In this last article of the trilogy, the unified biothermokinetic theory of ATP synthesis developed in the previous two papers is applied to a major problem in comparative physiology, biochemistry, and ecology-that of metabolic scaling as a function of body mass across species. A clear distinction is made between intraspecific and interspecific relationships in energy metabolism, clearing up confusion that had existed from the very beginning since Kleiber first proposed his mouse-to-elephant rule almost a century ago. It is shown that the overall mass exponent of basal/standard metabolic rate in the allometric relationship [Formula: see text] is composed of two parts, one emerging from the relative intraspecific constancy of the slope (b), and the other (b\') arising from the interspecific variation of the mass coefficient, a(M) with body size. Quantitative analysis is shown to reveal the hidden underlying relationship followed by the interspecific mass coefficient, a(M)=P0M0.10, and a universal value of P0=3.23 watts, W is derived from empirical data on mammals from mouse to cattle. The above relationship is shown to be understood only within an evolutionary biological context, and provides a physiological explanation for Cope\'s rule. The analysis also helps in fundamentally understanding how variability and a diversity of scaling exponents arises in allometric relations in biology and ecology. Next, a molecular-level understanding of the scaling of metabolism across mammalian species is shown to be obtained by consideration of the thermodynamic efficiency of ATP synthesis η, taking mitochondrial proton leak as a major determinant of basal metabolic rate in biosystems. An iterative solution is obtained by solving the mathematical equations of the biothermokinetic ATP theory, and the key thermodynamic parameters, e.g. the degree of coupling q, the operative P/O ratio, and the metabolic efficiency of ATP synthesis η are quantitatively evaluated for mammals from rat to cattle. Increases in η (by ∼15%) over a 2000-fold body size range from rat to cattle, primarily arising from an ∼3-fold decrease in the mitochondrial H+ leak rate are quantified by the unified ATP theory. Biochemical and mechanistic consequences for the interpretation of basal metabolism, and the various molecular implications arising are discussed in detail. The results are extended to maximum metabolic rate, and interpreted mathematically as a limiting case of the general ATP theory. The limitations of the analysis are pointed out. In sum, a comprehensive quantitative analysis based on the unified biothermokinetic theory of ATP synthesis is shown to solve a central problem in biology, physiology, and ecology on the scaling of energy metabolism with body size.

The nonequilibrium coupled processes of oxidation and ATP synthesis in the biological process of oxidative phosphorylation (OXPHOS) are fundamental to all life on our planet. These steady-state energy transduction processes ‒ coupled by proton and anion/counter-cation concentration gradients in the OXPHOS pathway ‒ generate ∼95 % of the ATP requirement of aerobic systems for cellular function. The rapid energy cycling and homeostasis of metabolites involved in this coupling are shown to be responsible for maintenance and regulation of stable nonequilibrium states, the latter first postulated in pioneering biothermodynamics work by Ervin Bauer between 1920 and 1935. How exactly does this occur? This is shown to be answered by molecular considerations arising from Nath\'s torsional mechanism of ATP synthesis and two-ion theory of energy coupling developed in 25 years of research work on the subject. A fresh analysis of the biological thermodynamics of coupling that goes beyond the previous work of Stucki and others and shows how the system functions at the molecular level has been carried out. Thermodynamic parameters, such as the overall degree of coupling, q of the coupled system are evaluated for the state 4 to state 3 transition in animal mitochondria with succinate as substrate. The actual or operative P to O ratio, the efficiency of the coupled reactions, η, and the Gibbs energy dissipation, Φ have been calculated and shown to be in good agreement with experimental data. Novel mechanistic insights arising from the above have been discussed. A fourth law/principle of thermodynamics is formulated for a sub-class of physical and biological systems. The critical importance of constraints and time-varying boundary conditions for function and regulation is discussed in detail. Dynamic internal structural changes essential for torsional energy storage within the γ-subunit in a single molecule of the FOF1-ATP synthase and its transduction have been highlighted. These results provide a molecular-level instantiation of Ervin Bauer\'s pioneering concepts in biological thermodynamics.