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MitoNews
Mitochondrial Research Bulletin
Published by:
MitoSciences
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com
Written & Edited by:
Dr. Roderick Capaldi
[email protected]
Volume 01, Issue 06 - June 28, 2005
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Past issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html
In This Issue...
1. The ATP Synthase: An Enzyme That Does More That You Are
Probably Aware
A. Introduction
B. The Structure: A Short Primer
C. New Studies On Superstructures Involving The Enzyme
2. A Plasma Membrane ATP Synthase?
3. One of the Subunits of the F1F0, Either from the Plasma
Membrane Form or from Mitochondria, is Released and Acts
in Blood Pressure Regulation
4. ATP Synthase May Function as a Fuel Sensor in Pancreatic
Beta Cells
5. When ATP Synthesis is Slowed, ATP Hydrolysis Can Take
Over, Further Depleting Energy Stores and Inducing Cell Death
During Ischemia
6. But Wait, There's More....
....................................................................................................
1. The ATP Synthase: An Enzyme That Does More That You Are
Probably Aware
A. Introduction
The mitochondrial ATP synthase or F1F0ATPase has been
studied for many years by bioenergeticists interest in the
mechanism of proton gradient-driven ATP synthesis. This
large body of work has culminated in a detailed description
of how the enzyme complex functions and has shown it to
be a tiny rotary motor. The seminal work leading to the
understanding of the motor properties was honored in the late
1990's with a Nobel Prize. Now research on the ATP synthase
has a new lease of life and is becoming the subject for
exploration by cell biologists and medical scientists. As a
change from reviewing a set of recent papers covering
several aspects of mitochondriology, here I focus on exciting
new discoveries about the properties of the ATP synthase
and the many areas of biology being impacted by this work.
B. The Structure: A Short Primer
The eukaryote enzyme (and it's bacterial counterpart) is made
up of an F1 part and an F0 part, which are joined by 2 narrow
bridges, a central stalk, which acts as a rotor, and a peripheral
stalk that is the stator for the motor. There are several excellent
reviews of this arrangement (see below) as well as about how
the protein performs it's motor function to drive proton
gradient-driven ATP synthesis, and in the reverse direction, to
generate a proton gradient from hydrolysis of ATP.
The F1 part is composed of 5 subunits, alpha, beta, gamma,
delta and epsilon in the ratio 3.3.1.1.1 respectively. The F0
part of the complex contains 10 different subunits a,b,c,d,e,f,g,
OSCP,CF6 and 6AL, all in unit stoichiometry except for the c
subunit which, very surprisingly, is present in different
numbers of copies in different eukaryote species, this number
being between 9 and 14. The central stalk and rotor part is
formed from the gamma subunit, which interacts directly with
alpha and beta subunits at one end, and the c subunits, which
are arranged as a ring at the other end. The stator part
contains the protein called OSCP (oligomycin sensitivity
conferring protein : a misnomer) along with subunits b,e,g,
CF6 and probably others. An important additional component
of the F1F0 is the inhibitor protein (IP), which as the name
implies, inhibits ATP hydrolysis. Recent evidence is that IP
does not block ATP synthesis, so that a presumed function is
to ensure that ATP produced in the mitochondrion is not
re-hydrolyzed when substrate ADP is low.
THE MOLECULAR MECHANISM OF ATP SYNTHESIS BY
F1FOATP SYNTHASE. Senior.AE, Nadanaciva.S & Weber.
J. Biochim Biophys Acta. 1553. 188-211 (2002).
MECHANISM OF THE F1F0TYPE ATP SYNTHASE, A
BIOLOGICAL ROTARY MOTOR. Capaldi.RA & Aggeler R.
Trends Biochem Sci. 27. 154-60 (2002)
C. New Studies On Superstructures Involving The Enzyme
Several interesting aspects of the structure of the ATP
synthase have come to light in the last 2-3 years. First there is
evidence that the ATP synthase is part of a supercomplex
termed the ATP synthesome and has tight association with
both the ADP/ATP translocase (ANT) and the phosphate
carrier. Second, there is mounting evidence that F1F0 is a
dimer or higher aggregate in the mitochondrial inner
membrane, and that these associations maintain the integrity
of the cristae, which traverse the interior of the organelle.
THE ATP SYNTHASE IS INVOLVED IN GENERATING
MITOCHONDRIAL CRISTAE MORPHOLOGY. Paumard.P,
Vaillier.J, Coulary.B, Schaeffer.J, soubannier.V, Mueller.DM,
Brethes.D, di Rago.JP. & Velours
J. EMBO. J. 21. 221-30 (2002).
MITOCHONDRIAL ATP SYNTHASOME; THREE
DIMERNSIONAL STRUCTURE BY ELECTRON MICROSCOPY
OF THE ATP SYNTHASE IN COMPLEX FORMATION WITH
CARRIERS FOR PI AND ADP/ATP. Chen.C, Ko.Y, Delannoy.M,
Ludtke.SJ, Chiu.W & Pedersen.PL.
J. Biol. Chem. 279. 31761-8 (2004)
2. A Plasma Membrane ATP Synthase?
One of the more interesting of the new developments
regarding the ATP synthase is the finding that the enzyme is
not only present in the mitochondrion but is also found on the
plasma membrane of a number of different cells where it acts
in several unexpected functions. Recent studies indicate that
the F1F0, which synthesizes ATP on the outside of the cell, is
localized in lipid rafts. In hepatocytes it acts as the HIGH
DENSITY LIPOPROTEIN RECEPTOR, according to one of
the papers below.
In endothelial cells it is the ANGIOSTATIN RECEPTOR. Two
other papers below, argue that the beta subunit of the ATP
synthase alone on the cell surface, but not the intact complex,
controls fat uptake by acting as the receptor for
ENTEROSTATIN, a peptide released from procolipase during
fat digestion. The beta subunit also binds the enterostatin
antagonist beta-casomorphin1-7.
Finally, in CANCER CELLS, there is an abundance of F1F0
on the plasma membrane with the assumed function of allowing
these cells to survive in an acid environment. An obvious
question inherent to all the above findings is how does it get
there? Is there fusion of mitochondria with the plasma
membrane?
ENDOTHELIAL CELL SURFACE ATP SYNTHASE
TRIGGERED CASPASE-APOPTOTIC PATHWAY IS ESSENTIAL
FOR K1-5-INDUCED ANTIANGIOGENESIS. Venitonmake.N,
Cao.R, Wu.LH, Moser.TL, Li.B, Pizzo.SV, Zhivotovsky.B &
Cao.Y.
Cancer Res 64. 3679-86 (2004)
AN INHIBITOR OF THE F1 SUBUNIT OF ATP SYNTHASE
(IF1) MODULATES THE ACTIVITY OF ANGIOSTATIN ON
THE ENDOTHELIAL CELL SURFACE. Burwick. NR, Wahl.ML,
Fang.J, Zhong.Z, Moser.TL, Li.B, Capaldi.RA, Kenan.DJ &
Pizzo.SV.
J Biol Chem 280. 1740-5 (2005)
LIPID RAFT PROTEOME REVEALS ATP SYNTHASE
COMPLEX IN THE CELL SURFACE. Bae.TJ, Kim.MS,
Kim.JW,Kim.BW, Choo.HJ. Lee.JW. Kim.KB, Lee.CS,
Kim.JH, Chang.SY, Kang.CY, Lee.SW & Ko.YG.
P_roteomics 4. 3536-48 (2004)
ECTOPIC BETA CHAIN OF ATP SYNTHASE IS AN
APOLIPOPROTEIN A-1 RECEPTOR IN HEPATIC HDL
ENDOCYTOSIS
Martinez.LO, Jaquet.S, Esteve.JP, Rolland. C, Cabezon.E,
Champagne.E, Pineau.T, Georgeaud.V, Walker.JE, Terce.F,
Collet.X, Perret.B & Barbaras.R.
Nature.421. 75-9 (2004)
EXTRACELLULAR ATP IS GENERATED BY ATP SYNTHASE
COMPLEX IN ADIPOCYTE LIPID RAFTS. Kim.BW, Choo.HJ,
Lee.JW, Kim.JH & Ko.YG.
Exp Mol Med 36. 476-85 (2004).
THE F1ATPASE BETA SUBUNIT IS THE PUTATIVE
ENTEROSTATIN RECEPTOR. Park.M, Lin.L, Thomas.S,
Braymer.HD, Smith.PM, Harrison.DH & York.DA.
Peptides 25. 2127-33 (2004)
ENTEROSTATIN AND ITS TARGET MECHANISMS DURING
FAT REGULATION OF FAT INTAKE. Berger.K, Winzell.MS,
Mei.J & Erlanson-Albertsson.C.
Physiol. Behav. 83. 623-30 (2004)
3. One of the Subunits of the F1F0, Either from the Plasma
Membrane Form or from Mitochondria, is Released and Acts
in Blood Pressure Regulation
In a set of very interesting papers published over the last 4
years, Okumura and colleagues have provided evidence of a
role of one of the subunits of the ATP synthase, CF6, in
hypertension. These workers have shown that this polypeptide
is on the surface of endothelial cells (not suprising from the
above), and that it is sloughed off by sheer into the plasma
of the circulatory system, where it suppresses the synthesis
of prostacyclin. Intravenous injection of this polypeptide
increased blood pressure while a specific antibody to the
peptide decreased systemic blood pressure concomitantly
with an increase in plasma prostacyclin. Most recently it was
shown that the amount of CF6 on the plasma membrane of
endothelial cells is controlled by tumor necrosis factor alpha.
MITOCHONDRIAL COUPLING FACTOR 6 AS A POTENT
ENDOGENOUS VASOCONSTRICTOR
Osanai.T, Tanaka.M, Kamada.T, Nakano.T, Takahashi.K,
Okada.S, Sirato.K, Magota.K, Kodama.s & Okamura.K.
J. Clin. Invest. 108. 1023-30 (2001)
TUMOR NECROSIS FACTOR ALPHA AS AN ENDOGENOUS
STIMULATOR FOR CIRCULATING COUPLING FACTOR 6.
Sasaki.S, Osanai.T, Tomita.H, Matsunaga.T, Magota.K &
Okumura.K.
Cardiovasc. Res. 62. 578-86 (2004)
4. ATP Synthase May Function as a Fuel Sensor in Pancreatic
Beta Cells
In a recent study, leucine culture was used to alter beta glucose
sensing in cultures of rat islets Up regulation of the beta subunit
of the ATP synthase by 3.2 fold was seen along with a
decreased threshold for glucose-induced insulin secretion and
increased maximal insulin secretion. Down regulation of the
beta subunit by siRNA decreased insulin secretion, indicating
the key regulatory role of the ATP synthase in insulin secretion,
and adding to the possible uses for drugs that modulate the
enzyme function in medicine.
LEUCINE CULTURE REVEALS THAT ATP SYNTHASE
FUNCTIONS AS A FUEL SENSOR IN PANCREATIC BETA
CELLS Yang.J, Wong.RK, Wang.X, Moibi.J, Hessner.MJ,
Greene.s, Wu.J, Sukumvanich.s, Wolf.BA & Gao.Z.
J. Biol. Chem. 279.53915-23 (2004).
5. When ATP Synthesis is Slowed, ATP Hydrolysis Can Take
Over, Further Depleting Energy Stores and Inducing Cell Death
During Ischemia
It has been known for many years that in ischemia loss of
oxidative phosphorylation reduces ATP levels, which is then
exacerbated by the ATP synthase hydrolyzing what ATP
remains in mitochondria. The result is cell death by necrosis,
apoptosis or both. The inhibitor protein is supposed to prevent
this but does not for reasons not fully understood. Ischemic
preconditioning protects against the adverse effects. Such
results have led to a search for small molecule inhibitors that
target ATP hydrolysis by the ATP synthase without affecting
ATP synthesis. Recently several reports have appeared
describing such potentially important drug lead compounds.
EXCESSIVE ATP HYDROLYSIS IN ISCHEMIC MYOCARDIUM
BY MITOCHONDRIAL F1F0ATP SYNTHASE; EFFECT OF
SELECTIVE PHARMACOLOGICAL INHIBITION OF
MITOCHONDRIAL ATPASE HYDROLASE ACTIVITY.
Grover.GW, Atwal.KS, Sleph.PG, Wang.FL, Monshizadegan.H,
Monticello.T & Green.DW. Am.
J. Physiol.Heart Circ. Physiol. 287. H1747-55 (2204).
BENZODIAZEPINE-BASED SELECTIVE INHIBITORS OF
MITOCHONDRIAL F1F0 ATP HYDROLASE. Hamann.LG,
Ding.CZ, Miller AV, Madsen.CS, Wang.P, Stein.PD,
Pudzianowski.AT, Green.DW, Monshizadegan.H & Atwal.KS.
Bioorg. Med. Chem.Lett.14. 1031-40 (2004)
N-[1-ARYL-2-(1-IMIDAZOLO)ETHYL]-GUANIDINE
DERIVATIVES AS POTENT INHIBITORS OF BOVINE
MITOCHONDRIAL F1F0ATP HYDROLASE Atwal.KS and
17 others
Bioorg.Med.Chem.Lett. 14. 1027-30 (2004).
6. But Wait, There's More...
Recent editions of MitoNews have reviewed some of the
other important finding of the role and possible treatments
of dysfunction of the ATP synthase in human disease.
The reader is referred to the FEBRUARY newsletter for a
review of an article showing that novel inhibitors of the ATP
synthase, the diarylquinolines, can be used to treat
TUBERCULOSIS because of their specificity in inhibiting
the parasite enzyme without effect on the human ATP synthase.
Also, the MAY issue describes work on another inhibitor of
the ATP synthase that appears effective in control of the
autoimmune disease LUPUS.
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