Cardiolipin is a mitochondrion-specific phospholipid that stabilizes the 
assembly of respiratory chain complexes, favoring full-yield operation. It also 
mediates key steps in apoptosis. In Barth syndrome, an X chromosome-linked 
cardiomyopathy caused by tafazzin mutations, cardiolipins display acyl chain 
modifications and are present at abnormally low concentrations, whereas 
monolysocardiolipin accumulates. Using immortalized lymphoblasts from Barth 
syndrome patients, we showed that the production of abnormal cardiolipin led to 
mitochondrial alterations. Indeed, the lack of normal cardiolipin led to changes 
in electron transport chain stability, resulting in cellular defects. We found a 
destabilization of the supercomplex (respirasome) I+III2+IVn but also decreased 
amounts of individual complexes I and IV and supercomplexes I+III and III+IV. No 
changes were observed in the amounts of individual complex III and complex II. 
We also found decreased levels of complex V. This complex is not part of the 
supercomplex suggesting that cardiolipin is required not only for the 
association/stabilization of the complexes into supercomplexes but also for the 
modulation of the amount of individual respiratory chain complexes. However, 
these alterations were compensated by an increase in mitochondrial mass, as 
demonstrated by electron microscopy and measurements of citrate synthase 
activity. We suggest that this compensatory increase in mitochondrial content 
prevents a decrease in mitochondrial respiration and ATP synthesis in the cells. 
We also show, by extensive flow cytometry analysis, that the type II apoptosis 
pathway was blocked at the mitochondrial level and that the mitochondria of 
patients with Barth syndrome cannot bind active caspase-8. Signal transduction 
is thus blocked before any mitochondrial event can occur. Remarkably, basal 
levels of superoxide anion production were slightly higher in patients' cells 
than in control cells as previously evidenced via an increased protein 
carbonylation in the taz1Δ mutant in the yeast. This may be deleterious to cells 
in the long term. The consequences of mitochondrial dysfunction and alterations 
to apoptosis signal transduction are considered in light of the potential for 
the development of future treatments.