The mitochondrial permeability transition regulates cytochrome c release for apoptosis during endoplasmic reticulum stress by remodeling the cristae junction.
The role of the mitochondrial permeability transition (MPT) in apoptosis and necrosis is controversial. Here we show that the MPT regulates the release of cytochrome c for apoptosis during endoplasmic reticulum (ER) stress by remodeling the cristae junction (CJ). CEM cells, HCT116 colon cancer cells, and murine embryo fibroblast cells were treated with the ER stressor thapsigargin (THG), which led to cyclophilin D-dependent mitochondrial release of the profusion GTPase optic atrophy 1 (OPA1), which controls CJ integrity, and cytochrome c, leading to apoptosis. Interference RNA knockdown of Bax blocked OPA1 and cytochrome c release after THG treatment but did not prevent the MPT, showing that Bax was essential for the release of cytochrome c by MPT. In isolated mitochondria, MPT led to OPA1 and cytochrome c release independently of voltage-dependent anion channel and the outer membrane, indicating that the MPT is an inner membrane phenomenon. Last, the MPT was regulated by the electron transport chain but not mitochondrial reactive oxygen species, since THG-induced cell death was not blocked by antioxidants and did not occur in cells lacking mitochondrial DNA. Our results show that the MPT regulates CJ remodeling for cytochrome c-dependent apoptosis induced by ER stress and that mitochondrial electron transport is indispensable for this process.
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore; Institute of Bioengineering and Nanotechnology, Singapore 138669, Singapore.
Dawei
D
Zhang
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore.
Chao
C
Lu
Peninsula Medical School, Universities of Exeter and Plymouth, Exeter EX1 2LU, United Kingdom.
Matthew
M
Whiteman
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Britton
B
Chance
Department of Biochemistry, National University of Singapore, Singapore 117597, Singapore. Electronic address: bchjsa@nus.edu.sg.
Jeffrey S
JS
Armstrong
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010539:Permeability; D017382:Reactive Oxygen Species
D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C498809:Opa1 protein, mouse