2014 – CARDIOLIPIN, MITOPHAGY AND HEMATOPOIETIC STEM CELL REGENERATION

Hematopoietic Stem Cells (HSC) are known for their regenerative potential which allowed their use in bone marrow transplantation to treat hematological disorders. However, aging results in HSC functional decline. Some consequences of HSC aging include inflammation leading to clonal hematopoiesis and myelodysplastic syndrome. The central goal of this project is to understand the mechanisms leading to HSC aging. Mitochondria are critical for HSC differentiation and homeostasis. We show that in aged HSC, mitochondria have increased sphericity, polarized network, lower mitochondrial membrane potential (MPP), but increased mass. We also show a decrease in number of lysosomes and in mitophagy events in aged HSC. A lipid trafficking assay showed an atypical pattern of lipid incorporation by mitochondria in aged HSC suggesting that mitochondrial lipids become abnormal upon aging. Cardiolipin (CL), a signature mitochondrial membrane lipid is essential to maintain mitochondrial membrane structure for optimum organelle-to-organelle interactions. We found reduced CL content in aged HSC, along with decreased protein expression of tafazzin, encoded by the gene TAZ, which is crucial for remodeling CL, compared to young. Using a doxycycline inducible, sh-RNA mediated TAZ KD mouse model, reduced Taz expression caused decreased HSC regenerative potential in competitive serial transplant assay. Furthermore, TAZ KD HSC exhibited fewer lysosomes localized near mitochondria, suggesting CL is crucial for channeling lysosomes towards mitochondria and initiating mitophagy. Incubation with a cardiolipin booster, Alcar, rescued the MPP and morphology in aged HSC. This work suggests that reduced levels of CL results in accumulation of abnormal mitochondria in aged HSC further contributing to decline in HSC functions with age.