Metabolic homeostasis: oxidative phosphorylation and the metabolic requirements of higher plants and animals

A model of oxidative phosphorylation and its regulation is presented, which is consistent with the experimental data on metabolism in higher plants and animals. The variables that provide real-time control of metabolic status are: intramitochondrial [NAD⁺]/[NADH], energy state ([ATP]/[ADP][Pi]), and local oxygen concentration ([O₂]). ATP consumption and respiratory chain enzyme content are tissue specific (liver vs. heart muscle), and the latter is modulated by chronic alterations in ATP consumption (i.e., endurance training etc.). ATP consumption affects the energy state, which increases or decreases as necessary to match synthesis with consumption. [NAD⁺]/[NADH], local [O₂], and respiratory chain content determine the energy state at which match of synthesis and utilization is achieved. Tissues vary widely in their ranges of ATP consumption. Expressed as the turnover of cytochrome c, the rates may change little (7 to 12/s) (liver) or a lot (1 to >300/s) (flight muscle of birds, bats, and insects). Ancillary metabolic pathways, including creatine or arginine kinase, glycerol phosphate shuttle, fatty acid, and citric acid cycle dehydrogenases, are responsible for meeting tissue-specific differences in maximal rate and range in ATP utilization without displacing metabolic homeostasis. Intramitochondrial [NAD⁺]/[NADH], [ATP], and [Pi] are adjusted to keep [ADP] and [AMP] similar for all tissues despite large differences in ranges in ATP utilization. This is essential because [ADP] and [AMP], particularly the latter, have major roles in regulating the activity of many enzymes and signaling pathways (AMP deaminase, AMP dependent protein kinases, etc.) common to all higher plants and animals.NEW & NOTEWORTHY Oxidative phosphorylation has an intrinsic program that sets and stabilizes cellular energy state ([ATP]/[ADP][Pi]), and thereby metabolic homeostasis. A computational model consistent with regulation of oxidative phosphorylation in higher plants and animals is presented. Focus is on metabolism ancillary to oxidative phosphorylation by which it was integrated into preexisting metabolic regulation and adapted by evolution to develop cells and tissues with differing rates of ATP utilization: i.e., liver versus brain versus muscle.