The Redox architecture of physiological function

Abstract

The ability of organisms to accommodate variations in metabolic need and environmental conditions is essential for their survival. However, an explanation is lacking as to how the necessary accommodations in response to these challenges are organized and coordinated from (sub)cellular to higher-level physiological functions, especially in mammals. We propose that the chemistry that enables coordination and synchronization of these processes dates to the origins of Life. We offer a conceptual framework based upon the nature of electron exchange (Redox) processes that co-evolved with biological complexification, giving rise to a multi-layered system in which intra/intercellular and inter-organ exchange processes essential to sensing and adaptation stay fully synchronized. Our analysis explains why Redox is both the lingua franca and the mechanism that enable integration by connecting the various elements of regulatory processes. We here define these interactions across levels of organization as the 'Redox Interactome'. This framework provides novel insight into the chemical and biological basis of Redox signalling and may explain the recent convergence of metabolism, bioenergetics, and inflammation as well as the relationship between Redox stress and human disease.

Scheme 1

The Redox landscape on Earth. The Redox landscape of the biosphere (green ellipses) is connected to the inorganic chemistry of the atmosphere, the oceans, and the earth mantle through interactions among Reactive Nitrogen, Carbon, Oxygen and Sulfur Species.

Scheme 2

Increasing complexity of major Redox-active biomolecules. Examples of contemporary Redox cofactors displaying various types of Redox reactivity (heterocycles, aromatics, unsaturated bonds, thiols, metallo-complexes etc.).

Scheme 3

Complexification and stabilizing Redox machineries. Examples of increasingly complex Redox systems showing compartmentalization and synchronization of different Redox biochemistries, including the catalytic pocket of a protein, the isolated oxidative chemistry of a peroxisome, the build-up of transmembrane electrochemical gradients in a chloroplast, the intracellular coupling of Redox processes within a cell, and the variations in Redox environments coupled to organismal evolution.

Scheme 4

Orthogonality of Redox regulation across levels of biological organization. Upper panel: The Redox Spine connecting all layers of regulation. Lower panel: 1. Multiplicity and evolution of Redox agents; arrows reflect the various types of Redox chemistry as a function of time/environment. 2. The complexification of Redox structure as a function of time, from biomolecules to organisms. 3. Evolution and diversification of Redox function, from sensing to adaptation.