Cardiolipin is becoming an increasingly recognised mediator of mitochondrial health and disease. Its close association with proteins of the electron transport chain renders it an essential component of basic cellular function. As such, perturbations in cardiolipin instigate a myriad of downstream effects including the apoptotic initiation, lipid oxidation, ROS formation, and mitophagy. Emerging evidence links mitochondrial dysfunction to several forms of neurodegeneration, including Alzheimer’s dementia, MEGDEL syndrome, and Parkinson’s disease.
Although NCL has been predominantly studied as a lysosomal disorder, emerging evidence of mitochondrial involvement raises the question of whether cardiolipin dysregulation contributes to its pathogenesis. Select CLN mutations impair lysosomal function by inhibiting bis (monoacylglycerol) phosphate (BMP) synthesis. While this has improved our understanding of CLN-associated lysosomal dysfunction, little is known about downstream effects on extra-lysosomal phospholipids. Given established phospholipid trafficking between the lysosomes, the ER, and mitochondria, lysosomal perturbations may alter phospholipid metabolism in other organelles.
We aim to characterise mitochondrial cardiolipin in ovine CLN5/CLN6 mutants to investigate whether disrupted BMP synthesis alters cardiolipin synthesis via their shared precursor, phosphatidyl glycerol. Phospholipid profiles of control and affected sheep will be examined by thin layer chromatographic and hyphenated mass spectrometric techniques to quantify the cardiolipin and related species.
We hypothesise that CLN mutations generate excess phosphatidyl glycerol in the ER and mitochondria, causing an oversupply to the functional cardiolipin biosynthetic pathway. This may lead to cardiolipin accumulation in mitochondrial membranes and drive the pathological build-up of mitochondrial subunit c (SCMAS), a hallmark of NCL. Validating this hypothesis would provide the first mechanistic explanation for SCMAS accumulation in Batten disease, linking lysosomal dysfunction with observed mitochondrial abnormalities, and offering new insight into the biochemistry of neurodegeneration for this disease.