LCLAT1 regulates cardiolipin composition, mitochondrial phenotype, Lin28A, and oncogenic signaling networks in ETMR

BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is an aggressive pediatric brain tumor that carries a poor prognosis, and there is currently no standard of care. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the progression of diverse cancers. Cardiolipins are mitochondrial-specific lipids, and their fatty acid composition has been shown to regulate mitochondrial structure and function. Despite the known functional significance of cardiolipins, their structure-specific accumulation in relation to mitochondrial phenotypes in ETMR remains ill-defined.

Spatial lipidomic profiles in patient samples and 3D models were determined using mass spectrometry imaging. Cell proliferation and mitochondrial bioenergetics and dynamics were characterized using immunohistochemistry, transmission electron microscopy, Western blotting, and metabolic assays. LCLAT1 KD was carried out using siRNA.

We detected a structure-specific accumulation of cardiolipins and increased expression of the cardiolipin acyl chain remodeling enzyme, lysocardiolipin acyltransferase 1 (LCLAT1), within proliferating tumor cells in patient samples and the 3D tumorspheres. Orthogonal imaging techniques correlated the structure-specific accumulation of cardiolipin with fragmented mitochondria displaying aberrant cristae structure, altered mitochondrial dynamics, decreased expression of respiratory chain enzymes, and a more glycolytic phenotype. LCLAT1 KD altered cardiolipin profiles, reduced growth and proliferation, decreased Sox2 and N-Myc expression, increased p53 and p21 expression, and increased LIN28A and Dcx expression. Additional therapeutic targeting of the fragmented mitochondrial phenotype identified also resulted in selective inhibition of ETMR growth and viability.

Our findings provide novel insight into ETMR biology based on mitochondrial phenotypes and the fatty acid composition of the multifunctional mitochondrial-specific lipid, cardiolipin.