Paired moving charge model of energy coupling. III. Intrinsic ionophores in energy coupling systems.

Abstract

The experimental basis for the postulated role of intrinsic ionophores in mitochondrial ion transport and energy coupling is summarized. Intrinsic ionophores appear to be linked to, or contained within, specific ionophoroproteins localized in the inner membrane, and the isolation of these ionophores requires their release from the ionophoroproteins. At least ten different species of ionophores have been isolated from the mitochondrion, five of which have been wholly or in part chemically identified. Intrinsic ionophores have been implicated in the activation of inorganic phosphate in ATP synthesis and hydrolysis, and in the control of the coupling modes. The presence of ionophores in soluble proteins such as troponin and in ATP-energized kinases has been demonstrated.Ionophores occupy a central position in energy coupling systems by virtue of their unique capability for charge separation (1, 2). The present communication has two objectives-first, to summarize the rapidly growing body of experimental evidence relevant to the intrinsic ionophores of the mitochondrion, and second, to provide a framework and perspective for the new field of experimental inquiry revolving about these intrinsic ionophores.Historical. The use of antibiotic ionophores in the study of energy coupling in mitochondria has a long history dating back to the discovery by Dubos and Hotchkiss (3) that the polypeptide antibiotics produced by Bacillus brevis, collectively referred to as gramicidin, were uncouplers of mitochondrial oxidative phosphorylation (4, 5) and facilitated the movement of K+ across bacterial membranes (6). Lardy (7,8) and Pressman (9, 10) have been the pioneers in examining the modulating role of antibiotic ionophores on mitochondrial energy coupling and in introducing the use of antibiotic ionophores for the study of energy coupling. Eisenman (11,12) and Eigen (13) have developed the framework of principles which underlie the transport of ions across membranes by antibiotic ionophores. In recent years, ionophoretic activity has been demonstrated in a wide variety of molecular structures (14); moreover, the synthetic chemist has shown great aptitude in designing molecular structures that exhibit ionophoretic capability (14).The curious point is that, although these experimental and theoretical developments established beyond peradventure that ionophores were active at incredibly high dilutions in facilitating ion transport, and provided the perfect models for the natural mediators of active transport and ion movements generally, nonetheless there was great reluctance, nay strong opposition, to taking the next obvious step of identifying the natural mediators of ion movements as ionophores. What was the basis for this resistance to the next obvious step? There were three main reasons. First, since extrinsic ionophores were antibiotics and potentially lethal reagents, the presence of natural counterparts of these ionophores in coupling systems was deemed to be highly improbable. Second, the concept of fixed channels i...

Isolation of a low molecular weight Ca2+ carrier from calf heart inner mitochondrial membrane.

“…Isolation of this site may yield a moiety similar to bacterial antibiotic ionophores, e.g., valinomycin, with a hydrophobic exterior. This seems very likely in the case of carrier-mediated Ca2+ transport in mitochondria, where it is thought that Ca2+ is driven by the electrochemical potential of the hydrogen ion (17) or by paired moving charges in which the ion-ionophore complex plays a major role (18,19). This means we should be able to isolate a low molecular weight protein that shows high affinity for Ca2+ and transports Ca2+ in a manner similar to ionophores such as X537A and A23187 (20,21).…”

Physical basis of charge pairing in mitochondria.

“…For dielectric constants 10 or less pairing is absolute, for 20 there is some tendency towards pairing, and at 78 it is nonexistent. Pairing, partner exchange or charge substitution, inhibition, and antiport uncoupling can be rationalized within this framework.In the charge pair model presently under development (1)(2)(3)(4)(5) the pairing of opposite charges is the fundamental principle by which the operation of mitochondria and of other bioenergetic systems is rationalized. This pairing has so far been treated as a postulate.…”

“…In the charge pair model presently under development (1)(2)(3)(4)(5) the pairing of opposite charges is the fundamental principle by which the operation of mitochondria and of other bioenergetic systems is rationalized. This pairing has so far been treated as a postulate.…”