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2015 ; 6
(ä): 210
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Three toxic gases meet in the mitochondria
#MMPMID26347655
Decréau RA
; Collman JP
Front Physiol
2015[]; 6
(ä): 210
PMID26347655
show ga
The rationale of the study was two-fold: (i) develop a functional synthetic model
of the Cytochrome c oxidase (CcO) active site, (ii) use it as a convenient tool
to understand or predict the outcome of the reaction of CcO with ligands
(physiologically relevant gases and other ligands). At physiological pH and
potential, the model catalyzes the 4-electron reduction of oxygen. This model was
immobilized on self-assembled-monolayer (SAM) modified electrode. During
catalytic oxygen reduction, electron delivery through SAMs is rate limiting,
similar to the situation in CcO. This model contains all three redox-active
components in CcO's active site, which are required to minimize the production of
partially-reduced-oxygen-species (PROS): Fe-heme ("heme a3") in a myoglobin-like
model fitted with a proximal imidazole ligand, and a distal tris-imidazole Copper
("CuB") complex, where one imidazole is cross-linked to a phenol (mimicking
"Tyr244"). This functional CcO model demonstrates how CcO itself might tolerate
the hormone NO (which diffuses through the mitochondria). It is proposed that CuB
delivers superoxide to NO bound to Fe-heme forming peroxynitrite, then nitrate
that diffuses away. Another toxic gas, H2S, has exceptional biological effects:
at ~80 ppm, H2S induces a state similar to hibernation in mice, lowering the
animal's temperature and slowing respiration. Using our functional CcO model, we
have demonstrated that at the same concentration range H2S can reversibly inhibit
catalytic oxygen reduction. Such a reversible catalytic process on the model was
also demonstrated with an organic compound, tetrazole (TZ). Following studies
showed that TZ reversibly inhibits respiration in isolated mitochondria, and
induces deactivation of platelets, a mitochondria-rich key component of blood
coagulation. Hence, this program is a rare example illustrating the use of a
functional model to understand and predict physiologically important reactions at
the active site of CcO.
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