  Mitochondrial oxidative phosphorylation (mOxPhos) makes ATP, the energy
currency of life. Chemiosmosis, a proton centric mechanism, advocates that
Complex V harnesses a transmembrane potential (TMP) for ATP synthesis. This
perception of cellular respiration requires oxygen to stay tethered at Complex
IV (an association inhibited by cyanide) and diffusible reactive oxygen species
(DROS) are considered wasteful and toxic products. With new mechanistic
insights on heme and flavin enzymes, an oxygen or DROS centric explanation
(called murburn concept) was recently proposed for mOxPhos. In the new
mechanism, TMP is not directly harnessed, protons are a rate limiting reactant
and DROS within matrix serve as the chemical coupling agents that directly link
NADH oxidation with ATP synthesis. Herein, we report multiple ADP binding sites
and solvent accessible DROS channels in respiratory proteins, which validate
the oxygen or DROS centric power generation (ATP synthesis) system in mOxPhos.
Since cyanide's heme binding Kd is high (mM), low doses (uM) of cyanide is
lethal because cyanide disrupts DROS dynamics in mOxPhos. The critical study
also provides comprehensive arguments against Mitchell's and Boyer's
explanations and extensive support for murburn concept based holistic
perspectives for mOxPhos.
