Age-related changes in cardiolipin profile and functional consequences of altered fatty acid supply

Cardiolipins (CLs) are primarily expressed in the inner mitochondrial membrane where they play essential roles in membrane architecture and mitochondrial functions. CLs have a unique structure characterized by four acyl chains with different stoichiometries such as chain length and degree of saturation. CL composition changes with disease and age, but it is largely unknown how dynamic changes affect mitochondrial function. Here, we compared CL profiles in different mouse tissues across different age groups using liquid chromatography and triple quadrupole mass spectrometry. A key finding was that CLs in the brain differ significantly from those in peripheral organs, with a tendency towards longer-chain variants. We hypothesized that these differences may be influenced by the availability of fatty acids (FA), which in the brain could be affected by the blood-brain barrier. In support of this notion, we found that FA concentrations varied in the different compartments. In addition, we found that CL profiles changed during aging. In cultivated macrophages supplemented with different FAs, we tested how altered CL profiles may affect both, mitochondrial morphology and function such as cristae density, and mitochondrial membrane potential and respiration, respectively. Finally, we validated our in vitro results in vivo by altering the CL profile in mice by using palmitic acid and oleic acid enriched diets. Our study highlights a dynamic adaptation of CL profiles in response to FA availability and aging and emphasizes its functional importance for mitochondrial function. Furthermore, FA supplementation may be a promising therapeutic strategy to address disease- and age-related mitochondrial malfunctions.