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      For the pursuit of oxygen and carbon dioxide channels in mitochondria

      , M.D., Ph.D. * ,
      Medical Gas Research
      Medknow Publications & Media Pvt Ltd

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          Respiratory gas exchange is a vital activity for many organisms including human being. Through respiration, carbon dioxide (CO2) is exhaled for the exchange of oxygen (O2) from the air. At the cellular level, O2 is used to convert biochemical energy from nutrients into adenosine triphosphate (ATP) with the production of CO2. In the resting state, a healthy adult consumes about 550 L of pure oxygen and produces over 2 pounds (~0.91 kg) of CO2 every day (Jequier et al., 1987). Given that continuous production of ATP is absolute essential for both cell survival and conduction of normal cellular function, exchange of O2 and CO2 at both the respiratory and cellular levels is critical. The mitochondrion is the powerhouse of cells that performs most cellular oxidations and produces majority of ATP (Cheng et al., 2015; d’Esterre et al., 2015; Jing et al., 2015; Shenoda, 2015; Alhadidi et al., 2016). Mitochondria are unusual organelles with two membranes and their own genome. It is believed that the mitochondrial outer membrane has many protein-based pores that are big enough to allow the passage of ions and molecules as large as small proteins. On the other hand, the inner membrane has much more restricted permeability as the plasma membrane of the cell (Mannella, 1992). As the site for main cellular respiration processes of citric acid cycle and oxidative phosphorylation, mitochondria matrix are not only the final destiny for O2 but also the site for CO2 production. O2 and CO2 have to be transported across the cellular membrane, the inner and outer mitochondrial membrane to reach the destiny or release out of the cell. The classical concept of the plasma membranes is extremely permeable to gases, which has been extended to the solubility-diffusion mechanism for the gas transport across plasma membrane, including O2 and CO2 (Finkelstein, 1976; Harch, 2015; Katz et al., 2015; Langston and Toombs, 2015; Parra et al., 2015; Stoller, 2015). It is generally believed that both O2 and CO2 molecules are transport across the plasma membrane through diffusion. Nonetheless, the O2 permeability coefficient for the plasma membrane has been found to be two times lower than that for a water layer of the same thickness as the membrane (Subczynski et al., 1992). Furthermore, plasma membrane has been found to be even less permeable for CO2 (Boron et al., 1994; Waisbren et al., 1994; Endeward and Gros, 2005). Thus, trans-membrane CO2 and O2 channels might serve as an alternative mechanism to increase the permeability of O2 and CO2 cross the plasma membrane. In the last two decades, an increasing evidence has been emerged that aquaporin (APQ) may serve as plasma membrane CO2 channels including AQP1, AQP4, and AQP5 with varied affinities (Herrera and Garvin, 2011; Endeward et al., 2014). On the other hand, pursuing membrane O2 channel has been even more elusive (Endeward et al., 2014). The unique double membrane structure of mitochondria creates even a greater barrier for the cross membrane transport of CO2 and O2. Ironically, much less effort has been invested for the pursuit of mitochondrial membrane channels for O2 and CO2. Water is one of the major end products of mitochondrial oxidative phosphorylation. Therefore it might not be a surprise that the mitochondrial membrane express extensive water channels. Osmotic swelling is one of the fundamental features exhibited by mitochondria in pathological conditions (Halestrap, 1989). The mitochondrial permeability transition pore (MPTP) has been indicted to permit the passage of molecule of mass < 1.5 kDa in a nonselective manner including water, thus, has long been postulated to be the primary mediator for water movement in term of mitochondrial swelling. However the molecular identity of MPTP remains obscure. The discovery of the expression of APQ channels, AQP8 and 9, in the mitochondria inner membrane indicated that APQs may function as transporters for water and CO2 trafficking in the mitochondria (Lee and Thevenod, 2006). Otherwise, no other potential gas channel has been identified in mitochondria for the trans-membrane transport of CO2 and O2. CO2 molecule is distinct from O2 molecule in the difference of plasma membrane permeability and solubility. The absolute solubility of CO2 in both water and lipid are more than an order of magnitude greater than those of O2 (Endeward et al., 2014). Therefore, it is plausible that CO2 is transported across cellular as well as mitochondrial membrane via different mechanisms from O2. Nevertheless, identification of the precise mechanism underlying the transportation of O2 and CO2 crossing mitochondrial membranes will provide significant insights for our understanding of mitochondria function and its role in both physiological and pathological conditions. With the limited achievement of the plasma CO2 channels, the pursuit of mitochondrial gas channels will have a long way to go.

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            Water and nonelectrolyte permeability of lipid bilayer membranes

            Both the permeability coefficients (Pd's) through lipid bilayer membranes of varying composition (lecithin [L], lecithin:cholesterol [LC], and spingomyelin:cholesterol [SC]) and the n-hexadecane:water partition coefficients (Knc's) of H2O and seven nonelectrolytes (1,6 hexanediol, 1,4 butanediol, n-butyramide, isobutyramide, acetamide, formamide, and urea) were measured. For a given membrane compositiin, Pd/DKnc (where D is the diffusion constant in water) is the same for most of the molecules tested. There is no extraordinary dependence of Pd on molecular weight; thus, given Pd(acetamide), Pd(1,6 hexanediol) is correctly predicted from the Knc and D values for the two molecules. The major exceptions are H2O, whose value of Pd/DKnc is about 10-fold larger, and urea, whose value is about 5-fold smaller than the general average. In a "tight" membrane such as SC, Pd(n- butyramide)/Pd(isobutyramide)=2.5; thus this bilayer manifests the same sort of discrimination between branched and straight chain molecules as occurs in many plasma membranes. Although the absolute values of the Pd's change by more than a factor of 100 in going from the tightest membrane (SC) to the loosest (L), the relative values remain approximately constant. The general conclusion of this study is that H2O and nonelectrolytes cross lipid bilayer membranes by a solubility- diffusion mechanism, and that the bilayer interior is much more like an oil (a la Overton) than a rubber-like polymer (a la Lieb and Stein).
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              Aquaporins as gas channels.

              Gas molecules play important roles in human physiology. Volatile substances produced by one cell often regulate neighboring cells in a paracrine fashion. While gaseous molecules have traditionally been thought to travel from cell to cell by free diffusion through the bilayer portion of the membrane, this does not explain their rapid physiological actions. The recent observations that: (1) water channels can transport other molecules besides water, and (2) aquaporins are often expressed in tissues where gas (but not water) transport is essential suggest that these channels conduct physiologically important gases in addition to water. This review summarizes recent findings on the role of aquaporins as gas transporters as well as their physiological significance.

                Author and article information

                Med Gas Res
                Med Gas Res
                Medical Gas Research
                Medknow Publications & Media Pvt Ltd (India )
                Oct-Dec 2016
                30 December 2016
                : 6
                : 4
                : 237-238
                [1]Center for Neuroscience Discovery, Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA
                Author notes
                [* ] Correspondence to: Shao-hua Yang, shaohua.yang@ 123456unthsc.edu .
                Author information
                Copyright: © 2016 Medical Gas Research

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.


                Molecular medicine
                Molecular medicine


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