Molecular Biology of the Cell
Vol. 19, 5143–5155, December 2008
The Cardiolipin Transacylase, Tafazzin, Associates with
Two Distinct Respiratory Components Providing Insight
into Barth Syndrome
Steven M. Claypool,* Pinmanee Boontheung,* J. Michael McCaffery,†
Joseph A. Loo,*‡§and Carla M. Koehler*§
*Department of Chemistry and Biochemistry,‡Department of Biological Chemistry, David Geffen School of
Medicine, and the§Molecular Biology Institute, University of California, Los Angeles, CA 90095-1569; and
†Integrated Imaging Center, Department of Biology, Johns Hopkins University, Baltimore, MD 21218-2685
Submitted September 2, 2008; Accepted September 9, 2008
Monitoring Editor: Janet M. Shaw
Mutations in the mitochondrial cardiolipin (CL) transacylase, tafazzin (Taz1p), result in the X-linked cardioskeletal
myopathy, Barth syndrome (BTHS). The mitochondria of BTHS patients exhibit variable respiratory defects and abnormal
cristae ultrastructure. The biochemical basis for these observations is unknown. In the absence of its target phospholipid,
CL, a very large Taz1p complex is missing, whereas several discrete smaller complexes are still observed. None of the
identified Taz1p complexes represents Taz1p homodimers. Instead, yeast Taz1p physically assembles in several protein
complexes of distinct size and composition. The ATP synthase and AAC2, both required for oxidative phosphorylation,
are identified in separate stable Taz1p complexes. In the absence of CL, each interaction is still detected albeit in reduced
abundance compared with when CL is present. Taz1p is not necessary for the normal expression of AAC2 or ATP synthase
subunits or assembly of their respective complexes. In contrast, the largest Taz1p complex requires assembled ATP
synthase and CL. Mitochondria in ?taz1 yeast, similar to ATP synthase oligomer mutants, exhibit altered cristae
morphology even though ATP synthase oligomer formation is unaffected. Thus, the Taz1p interactome defined here
provides novel insight into the variable respiratory defects and morphological abnormalities observed in mitochondria of
The mitochondrial inner membrane (IM) forms a barrier that
not only compartmentalizes numerous critical cellular activ-
ities, including iron–sulfur cluster formation and the tricar-
boxylic acid cycle, but additionally maintains the electro-
chemical gradient established by the electron transport
chain and harnessed by the ATP synthase to generate ATP.
The composition of the mitochondrial IM is unique, contain-
ing a distinctively high ?3–4:1 protein:phospholipid ratio.
In contrast, the mitochondrial outer membrane (OM) ratio is
?1–1.6:1 (Sperka-Gottlieb et al., 1988; Ardail et al., 1990;
Simbeni et al., 1991). The IM also contains cardiolipin (CL),
the signature phospholipid of mitochondria. CL is a struc-
turally unusual phospholipid, with one negative charge as-
sociated with its two headgroups at physiological pH and
four associated fatty acyl chains (Schlame et al., 2000; Haines
and Dencher, 2002). CL is intimately associated with all of
the major players in oxidative phosphorylation, including
complexes I, III, IV, and V, and the major carrier proteins for
adenine nucleotides and phosphates (Schlame et al., 2000).
Moreover, CL is required to fully reconstitute the activity of
respiratory complex IV and the ADP/ATP carrier (AAC) in
vitro (Hoffmann et al., 1994; Sedlak and Robinson, 1999). In
organello, CL acts as a glue that stabilizes the assembly of
individual respiratory complexes into so-called respiratory
supercomplexes (Zhang et al., 2002, 2005; Pfeiffer et al., 2003)
that function to increase the efficiency of oxidative phos-
phorylation (Boumans et al., 1998; Zhang et al., 2005). Which
aspect of CL (e.g., its two phosphate headgroups or four
associated acyl chains) is responsible for these unique func-
tional properties of CL is at present unknown.
Cardiolipin synthase, Crd1p, synthesizes CL in the ma-
trix-facing leaflets of the mitochondrial IM (Schlame and
Haldar, 1993). Newly synthesized CL undergoes a remod-
eling process, the end result of which is the incorporation of
more unsaturated fatty acyl chains and the establishment of
a high degree of acyl chain symmetry (Schlame et al., 2005).
One pathway of CL remodeling is mediated by the CL
transacylase, tafazzin (Taz1p; Xu et al., 2006b), the mutant
gene product associated with the X-linked disease Barth
syndrome (BTHS). BTHS is characterized by cardiac and
skeletal myopathies and cyclic neutropenia (Barth et al.,
1983, 1999, 2004); the disease presents in infants and if
undiagnosed, is often fatal due to cardiac failure or sepsis.
There are three hallmarks of the loss of Taz1p activity in the
mitochondria of BTHS patients (Vreken et al., 2000; Valian-
This article was published online ahead of print in MBC in Press
on September 17, 2008.
Address correspondence to: Carla M. Koehler (Koehler@chem.
Abbreviations used: AAC, ADP/ATP carrier; BTHS, Barth syn-
drome; BN-PAGE, blue native PAGE; CL, cardiolipin; CNAP, con-
secutive nondenaturing affinity purification; IM, inner membrane;
IMS, intermembrane space; IP, immunoprecipitation; LC-MS/MS,
liquid chromatography–tandem mass spectrometry; MLCL, mono-
lysocardiolipin; OM, outer membrane; PC, phosphatidylcholine;
Taz1p, tafazzin; wt, wild-type.
© 2008 by The American Society for Cell Biology5143
pour et al., 2002, 2005; Schlame et al., 2003; Schlame and Ren,
2006): 1) CL content is reduced; 2) CL contains more ran-
domly distributed, saturated fatty acyl chains; and 3) there is
an accumulation of monolysocardiolipin (MLCL). These
three characteristics have been defined in the yeast Saccha-
romyces cerevisiae BTHS model (Vaz et al., 2003; Gu et al.,
2004; Testet et al., 2005; Claypool et al., 2006); all but the
accumulation of MLCL has been documented in the Dro-
sophila melanogaster BTHS model (Xu et al., 2006a), and the
mitochondrial phospholipids have not been characterized in
the zebrafish BTHS model (Khuchua et al., 2006). Currently,
it is not known whether it is the reduced steady-state abun-
dance, the altered profile of attached fatty acyl chains, the
accumulation of MLCL, a combination of all three, or some
unanticipated activity of Taz1p that results in the patholo-
gies associated with BTHS.
Early studies on BTHS patient samples revealed alter-
ations in mitochondrial structure (Barth et al., 1983) as well
as variable defects in oxidative phosphorylation (Barth et al.,
1983, 1996; Ades et al., 1993; Christodoulou et al., 1994).
Importantly, the multitude of available BTHS models collec-
tively reflects these phenotypes. Given the importance of CL
in the proper functioning of many of the components of the
oxidative phosphorylation machinery, a reasonable hypoth-
esis for the defects in respiration in BTHS patients, and
models alike, is that reduced CL content, altered acyl chain
content, and/or the increased abundance of MLCL destabi-
lize respiratory supercomplexes resulting in reduced re-
spiratory efficiency. Consistent with this postulate, the
assembly and stability of respiratory supercomplexes is
compromised in fibroblasts derived from BTHS patients
(McKenzie et al., 2006) and in one yeast BTHS model (Brand-
ner et al., 2005). However, we recently demonstrated in
another yeast BTHS model (a different strain than used in
Brandner et al., 2005), that although there are moderate but
significant changes in respiratory supercomplex function,
there are no discernable defects in respiratory supercomplex
assembly in the absence of Taz1p (Claypool et al., 2008).
Thus, the root cause for the assorted respiratory defects in
BTHS patients remains to be determined. The potential in-
volvement of Taz1p in establishing and/or maintaining mi-
tochondrial organization/ultrastructure is intriguing. Phos-
pholipases and acyltansferases that modulate the abundance
of certain classes of structural phospholipids have been hy-
pothesized to promote membrane curvature and membrane
fusion events (Chernomordik et al., 2006). Interestingly,
Taz1p has been localized to both the mitochondrial IM and
OM always facing the intermembrane space (IMS; Claypool
et al., 2006). Therefore, Taz1p has the functional capacity to
modulate lipids in a manner that can impact their intrinsic
structural properties and is localized to regions of the mito-
chondrion with defining morphological features including
contact sites between the IM and OM as well as the cristae of
Although much progress has been made, it remains un-
resolved why mutations in TAZ1 cause the numerous phe-
notypes of BTHS. Are they caused by changes to CL per se?
Or are they the consequence of altered functioning of a
protein(s) that requires the normal steady-state form of CL
and/or Taz1p for activity? Our previous work demon-
strated that yeast Taz1p assembles in several distinct-sized
complexes (Claypool et al., 2006). Proteins and/or lipids that
interact with Taz1p have not been identified. In the present
study, we addressed this deficiency by determining the
Taz1p interactome and the importance of CL for these inter-
actions. The Taz1p interactome defined herein identifies un-
expected associations that collectively provide new insight
into some of the pathologies observed in BTHS patients.
MATERIALS AND METHODS
All strains were derived from the wild-type (wt) parental S. cerevisiae yeast
strain GA74-1A (MAT a, his3-11,15, leu2, ura3, trp1, ade8, rho?, mit?). The ?taz1
(MAT a, leu2, ura3, trp1, ade8, ?taz1::HISMX6) and ?crd1 (MAT a, his3-11,15,
leu2, ura3, ade8, ?crd1::TRP) strains have been described (Claypool et al., 2006,
2008; Claypool et al., 2008). To generate the ?taz1?crd1 (MAT a, leu2, ura3,
ade8, ?taz1::HISMX6, ?crd1::TRP) and ?atp2 (MAT a, leu2, ura3, trp1, ade8,
?atp2::HISMX6) strains, the entire open reading frame of each gene was
replaced using the PCR-mediated one-step gene replacement strategy (Wach
et al., 1994).
To place the CNAP tag (amino acid sequence: MEDQVDPIDGK-GGAGG-
HHHHHHHHHH; the Protein C [PC] epitope tag is underlined, and the
His10tag is in bold) onto the N-terminus of Taz1p but still under control of
the Taz1p promoter, overlap extension was performed (Ho et al., 1989). The
sequence of every construct was verified by DNA sequencing. The sequences
of all primers are available upon request.
Most of the antibodies used in this work were generated in the Schatz lab or
our lab and have been described previously. Other antibodies used were as
follows: mouse anti-Sec62p (kind gift of Dr. David Meyers, University of
California, Los Angeles), mouse anti-? actin (Abcam, Cambridge, MA),
mouse anti-Myc tag (9E10; Evan et al., 1985; obtained from the Developmental
Studies Hybridoma Bank, developed under the auspices of the National
Institute of Child Health and Human Development and maintained by the
University of Iowa, Iowa City, IA), mouse anti-yAAC2 (clone 6H8; Panneels
et al., 2003), and mouse anti-PC (Roche, Indianapolis, IN) monoclonal anti-
bodies, and horseradish peroxidase–conjugated secondary antibodies (Pierce,
Conventional electron microscopy was performed as previously described
(Rieder et al., 1996). Briefly, the cells were fixed in 3% glutaraldehyde con-
tained in 0.1 M Na cacodylate, pH 7.4, 5 mM CaCl2, 5 mM MgCl2, and 2.5%
sucrose for 1 h at 25°C with gentle agitation; spheroplasted; embedded in 2%
ultra-lo- temperature agarose (prepared in water); cooled; and subsequently
cut into small pieces (?1 mm3). The cells were then postfixed in 1% OsO4/1%
potassium ferrocyanide contained in 0.1 M cacodylate/5 mM CaCl2, pH 7.4,
for 30 min at room temp. The blocks were washed thoroughly four times with
ddH20, 10 min total; transferred to 1% thiocarbohydrazide at room temper-
ature for 3 min; washed in ddH2O (four times, 1 min each); and transferred to
1% OsO4/1% potassium ferrocyanide in cacodylate buffer, pH 7.4, for an
additional 3 min at room temperature. The cells are then washed four times
with ddH2O (15 min total); en bloc–stained in Kellenberger’s uranyl acetate
(UA) for 2 h to overnight; dehydrated through a graded series of ethanol; and
subsequently embedded in Spurr resin. Sections were cut on a Reichert
Ultracut T ultramicrotome; poststained with UA and lead citrate; and ob-
served on a Philips TEM 420 microscope (Mahwah, NJ) at 80 kV. Images were
recorded with a Soft Imaging Systems Megaview III digital camera (Olympus
Soft Imaging Solutions, Lakewood, CO), and figures were assembled in
Adobe Photoshop 10.0 (San Jose, CA).
Subcellular fractionation, isolation of mitochondria, alkali extraction, submi-
tochondrial localization, and immunoblotting were as described (Claypool et
al., 2006); 2D Blue native/SDS-PAGE, consecutive nondenaturing affinity
purification (CNAP), immunoprecipitation (IP), and liquid chromatography–
tandem mass spectrometry (LC-MS/MS) were as described (Claypool et al.,
2008). The performed experiments used mitochondria harvested from yeast
grown at 30°C to OD600?3 as follows: in Figures 1, 3A, 7D, and 8 and
Supplemental Figure S1, rich lactate medium (1% yeast extract, 2% tryptone,
0.05% dextrose, and 2% lactic acid, 3.4 mM CaCl2?2H2O, 8.5 mM NaCl, 2.95
mM MgCl2?6H2O, 7.35 mM KH2PO4, and 18.7 mM NH4Cl); in Figures 2, 3, B
and C, 4, and 5, B and C, and in Supplemental Figures S2, S3, and S4, synthetic
lactate ?Leu (0.17% yeast nitrogen base minus amino acids and ammonium
sulfate, 0.5% ammonium sulfate, 0.2% dropout mix synthetic minus Leu,
0.05% dextrose, and 2% lactic acid, 3.4 mM CaCl2?2H2O, 8.5 mM NaCl, 2.95
mM MgCl2?6H2O, 7.35 mM KH2PO4, and 18.7 mM NH4Cl); and in Figures 5A,
6, and 7A, YP-dextrose. Protein synthesis was inhibited by the addition of 200
?g/ml cycloheximide for the final 4 h of growth before isolating mitochon-
dria. Phospholipid labeling and extraction and data collection was as de-
scribed (Claypool et al., 2006) except that the extracted phospholipids were
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The Taz1p Interactome
Vol. 19, December 20085155