I understand your points and agree with your theories, but these are not easy sentences to deal with-- they seem more to be transciptions of the spoken language, which use commas to indicate pauses for breathing and reflection more than do composed written sentences. If we consider them as the latter, however:
1- What I need you to do is, follow him and see where he lives. – The comma is wrong; we should not place a comma between S and V, and here What I need you to do is the subject of the sentence, while follow (and see) is the verb.
2- What do you mean, I am not taking interest in my job? – Here, I would keep the comma; What do you mean seems to be some sort of interjected (‘prejected’?) comment… or I am not taking interest in my job is the verb complement? This is not an easy sentence for me to analyze. If there were no What, however, the comma would be wrong: Do you mean I am not taking interest in my job?
3- What I really meant is, are you feeling up to it? – here, are you feeling up to it is the object; again, the verb should not be separated from it by a comma; still, ‘is are’ is confusing, so I would take Amy’s advice and restructure somehow.
These are just my opinions. As Alan says, the two basics are brevity and clarity: is the sentence short and clear enough to avoid commas?-- if so, do so.