Mutations in the human TAZ gene are associated with Barth Syndrome, an often 
fatal X-linked disorder that presents with cardiomyopathy and neutropenia. The 
TAZ gene encodes Tafazzin, a putative phospholipid acyltranferase that is 
involved in the remodeling of cardiolipin, a phospholipid unique to the inner 
mitochondrial membrane. It has been shown that the disruption of the Tafazzin 
gene in yeast (Taz1) affects the assembly and stability of respiratory chain 
Complex IV and its supercomplex forms. However, the implications of these 
results for Barth Syndrome are restricted due to the additional presence of 
Complex I in humans that forms a supercomplex with Complexes III and IV. Here, 
we investigated the effects of Tafazzin, and hence cardiolipin deficiency in 
lymphoblasts from patients with Barth Syndrome, using blue-native polyacrylamide 
gel electrophoresis. Digitonin extraction revealed a more labile Complex 
I/III(2)/IV supercomplex in mitochondria from Barth Syndrome cells, with Complex 
IV dissociating more readily from the supercomplex. The interaction between 
Complexes I and III was also less stable, with decreased levels of the Complex 
I/III(2) supercomplex. Reduction of Complex I holoenzyme levels was observed 
also in the Barth Syndrome patients, with a corresponding decrease in 
steady-state subunit levels. We propose that the loss of mature cardiolipin 
species in Barth Syndrome results in unstable respiratory chain supercomplexes, 
thereby affecting Complex I biogenesis, respiratory activities and subsequent 
pathology.