oligomerization in Ferroptosis induced by cysteine deprivation or ferroptosis-inducer RSL3. Our results demonstrate that the mitochondria-targeted Antioxidants MitoQ and MitoT effectively block Ferroptosis induction and that dysfunction of complex III of the mitochondrial electron transport chain contributes to Ferroptosis induction. Pharmacological inhibitors that target VDAC1 oligomerization have emerged as potent suppressors of Ferroptosis that reduce mitochondrial ROS production. These findings underscore the critical involvement of mitochondrial ROS production via complex III of the electron transport chain and the essential role of VDAC1 oligomerization in Ferroptosis induced by cysteine deprivation or RSL3. This study deepens our understanding of the intricate molecular networks governing Ferroptosis and provides insights into the development of novel therapeutic strategies targeting dysregulated cell death pathways.

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