ABSTRACT
Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in Aasdhppt that are likely pathogenic in humans.
ABSTRACT
RATIONALE: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction. Short-term S100A9 blockade during the inflammatory phase post-myocardial infarction inhibits systemic and cardiac inflammation and improves cardiac function long term. OBJECTIVE: To evaluate the impact of S100A9 blockade on postischemic cardiac repair. METHODS AND RESULTS: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in WT (wild type) C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin-Sca-1+c-Kit+ hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150+CD48-CCR2+ hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6CloMerTKhi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes, and a larger myocardial scar. The transcription factor Nur77 (Nr4a1 [nuclear receptor subfamily 4 group A member 1]) mediates the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6Chi/int monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9-/- mice with permanent myocardial ischemia, leading to depressed cardiac function long term. CONCLUSIONS: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to myocardial infarction. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute myocardial infarction.
