This is such an incredibly lame problem to have, but I'm kind of stuck... I'm at a boss battle in Darksiders 2 that requires me to blast a large sphere into a boss... Sadly the input command to do so is Mouse 3 or the mouse wheel, and for some reason my mouse is totally non responsive in the game for some reason. Does any body know what the input would be that I have to remap in the controls menu in order to get around this? It's super embarrassing and a dumb problem to have, but a problem regardless.

Hm do you play the game with mouse and keyboard or a controller? It reads like you play with a controller, but then you should have a different button prompt (right trigger) to throw stuff so I assume you play with mouse and keyboard?  
 
Anyway, when you have a controller connected and enabled you can't use the mouse ingame, it just doesn't work until you disconnect or disable the controller. That's the only thing I can think of.

Emem is right. When you have a controller connected, the only time you can use the mouse is within the menu. It is no longer an in-game control option.

I couldn't imagine playing this game with a mouse and keyboard, and I'm playing on my PC. When the combat gets tougher later on, it seems like it would be a total clusterfuck.