Protein kinase A catalytic subunit alters cardiac mitochondrial redox state and membrane potential via the formation of reactive oxygen species

Shiro Nagasaka, Hideki Katoh, Chun Feng Niu, Saori Matsui, Tsuyoshi Urushida, Hiroshi Satoh, Yasuhide Watanabe, Hideharu Hayashi
Circulation Journal: Official Journal of the Japanese Circulation Society 2007, 71 (3): 429-36

BACKGROUND: The identification of protein kinase A (PKA) anchoring proteins on mitochondria implies a direct effect of PKA on mitochondrial function. However, little is known about the relationship between PKA and mitochondrial metabolism.

METHODS AND RESULTS: The effects of PKA on the mitochondrial redox state (flavin adenine dinucleotide (FAD)), mitochondrial membrane potential (DeltaPsi(m)) and reactive oxygen species (ROS) production were investigated in saponin-permeabilized rat cardiomyocytes. The PKA catalytic subunit (PKAcat; 50 unit/ml) increased FAD intensities by 56.6+/-7.9% (p<0.01), 2'7'-dichlorofluorescin diacetate (DCF) intensities by 10.5+/-3.3 fold (p<0.01) and depolarized DeltaPsi(m) to 48.1+/-9.5% of the control (p<0.01). Trolox (a ROS scavenger; 100 micromol/L) inhibited PKAcat-induced DeltaPsi(m), FAD and DCF alteration. PKAcat-induced DeltaPsi(m) depolarization was inhibited by an inhibitor of the inner membrane anion channel (IMAC), 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS: 1 micromol/L) but not by an inhibitor of mitochondrial permeability transition pore (mPTP), cyclosporine A (100 nmol/L).

CONCLUSIONS: PKAcat alters FAD and DeltaPsi(m) via mitochodrial ROS generation, and PKAcat-induced DeltaPsi(m) depolarization was not caused by mPTP but rather by DIDS-sensitive mechanisms, which could be caused by opening of the IMAC. The effects of PKA on mitochondrial function could be related to myocardial function under the condition of extensive beta-adrenergic stimulation.

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