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Volume 01, Issue 11 - December, 2005

Mitochondrial Research Bulletin

Published by:
Advancing Vital Discoveries in Mitochondrial Research

Written by:
Dr. Roderick Capaldi

Volume 01, Issue 11 - December, 2005
Past Issues of MitoNews can be found at:


One of the more interesting recent discoveries is that mitochondrial proteins are not located exclusively within mitochondria but can, and do, occur on the plasma membrane of cells where they have important intracellular signaling properties. In this edition of MitoNews I focus on recent studies that begin to define the multiple and unexpected roles of the ATP Synthase when ectopically expressed in cells.

It has variously been reported that the "mitochondrial" ATP Synthase is present on the plasma membrane of several types of cancer cells (1), hepatocytes (2), adipocytes (3) endothelial cells i.e. HUVECs (4) and keratinocytes (5). Evidence ranges from immunolabeling of the enzyme in non- permeabilised cells (1,2,4) to proteomic analysis of plasma membrane preparations and also of lipid rafts isolated from these membranes (3,6).

The ATP Synthase on the surface of endothelial cells is the best characterized of the ectopic Synthases. It catalyzes ATP synthesis at the cell exterior and probably ATP hydrolysis as well. The enzyme is the receptor for, and is inhibited by, angiostatin in both the synthesis and hydrolysis modes at low tumor-like extracellular pH i.e pH6.7. The forward and back reactions of the mitochondrial ATP Synthase are controlled physiologically by an endogenous inhibitor protein (IF1) Two recent studies show that this protein is also present on the plasma membrane (7,8) where it inhibited ATP hydrolysis but not ATP synthesis. The result was conservation of ATP at the cell surface, which was optimal at low pH where IF1 is the most effective as an inhibitor.

In total the mitochondrial ATP Synthase contains 17 different subunits. Included is a subunit called CF6, which is a part of the peripheral stalk. In a set of remarkable experiments Okumura and colleagues have described a role for this protein quite unexpected given its previously described function in linking the F1 and F0 parts of the complex. First these authors found that CF6 could be found in the blood plasma of hypertensive rats, and later, of humans (9). More recent work has established that CF6 is released from vascular endothelial cells by shear stress (10), presumably from the plasma membrane ATP Synthase, although this has not been demonstrated directly. Injection of pure CF6 into rats increased blood pressure, subsequent injection of an antibody to CF6 reduced blood pressure as the CF6 became bound up by the antibody. Release of CF6 into the circulation was significantly reduced by PPAR gamma ligands and by NFkappa beta.ΚΚ

It is now clear that CF6 contributes directly to hypertension by increasing vasoconstriction. It does so by inhibiting prostacyclin (prostaglandin I 2) synthesis (11), a well described vasoldilator. How plasma levels of CF6 induce this effect has recently been characterized. The protein binds to a receptor on the plasma membrane to signal its effect, and this turns out to be the ATP Synthase, and more specifically, the beta subunit of the enzyme complex (12,13)). Thus it appears that CF6 works by an on-off mechanism with respect to binding to the Synthase. The exact mechanism of cellular signaling has not been worked out, but must involve either altered ATP synthesis at the exterior of the plasma membrane, or an ATP driven alteration in the pH of the cytosol of the cell induced by the enzyme working in reverse.

A largely overlooked paper adds to the interesting observations on CF6(14). This work shows that the levels of CF6 in plasma are significantly increased in acute myocardial infarction (AMI). In a study of 49 patients with AMI admitted to a Peking Hospital within 24h of onset of symptoms, Ding et al (14) measured CF6 levels by a radio-immune assay using a polyclonal antibody to CF6, and found that all had elevated levels of the protein. CF6 levels peaked at 72hrs in the same way as CK levels, but took 7 days to go down to levels observed on admission (a longer window of detection than CK), and these levels were still elevated compared to controls. Thus CF6 is a more prolonged marker than CK for a suspected AMI event. Hyperlipidemic patients had significantly higher CF6 levels at 24h after onset than those with normal lipid profiles. CF6 levels at entry were positively related to Killip classification of cardiac function (i.e. levels were higher in Killip class 2 than I). Moreover, CF6 levels were higher in smokers than non-smokers, and at 24h, correlated positively with total cholesterol and LDL levels. At 7 days, levels were lower in patients with successful reperfusion than those without.

NOTE. MitoSciences has antibodies to the alpha, beta, OSCP, d, CF6 and IF1 subunits of the ATP Synthase all of which react with the plasma membrane form of the enzyme in Westerns and in immunocytochemistry. The beta antibody actually inhibits the ATP Synthase activity by around 60% in humans and rodents. The CF6 mAb immunoprecipitates this subunit from solution.


1. Arakaki et. al. Mol.Cancer.Res. 1. 931-9 (2003)

2. Martinez et. al. Nature 421. 75-9 (2003)

3. Kim et. al. Exp. and Mol Med 36. 476-85 (2004

4. Moser et. al. PNAS 96. 2811-6 (1999)

5. Burrell et al J. Biol. Chem. 280. 29667-76 (2005)

6. Bae et al Proteomics 4. 3536-48 (2004)

7. Cortez-Hernandez et al. Biochem. Biophys. Res commun. 330. 844-849 (2005)

8. Burwick et. al. J. Biol. Chem 280. 1740-5 (2005)

9. Osanai et. al. J Biol Chem. 273. 31778-83 (1998)

10. Osanai et. al. Circulation 104. 3132-6 (2001)

11. Osanai et. al. Kidney Int 64. 2291-7 (2003)

12. Osanai et. al.Hypertension 46. 1140-46 (2005)

13. Watts. Hypertension 46. 1100-2 (2005)

14. Ding et al. Hypertens. Res. 27. 717-22 (2004)

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