The neonatal mammalian heart is capable of regeneration for a brief
window of time after birth. However, this regenerative capacity is lost within
the first week of life, which coincides with a postnatal shift from anaerobic
glycolysis to mitochondrial oxidative phosphorylation, particularly towards
fatty-acid utilization. Despite the energy advantage of fatty-acid
beta-oxidation, cardiac mitochondria produce elevated rates of reactive oxygen
species when utilizing fatty acids, which is thought to play a role in
cardiomyocyte cell-cycle arrest through induction of DNA damage and activation
of DNA-damage response (DDR) pathway. Here we show that inhibiting fatty-acid
utilization promotes cardiomyocyte proliferation in the postnatatal heart.
First, neonatal mice fed fatty-acid deficient milk showed prolongation of the
postnatal cardiomyocyte proliferative window, however cell cycle arrest
eventually ensued. Next, we generated a tamoxifen-inducible
cardiomyocyte-specific, pyruvate dehydrogenase kinase 4 (PDK4) knockout mouse
model to selectively enhance oxidation of glycolytically derived pyruvate in
cardiomyocytes. Conditional PDK4 deletion resulted in an increase in pyruvate
dehydrogenase activity and consequently an increase in glucose relative to
fatty-acid oxidation. Loss of PDK4 also resulted in decreased cardiomyocyte
size, decreased DNA damage and expression of DDR markers and an increase in
cardiomyocyte proliferation. Following myocardial infarction, inducible deletion
of PDK4 improved left ventricular function and decreased remodelling.
Collectively, inhibition of fatty-acid utilization in cardiomyocytes promotes
proliferation, and may be a viable target for cardiac regenerative
therapies.
Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid—PS—controls the movement of another lipid—cholesterol—between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.
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