Hence the aim of the present article is instead to provide in a first part a short focus on the methods of intracellular pH measurements and on the physical and chemical principles that govern intracellular pH regulation. In addition, this special issue, the present article is part of, also contains a set of articles covering several aspects of the field. In the last decades several colleagues have written excellent and comprehensive reviews on the various aspects of pH regulation in normal and pathological conditions. Those comprise pumps, leaks, and secondary transporters that can either translocate H +, bicarbonate or other buffers such as monocarboxylates. In this context, evolution has selected an array of molecular mechanisms that address the challenge of regulating their pH by transporting acid-base equivalents across membranes. In fine, pH, its gradients and dynamics dictate the space and time of macromolecular interactions. The later reason is of utmost importance because interactions between molecules are built through electrostatics that are dictated by surface charge. Those can directly be proton gradients such as in mitochondria, or indirectly provide and electro-osmotic driving force for protons, such as plasma membranes or in those of intracellular compartments, 3) the surface charge of macromolecules is dictated by their protonation state, which in turn depends on the availability of free H + ions, namely on pH. The reasons for this situation are at least threefold: 1) many reactions involve the fast release or consumption of protons an/or acid base equivalents, 2) cells are not simply chemical bags and use charge gradients across membranes to generate and store free energy. In the cytosol or in intracellular compartments pH is both one of the most controlled and one of the most challenging to control parameter. As the cologarithm of free H + concentration, pH quantifies the abundance of the smallest cation in the Universe, namely a proton, which is a hydrogen atom stripped of its electron. While recent publications show that temperature of biochemical mechanisms is far from being simple to measure and should receive more attention ( Chretien et al., 2018 Lane, 2018) this review will deal with several aspects pertaining to pH regulation. Also of note both pH and temperature have a vast biological impact from the tiniest molecular mechanisms to the planetary ecosystem. While cell mechanics have recently received a regain of attention, pH and temperature are often regarded as more trivial by non-specialists, possibly because they are easy to set and measure in everyday life, which in contrast is not the case at the cellular and subcellular scales. Temperature, pH and mechanical forces are fundamental physical parameters that affect living cells in all phyla. This latter section will highlight how modeling can yield fundamental insight into deep biological questions such as the utility of functional redundancy in natural selection. We will also test the presence or absence of intracellular buffering. For this purpose, we will use mathematical modeling to simulate cellular response to persistent and/or transient acidification, in the presence of different transporters, single or in combination. Following this we will discuss the large functional redundancy found in the transporters of H + or acid-base equivalents. After presenting the main techniques used for intracellular an vesicular pH measurements we will briefly recall the main molecular mechanisms that affect and regulate intracellular pH. Intracellular pH is a vital parameter that is maintained close to neutrality in all mammalian cells and tissues and acidic in most intracellular compartments. 4Université Côte d’Azur, CNRS, Institut de Physique de Nice, INPHYNI, Nice, France.3Centre Hospitalier Universitaire de Nice, Service de Médecine Intensive Réanimation, Hôpital Archet 1, Nice, France.2Laboratories of Excellence Ion Channel Science and Therapeutics, Nice, France.1Université Côte d’Azur, CNRS, Laboratoire de Physiomédecine Moléculaire, Nice, France.Pisani 1,2 Michel Tauc 1,2 Marc Cougnon 1,2 Mederic Argentina 4 Yann Bouret 3 Laurent Counillon 1,2* Denis Doyen 1,2,3 Mallorie Poët 1,2 Gisèle Jarretou 1,2 Didier F.
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