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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Cole, Laura K.^1,2  Kim, Jin Hee^1,3  Amoscato, Andrew A.⁴  Tyurina, Yulia Y.⁴  Bayir, Hulya⁶  Karimi, Benyamin^2,3,7  Siddiqui, Tabrez J.^2,3,7  Kagan, Valerian E.^4,5  Hatch, Grant M.^1,2,8  Kauppinen, Tiina M.^1,2,3 

[1] Univ Manitoba, Fac Hlth Sci, Dept Pharmacol & Therapeut, 753 McDermot Ave, Winnipeg, MB R3E 0W3, Canada

[2] Childrens Hosp Res Inst Manitoba, Winnipeg, MB, Canada

[3] Hlth Sci Ctr, Kleysen Inst Adv Med, Neurosci Res Program, Winnipeg, MB R3E 0Z3, Canada

[4] Univ Pittsburgh, Dept Environm & Occupat Hlth, Ctr Free Rad & Antioxidant Hlth, Pittsburgh, PA USA

[5] IM Sechenov Moscow State Med Univ, Dept Human Pathol, Lab Nav Redox Lipid, Moscow, Russia

[6] Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Crit Care Med, Safar Ctr Resuscitat Res, Pittsburgh, PA 15213 USA

[7] Univ Manitoba, Fac Hlth Sci, Dept Physiol & Pathophysiol, 753 McDermot Ave, Winnipeg, MB R3E 0W3, Canada

[8] Univ Manitoba, Ctr Res & Treatment Atherosclerosis, Childrens Hosp Res Inst Manitoba, DREAM,Biochem & Med Genet, Winnipeg, MB R3E 0T6, Canada

关键词: Cardiolipin;    Monolysocardiolipin;    Tafazzin;    Barth syndrome;    Brain;    Hippocampus;    Cognition;   

DOI  :  10.1016/j.bbadis.2018.07.022

来源: Elsevier

【 摘 要 】

Cardiolipin (CL) is a key mitochondrial phospholipid essential for mitochondrial energy production. CL is re-modeled 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 mitochondria] 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.

【 授权许可】

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