PKA Phosphorylates the ATPase Inhibitory Factor 1 and Inactivates Its Capacity to Bind and Inhibit the Mitochondrial H+-ATP Synthase

http://www.sciencedirect.com/science/article/pii/S2211124715009493

Javier García-Bermúdez, María Sánchez-Aragó, Beatriz Soldevilla, Araceli del Arco, Cristina Nuevo-Tapioles, José M. Cuezva

ATP synthase is the motor of the cell, generating most cellular ATP under normal conditions (watch a video of this here). The protein ATPase Inhibitory Factor 1 (IF1) is known to inhibit both hydrolysis and synthesis of ATP by ATP synthase, by blocking its rotation. This study investigates the mechanism of this protein's action, as well as its physiological and pathophysiological role.

Mechanistically, Protein Kinase A phosphorylates IF1 (p-IF1), which inhibits its ability to interact with ATP synthase, and so is expected to allow OXPHOS to occur. As a consequence, the authors find that dephosphorylated IF1 (dp-IF1) causes inhibition of oxidative phosphorylation and increased glycolytic flux.

Studies in yeast have shown that different energy pathways are activated, depending on the stage of the cell cycle. G1 is believed to be OXPHOS dependent, whereas G2/M is largely independent of oxygen consumption and relies on aerobic glycolysis. Consistent with this picture, the authors show that cells arrested in G1 phase had mostly p-IF1 and high levels of OXPHOS, whereas cells that were arrested in G2/M had dp-IF1 and low OXPHOS levels.

The authors also found hypoxia to be able to induce dephosphorylation of IF1, and thus inhibition of ATP synthase.  Indeed, a number of carcinomas investigated by the authors have an abundance of dp-IF1.

In terms of its physiological significance, the authors investigated the phosphorylation status of IF1 in mouse heart, in vivo. Fascinatingly, ~50% of IF1 is found in its phosphorylated state. Administration of drugs which induce an adrenaline response, causes a sharp increase in p-IF1 and OXPHOS activity. This suggests that the protein has a physiological role of fine-tuning mitochondrial output, in response to variable energy demands.

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Thoughts:
It is known that the maintenance of mitochondrial membrane potential (ΔΨ) is vital for cell viability, as mitochondria perform a plethora of functions besides energy production, which are ΔΨ dependent. If cells actively inhibit their ATP synthase during hypoxia (and so can't hydrolyse ATP and pump protons), and are unable to pump protons due to a lack of oxygen, how are the cells maintaining ΔΨ?