I sold mules to many lion hunters in Az. I let them try out the prospective mule purchase on a lion hunt, hee hee, as long as I got to go. I saw many lions shot. Guys shot them with all kinds of guns, but the more experienced guys used a gun that was minimal, with a 30/30 being a magnum. It is hard to comprehend just how lethal a 22 mag loaded with 40g Win Hp is on a lion. Your 22/250 with the 65 will be plenty adequate. If your gun does not like the 65g bullet, then try the 63g sierra, I saw a lion shot with it, called into an electronic call. The lion dropped like a toilet seat with the 63g at 3400 fps.
If/when you call in a lion, don't freek. Aim your gun to break the shoulder on the off side because you will get all his vitals. After the shot, allow time for the animal to expire. You don't want to walk up on a half dead lion. They will maim you for life on their last heart beat.
If you have never hunted lions off of mules and dogs, it is the thrill of a life time that you will never forget. When the dogs bay, the mules go crazy with excitement trying to get to the dogs. You just never know the capabilities of a mule in the roughest terrain until you have ridden one on a lion hunt. The thrill is simply unbelievable, and the mules deserve the academy awards for their performance.