Sometimes Krita refuses to save the document either via the Ctrl+S shortcut or File > Save. The only way to save is by closing the document and saying Yes when Krita asks if I want to save changes. I don't know how to trigger it, seems to be random. But the issue is present for quite a while.
Let's keep this in mind; Dmitry fixed one hang-up on saving this weekend. I encounter this problem sometimes, but like your files, my files are too big to be sane, I should scale them down. Wolthera reports she never encounters this issue, but her files are a sane size.
I haven't encountered this issue in a while.