Aerobic Respiration: Criticism of the Proton-centric Explanation Involving Rotary Adenosine Triphosphate Synthesis, Chemiosmosis Principle, Proton Pumps and Electron Transport Chain

Abstract

The acclaimed explanation for mitochondrial oxidative phosphorylation (mOxPhos, or cellular respiration) is a deterministic proton-centric scheme involving four components: Rotary adenosine triphosphate (ATP)-synthesis, Chemiosmosis principle, Proton pumps, and Electron transport chain (abbreviated as RCPE hypothesis). Within this write-up, the RCPE scheme is critically analyzed with respect to mitochondrial architecture, proteins' distribution, structure-function correlations and their interactive dynamics, overall reaction chemistry, kinetics, thermodynamics, evolutionary logic, and so on. It is found that the RCPE proposal fails to explain key physiological aspects of mOxPhos in several specific issues and also in holistic perspectives. Therefore, it is imperative to look for new explanations for mOxPhos.

Keywords: ATP-synthesis; electron transport chain; heme/flavin proteins; mitochondrial membrane; respiratory proteins.

Figure 1.

Cartoon representation of the salient components of mOxPhos, per the notions of the proton-centric scheme (for the Complex I ETC). The three multimeric complexes on the left side constitute the ETC, whereas the lone multimeric complex on the right constitutes the ATP-synthesizing “rotary enzyme”. The diagram is not drawn to scale with respect to the dimensions of proteins or the respective positions or distribution densities. ATP: adenosine triphosphate; ETC, electron transport chain; IMS, inter-membrane space; IPLM, inner phospholipid membrane; mOxPhos, mitochondrial oxidative phosphorylation; NADH, reduced nicotinamide adenine dinucleotide.

Figure 2.

The energy terms of input and expenses and the distinct “energetic windows” within the ETC (along with the classical metabolic blockers of the key steps shown in underlined text). ATP, adenosine triphosphate; CoQ, coenzyme Q; NADH, reduced nicotinamide adenine dinucleotide.

Figure 3.

Pictorial renditions of working analogies of RCPE hypothesis for mOxPhos. (In both images, factual components are in normal fonts and the analogy is italicized.). ATP: adenosine triphosphate; ETC, electron transport chain; IMS, inter-membrane space; IPLM, inner phospholipid membrane; mOxPhos, mitochondrial oxidative phosphorylation; NADH, reduced nicotinamide adenine dinucleotide.

Figure 4.

Top: a schematic representation of the existent ETC route and proton-pumping sites within Complex I. Clearly, the purported proton-pumping region and intra-molecular Fe-S ET have little connectivity. Bottom: the expected structure for a respiratory complex that could have potentially abided by the RCPE system. The prevailing ETC seeks a smaller matrix-ward projection (with a direct transfer of two electrons from the source to the membrane portion, without intervening solvent-accessible cavities), the burial of redox centers within TM region and specific relay of membrane-soluble redox relay agents. Then, such a series could have served as a kind of electron relay which could aid interspersed proton-pumping along the ET route. CoQ, coenzyme Q; ET, electron transfer; ETC, electron transport chain; FMN, flavin mononucleotide; IMS, inter-membrane space; IPLM, inner phospholipid membrane; mOxPhos, mitochondrial oxidative phosphorylation; NADH, nicotinamide adenine dinucleotide.

Figure 5.

The various steps and circuitry of Q-cycle transpiring at Complex III. The two CoQ-binding sites are marked in square boxes and the Cyt. c-binding site is marked by ellipse. The x and y prefixes for CoQ and Cyt. c connote two different molecules (not numbers). CoQ, coenzyme Q; Cyt. c, IMS, inter-membrane space; IPLM, inner phospholipid membrane.