Aberrant cardiolipin metabolism is associated with cognitive deficiency and hippocampal alteration in tafazzin knockdown mice

Abstract

Cardiolipin (CL) is a key mitochondrial phospholipid essential for mitochondrial energy production. CL is remodeled from monolysocardiolipin (MLCL) by the enzyme tafazzin (TAZ). Loss-of-function mutations in the gene which encodes TAZ results in a rare X-linked disorder called Barth Syndrome (BTHS). The mutated TAZ is unable to maintain the physiological CL:MLCL ratio, thus reducing CL levels and affecting mitochondrial function. BTHS is best known as a cardiac disease, but has been acknowledged as a multi-syndrome disorder, including cognitive deficits. Since reduced CL levels has also been reported in numerous neurodegenerative disorders, we examined how TAZ-deficiency impacts cognitive abilities, brain mitochondrial respiration and the function of hippocampal neurons and glia in TAZ knockdown (TAZ kd) mice. We have identified for the first time the profile of changes that occur in brain phospholipid content and composition of TAZ kd mice. The brain of TAZ kd mice exhibited reduced TAZ protein expression, reduced total CL levels and a 19-fold accumulation of MLCL compared to wild-type littermate controls. TAZ kd brain exhibited a markedly distinct profile of CL and MLCL molecular species. In mitochondria, the activity of complex I was significantly elevated in the monomeric and supercomplex forms with TAZ-deficiency. This corresponded with elevated mitochondrial state I respiration and attenuated spare capacity. Furthermore, the production of reactive oxygen species was significantly elevated in TAZ kd brain mitochondria. While motor function remained normal in TAZ kd mice, they showed significant memory deficiency based on novel object recognition test. These results correlated with reduced synaptophysin protein levels and derangement of the neuronal CA1 layer in hippocampus. Finally, TAZ kd mice had elevated activation of brain immune cells, microglia compared to littermate controls. Collectively, our findings demonstrate that TAZ-mediated remodeling of CL contributes significantly to the expansive distribution of CL molecular species in the brain, plays a key role in mitochondria respiratory activity, maintains normal cognitive function, and identifies the hippocampus as a potential therapeutic target for BTHS.

The role of cardiolipin concentration and acyl chain composition on mitochondrial inner membrane molecular organization and function

“…Alterations in the supramolecular organization of the mitochondria, particularly at the level of the inner membrane, would likely contribute to supercomplex dissociation, which would impair cristae stability and thereby promote membrane aggregation (60). More recently, Cole et al demonstrated that murine TAZ knockdown resulted in aberrant CL metabolism and was associated with cognitive deficiency (63). Specifically, TAZ knockdown mice exhibited reduced brain CL content, altered CL molecular species, and a 19-fold increase in MLCL levels relative to wild-type mice.…”

<p>Barth syndrome: mechanisms and management</p>

“…In about half of the patients older than 7 years, learning difficulties are evident 43. In a study of TAZ knockdown mice, significant memory deficits were detected on the novel object recognition test 57. Brains of TAZ knockdown mice exhibited reduced TAZ expression, reduced total cardiolipin levels, and a marked accumulation of monolysocardiolipin 57…”

Sex differences and gonadal hormone regulation of brain cardiolipin, a key mitochondrial phospholipid

“…For example, a correlation between alterations in brain CL metabolism and behaviour has been observed in animal models. Mice lacking tafazzin (a transacetylase enzyme that remodels CL), which have reduced CL and increased monolysocardiolipin levels in the brain together with altered fatty acid composition of both species, have impaired cognitive function, as assessed by the novel object recognition test . Cognitive dysfunction has been also observed in mice that have changes in CL content and composition in the hippocampus as a consequence of their deficiency in the enzyme calcium‐independent phospholipase A2‐γ, which transforms cardiolipin in monolysocardiolipin …”

“…BTHS is manifested in children as a severe cardiomyopathy, although it is a multi‐syndrome disorder including learning and attention deficits and reduced visual spatial skills . In a recent study, these effects were successfully modelled in an inducible tafazzin‐knockdown mouse …”