When does the performance hit occur?

If it is only when an exception has been raised, and its own class is not listed by the except clause, then I personally wouldn't worry about it; tracing the MRO *could* get arbitrarily long already; it just doesn't in practice.  The same should be true of virtual subclassing.

On the other hand, if it adds another module or three to the required startup set, that might be a concern...