Cardoso 2022 MitoFit rTCA
Cardoso LHD, Gnaiger E (2022) Reverse citric acid cycle and mitochondrial succinate formation under anoxia: from parasites and invertebrates to ischemia-reperfusion. (in prep) |
Abstract: The catabolic pathway through the individual steps of the citric acid cycle (Krebs cycle, tricarboxylic acid TCA cycle) has been characterized by the kinetic and regulatory properties of the enzymes involved and is substantiated by the Gibbs energy (exergy) and enthalpy changes (Burton, Krebs 1953; Krebs et al 1957). Following the latter approach, it was possible to prove on thermodynamic and stoichiometric grounds that (1) the simple stoichiometries of fermentation products per glucose β whole numbers such as 2 lactate per glucose β do not hold for succinate, and (2) the textbook ATP yields per glucose (Hochachka, Somero 1984, 2002) are not only inaccurate but are simply impossible according to the 2nd Law of thermodynamics (Gnaiger 1977, 1983, 1993).
In view of a renaissance of the interest in the reverse or reductive TCA cycle (rTCA; Smith, Morowitz 2004) and the role of succinate in ischemia-reperfusion (Chouchani et al 2014), reflections are warranted on the fundamental biochemistry and thermodynamics of this anaerobic pathway. Proper analysis of the rTCA pathway to succinate requires a paradigm shift (1) from linear and branched pathways (Hochachka, Somero 1984) to anticyclic processes (Gnaiger 1977), (2) from serial NAD+/NADH redox balance in glycolysis with formation of lactate to parallel redox balance in the forward and reverse direction of the TCA cycle, (3) from simple whole-number (2 lactate/glucose) to fractional stoichiometries of fermentation product formed per glucose utilized (1.7 succinate/glucose), and (4) in turn from a simple ATP/glucose yield to fractional stoichiometries of ATP yield (Gnaiger 1993). Importantly, even trace amounts of dissolved oxygen in the mitochondrial microenvironment of the living cell (Gnaiger 1991) and simultaneous utilization of several fermentable substrates β including aspartate and glutamate (Hochachka, Somero 1984) β exert profound implications on the redox balance and ATP yield.
β’ Bioblast editor: Gnaiger E
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