The molecular composition of cardiolipins is tightly coupled with the nutritional lipid environment

Cardiolipins are mitochondrial phospholipids with four fatty acyl side chains that are iteratively remodeled by the enzyme tafazzin. Loss of function variants impairing this remodeling process causeBarth Syndrome (BTHS) and result in abnormal cardiolipin profiles in patients. The exact molecular compositions of cardiolipins are organism-, tissue-, and cell type-specific, highly reproducible, and thus appear to originate from a tightly regulated process. Although cardiolipin remodeling generates highly specific lipid species profiles, the individual components involved are often reported to be non-specific or promiscuous in themselves, including tafazzin. To investigate the still largely unclear regulatory origin of tissue-specific cardiolipin states, we conducted integrative analyses of lipidomics and transcriptomics datasets in mouse tissues and additionally employed data-driven machine learning strategies. We found that rather than through transcriptional regulation, the control of cardiolipin specificity is largely mitigated through the phospholipid side chain environment, particularly their linoleoyl content.Utilizing a tafazzin-deficient cell culture model for BTHS, we could describe an equally strong impact of the nutritional lipid composition on the cardiolipin states of cells. Interestingly, this effect was independent of the presence or absence of functional tafazzin. At the same time this allowed us to systematically study the effect of tafazzin deficiency on the composition of other phospholipids. We found that some lipid environments promoted tafazzin-related alterations in phospholipid classes other than cardiolipin, whereas others – including standard cell culturing conditions – masked many of the potential effects. The strong influence of the lipid environment on cardiolipins provides a deeper understanding of the regulatory origin of its tissue-specificity. It is important to take these effects into account in further research, especially when comparing different model systems, as well as when designing novel treatment options for BTHS.