Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity.

Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Advances in the understanding of Barth syndrome.

Barth syndrome (BTHS) is an X-linked autosomal recessive disorder characterized by neutropenia, cardiomyopathy and growth retardation. BTHS was first described as mitochondrial disease affecting neutrophils as well as cardiac and skeletal muscles. Patients with neutropenia may have extremely low levels of circulating neutrophils and suffer from recurring sometimes life-threatening bacterial infections. Sepsis is not infrequent, may occur unexpectedly in a patient with no history for pronounced bacterial infections and may lead to death. The reduced level of circulating neutrophils suggests either a reduced production of myeloid cells in the bone marrow and premature apoptosis or aberrant clearance of neutrophils in peripheral blood. The underlying molecular defects are truncation, deletion or substitution mutations in the TAZ gene that appear to result in loss-of-function of the gene product tafazzin. Molecular mechanisms triggering neutropenia and cardiomyopathy in BTHS remain largely unclear. The current review focusses on recent advances in the understanding of molecular and cellular bases of neutropenia in Barth syndrome and covers the functional implications of the TAZ mutations, experimental models for neutropenia, the specific cellular abnormalities triggered by loss of TAZ function and potential novel therapeutic strategies for restoring the normal phenotype.