Breaking the Q-cycle: finding new ways to study Qo through thermodynamic manipulations

Thirty years ago, Peter Mitchell won the Nobel Prize for proposing how electrical and proton gradients across bioenergetic membranes were the energy coupling intermediate between photosynthetic and respiratory electron transfer and cellular activities that include ATP production. A high point of his thinking was the development of the Q-cycle model that advanced our understanding of cytochrome bc ₁. While the principle tenets of his Q-cycle still hold true today, Mitchell did not explain the specific mechanism that allows the Qo site to perform this Q-cycle efficiently without undue energy loss. Though much speculation on Qo site mode of molecular action and regulation has been introduced over the 30 years after Mitchell collected his Prize, no single mechanism has been universally accepted. The mystery behind the Qo site mechanism remains unsolved due to elusive kinetic intermediates during Qo site electron transfer that have not been detected spectroscopically. Therefore, to reveal the Qo mechanism, we must look beyond traditional steady-state experimental approaches by changing cytochrome bc ₁ thermodynamics and promoting otherwise transient Qo site redox states. Invited paper to special issue “Peter Mitchell 30th anniversary” for JBB.