Depletion of cardiolipin induces major changes in energy metabolism in Trypanosoma brucei bloodstream forms

The mitochondrial inner membrane glycerophospholipid cardiolipin (CL) associates with mitochondrial proteins to regulate their activities and facilitate protein complex and supercomplex formation. Loss of CL leads to destabilized respiratory complexes and mitochondrial dysfunction. The role of CL in an organism lacking a conventional electron transport chain (ETC) has not been elucidated. Trypanosoma brucei bloodstream forms use an unconventional ETC composed of glycerol-3-phosphate dehydrogenase and alternative oxidase (AOX), while the mitochondrial membrane potential (Delta psi m) is generated by the hydrolytic action of the FoF1-ATP synthase (aka FoF1-ATPase). We now report that the inducible depletion of cardiolipin synthase (TbCls) is essential for survival of T brucei bloodstream forms. Loss of CL caused a rapid drop in ATP levels and a decline in the Delta psi m. Unbiased proteomic analyses revealed a reduction in the levels of many mitochondrial proteins, most notably of FoF1-ATPase subunits and AOX, resulting in a strong decline of glycerol-3-phosphate-stimulated oxygen consumption. The changes in cellular respiration preceded the observed decrease in FoF1-ATPase stability, suggesting that the AOX-mediated ETC is the first pathway responding to the decline in CL. Select proteins and pathways involved in glucose and amino acid metabolism were upregulated to counteract the CL depletion-induced drop in cellular ATP.

Automated summary

Cardiolipin plays a crucial role in Trypanosoma brucei bloodstream forms, where its depletion leads to decreased ATP levels and mitochondrial membrane potential, affecting respiration and cellular energy metabolism pathways. Additionally, the loss of cardiolipin also impacts protein stability, particularly those associated with oxygen consumption.