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Are you asking about sending email through sales insight?
Not SI specifically but in general are there any issues with the lead owner's email domain being different than the domain connected to Marketo.
If the email is being sent from Marketo, you can edit the "From" and "Reply-to" addresses from the email editor itself.
If the email is being sent through Sales Insight, the email will have the "From" and "Reply-to" address set to the value of the Salesforce User Email Address field by default. You can change this setting in the Admin > Sales Insight tab to be a different email address field that is present on the Salesforce user. It will work if your reps change their Salesforce User Email Address but there may be a brief period where a sync will need to occur before the change has propogated. After they change their email address, make sure to send a test to ensure the change was processed.