The last we saw, Mewtwo left the island he and his clones were hiding upon in Mewtwo Returns and seemed to be migrating from place to place. Even stopping at a location that resembled New York City, which could perhaps be today's Castelia City. Now I doubt the game developers and writers thought this far ahead at the time when they incorporated that ending scene in Mewtwo Returns, but I think deep down they always knew they wanted to create a location that was based off of New York. So Mewtwo being reawakened somewhere in Unova would make perfect sense when you think about it.
Given the likeliness of a heavy Team Rocket vs. Team Plasma plot here, it would be more effective for them to use the same Mewtwo we saw from the original movie anyway.