Sadiq Khan says fears about the future of central of London "keep him awake at night".
The Mayor of London is worried that employees preferring to keep operating from the suburbs instead of commuting will pose an "existential threat" to the centre of the city.
The coronavirus has meant those who usually commute into the centre of the city are now working from home, with the London mayor worried many will remain in the suburbs.
Surveys show people are reluctant to return to long commutes into city centres, while London suburb house prices are rising.
Mr Khan told the Observer New Review: "I think we've got to accept the fact that there is potentially an existential threat to central London as we know it.
"Are there going to be satellite-type offices in outer London because people may not want to work from home but in a co-working space in zone 5 or zone 4?"
After months of being warned to remain at a distance on public transport and only use it when necessary, Mr Khan worries people will continue to avoid trains and buses after the pandemic ends.
Some data suggests people feel more efficient at home and enjoy the extra free time afforded by not having to travel into work.
The Labour mayor - who served as MP for Tooting until 2016 - went on to insist cultural attractions and the financial services sector would ensure central London remained relevant, however.
He also said he has found it "really hard" working from home but is "lucky" to have a wife and kids in a "decent-sized house".
"But I thrive on company, sharing ideas. Zoom meetings aren't the same," he added.
In the wide-ranging interview, he admitted he "blinked" first in talks with Prime Minister Boris Johnson over a £1 billion grant and £500 loan for Transport for London that involved strict conditions.
