DHCR24 and the calcium-mediated DNA damage pathway in aging endothelium
Loss of the enzyme DHCR24 increased calcium accumulation and markers of DNA damage in models of endothelial aging
On August 25, Aging Cell published a study of the cells lining the inner surface of blood vessels. The authors examined cultured human endothelial cells and mice in which Dhcr24 was deleted specifically in these cells.
The endothelium is the layer of cells lining the inner surface of blood vessels. DHCR24 is an enzyme found in the endoplasmic reticulum, a system of membranes within the cell that also serves as one of its calcium stores. In the final step of cholesterol synthesis, DHCR24 converts desmosterol, a cholesterol precursor, into cholesterol. In a 2024 study by the same group, DHCR24 deficiency was associated with excess reactive oxygen species and impaired endothelial function. The new study traces the pathway from loss of the enzyme to the cellular DNA damage response.
DHCR24 levels were lower in cultured human cells that had aged through repeated divisions. Markers of the DNA damage response were more common in pulmonary microvascular endothelial cells from fourteen-month-old mice than in cells from three-month-old mice. The researchers then suppressed DHCR24 in young human cells and deleted Dhcr24 specifically in the endothelium of mice. Both interventions increased the DNA damage response, as shown by higher levels of p-ATM and γH2AX, two protein markers of this response.
Calcium was the next step in the pathway. Suppressing DHCR24 increased calcium levels both throughout the cell and within the endoplasmic reticulum. At the same time, the endoplasmic reticulum developed signs of stress, while the mitochondria that supply the cell with energy functioned less effectively. They lost membrane potential, one measure of mitochondrial function, and produced more reactive oxygen species. These findings traced a pathway from DHCR24 deficiency to oxidative stress through excess calcium, endoplasmic reticulum stress, and mitochondrial dysfunction.
Analysis of gene activity identified ENKUR, a protein associated with calcium channels. ENKUR levels increased when DHCR24 was deficient. When the researchers suppressed ENKUR and DHCR24 together, calcium levels, markers of endoplasmic reticulum stress, mitochondrial dysfunction, and the DNA damage response were all reduced compared with suppression of DHCR24 alone.
The results from human cell cultures and mouse endothelium supported the following sequence: reduced DHCR24 increased ENKUR, excess calcium caused endoplasmic reticulum stress and mitochondrial dysfunction, and the DNA damage response subsequently increased. Combined suppression of DHCR24 and ENKUR reduced the downstream effects, providing experimental evidence that ENKUR mediates this pathway.