cAMP regulates the functional activity, coupling efficiency and structural organization of mammalian F O F 1 ATP synthase

Abstract

The present study shows that in isolated mitochondria and myoblast cultures depletion of cAMP, induced by sAC inhibition, depresses both ATP synthesis and hydrolysis by the FOF1 ATP synthase (complex V) of the oxidative phosphorylation system (OXPHOS). These effects are accompanied by the decrease of the respiratory membrane potential, decreased level of FOF1 connecting subunits and depressed oligomerization of the complex. All these effects of sAC inhibition are prevented by the addition of the membrane-permeant 8-Br-cAMP. These results show, for the first time, that cAMP promotes ATP production by complex V and prevents, at the same time, its detour to a mitochondrial membrane leak conductance, which is involved in cell death.

Phosphoregulation on mitochondria: Integration of cell and organelle responses

“…Similarly, mitochondrial PKA can modulate complex V activity. Local PKA phosphorylation of ATPase inhibitory factor 1 (AIF1) on Ser39 prevents the interaction between AIF1 and complex V maintaining ATP synthase activity . Also, decreasing PKA activity in mitochondria can lead to the proteolytic degradation of complex V components resulting in less ATP synthesis .…”

“…117,118 Also, decreasing PKA activity in mitochondria can lead to the proteolytic degradation of complex V components resulting in less ATP synthesis. 118,119 The proximity of PKA to the bioenergetic machinery makes the kinase a useful regulator of ATP production and the ETC Furthermore, the relationship between ATP production and mitochondrial PKA activity extends to the PKA phosphorylation of TOM22 can also impair its transport functions. 124 Similarly, PKA can phosphorylate TOM70 on Ser174, which inhibits TOM70 receptor-type activities toward chaperone functions such as Hsp70.…”

Development and characterization of mitochondrial membrane affinity chromatography columns derived from skeletal muscle and platelets for the study of mitochondrial transmembrane proteins

“…It has been reported that F-ATPase/ATP synthase retains the hydrolytic and synthase activities in isolated mitochondria [21]. Further, it is known that under the right storage conditions, the mitochondrial ATPase has been shown to remain active for weeks after isolation [22].…”

Mitochondrial cAMP signaling

“…Given that CO 2 is the end product of the TCA cycle, the cAMP-PKA pathway provides a feed-forward regulation on two modules of energy metabolism: TCA cycle and ETC complexes. Recently, Complex V activity has also been found under the regulation of matrix cAMP-PKA pathway [123–125]. Complex V (mitochondrial ATP synthase) catalyzes the synthesis of ATP through the proton gradient generated by the ETC complexes and executes the reverse hydrolysis when the membrane potential falls below a threshold (pH of ~6.7 or below) [126].…”

“…Thus the phosphorylation status of IF1 appears to be key in regulating the flux of glycolysis and OXPHOS corresponding to certain physiological context [124]. Furthermore, De Rasmo and colleagues recently have demonstrated the importance of the sAC-cAMP signaling for the organization and activity of Complex V in isolated rat mitochondria and myoblast cultures [125]. …”