Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II.
Alpha-tocopheryl succinate (alpha-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of alpha-TOS has not been identified. Here, we show that alpha-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q(P) and Q(D), respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of alpha-TOS compared to that of UbQ for the Q(P) and Q(D) sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of alpha-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to alpha-TOS. We propose that alpha-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.
Dong
L-F
LF
Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Low
P
P
Dyason
J C
JC
Wang
X-F
XF
Prochazka
L
L
Witting
P K
PK
Freeman
R
R
Swettenham
E
E
Valis
K
K
Liu
J
J
Zobalova
R
R
Turanek
J
J
Spitz
D R
DR
Domann
F E
FE
Scheffler
I E
IE
Ralph
S J
SJ
Neuzil
J
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D042963:Electron Transport Complex II / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D011487:Protein Conformation; D017382:Reactive Oxygen Species; D024505:Tocopherols; D014451:Ubiquinone / Q000737:chemistry*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; C478189:respiratory complex II; D014451:Ubiquinone; D014810:Vitamin E; D042963:Electron Transport Complex II; D024505:Tocopherols