350 MPH is a fast speed to be entering combat, faster than that of the Bf-109. The bomber formations would be inbetween 15,000 - 30,000 feet, the Mustang would be a more than capable plane at those altitudes.
The Mustang seperates from the formation and goes roaming out in front. The Bf-109s come down on to these Mustangs, if the Mustangs do not see the Bf-109s it's an unlucky day for them because someone is going to get shot down. However, if they do the Bf-109 has to degrade the Mustang to his level. The Mustang is going fast already and it won't take long to go faster, the Bf-109 has to keep pace with the Mustang to shoot him down while keeping his fuel up so he can intercept the bombers when they come.
Something easy for the Mustang to do. An easy plane to fly, an easy plane to fight in and an extremely long range. Something that allows the Mustang to keep these superior interceptors away. That's what makes it an excellent machine; it does it's job and it does it well.
On top of all that though, a bomber formation going at 15,000 feet would allow Mustangs to roam much higher. And they did bomb at 15,000 feet sometimes.