Cardiolipin synthesis and remodeling regulate mitochondrial metabolic plasticity and signaling function
Mauro Corrado, PhD, University of Cologne
Membranes define cell boundaries and internal organelles in eukaryotes and work as the points of contact among them. Lipid compositions, together with specific protein decoration, dictates membrane properties and thus organellar functions. Cardiolipin is the distinctive inner mitochondrial membrane phospholipid coupling structure with metabolism and signaling function. The importance of cardiolipin in mitochondrial function is evidenced by the X-linked inherited pathology Barth syndrome a result of cardiolipin remodeling deficiency. Cardiomyopathy and muscle weakness are life-threatening features of Barth syndrome, limiting patients’ physical activity and often driving them to heart transplantation. In addition, systemic effects of cardiolipin deficiency like neutropenia, T cell defects or other immune-related pathologies are important comorbidity factors in Barth syndrome patients in particular in respect to their higher susceptibility to recurrent infections.
My previous work started to shed light on the effects of cardiolipin deficiency in CD8+ T cell immune response (Corrado et al., Cell Metabolism, 2020). Briefly, CD8+ T cells, responsible for fighting infections and safeguarding our organism from cancer, rely on the presence of cardiolipin and on its regulated synthesis and remodeling to properly activate, expand and eliminate pathogens or tumor cells. Less efficient responses to T-cell mediated vaccines, lower susceptibility to acute organ rejection after heart transplant or altered inflammatory response when needed might be expected in Barth syndrome patients compared to non-affected age-matched individuals if our hypothesis holds true. Moreover, it is possible that the adaptive immune phenotype in Barth syndrome patients might exacerbate the impact of neutropenia in causing susceptibility to infections by a combination of the impaired activation, proliferation, and differentiation of T cells. Defects in the adaptive branch of immunity might also further deteriorate muscle function if inflammation is modulated by cardiolipin deficiency. Rare reports of sporadic vomiting or diarrhea and of higher levels of the pro-inflammatory cytokine IL-6 are described for Barth syndrome patients, suggesting that a possible inflammatory state might extend to Barth syndrome patients. Whether this might be mediated by the reduction or loss of cardiolipin or the accumulation of specific cardiolipin species, how this could happen and whether this could exacerbate or worsen muscle condition in Barth syndrome patients will be the core of this project.
Thus, having a more comprehensive understanding of how immune system crosstalk with muscle function is pivotal to develop new strategies to ameliorate Barth syndrome patients’ condition. Of note, investigating further the effects of cardiolipin deficiency or modification (oxidation/saturation) in the adaptive immune response is pivotal in the context of current (Tazpower) or future trials impacting cardiolipin remodeling and/or oxidation.
This project’s funding was made possible by the generous support of the Paula and Woody Varner Fund.
