SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.

BACKGROUND: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3). METHODS: The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3KO mice subjected to permanent nonreperfused myocardial infarction. RESULTS: Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity. CONCLUSIONS: Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.

Temporally-topological defect modes in photonic time crystals.

In this paper, we investigate the properties of temporally-topological defect modes (TTDMs) (or temporally-topological interface states) in the topological photonic time crystal (PTC) systems. The PTC systems are constructed by the cascade of multiple sub-PTCs that possess temporal inversion symmetries and different topologies. The cases of two-, three-, and multiple-sub-PTC for the topological PTC system are studied. By transfer matrix method, we find that the TTDMs appear when the topological signs of the corresponding gaps in the sub-PTCs are different. The positions of TTDMs can be adjusted by changing the modulation strength of the refractive index, the time duration, and the period of the sub-PTCs. Moreover, the number of TTDMs is one less than the number of sub-PTCs. In addition, the robustness of the systems is also studied. We find that the topological PTC systems have good robustness, especially on the random configuration of the refractive index and time duration for the temporal slabs in the systems. Such research may provide a new degree of freedom for PTC applications, such as novel PTC lasers, tunable band-stop or band-suppression PTC filters, and many others, in the field of integrated photonic circuits for optical communications.