Failure

Obviously a game-ending TPK is the end all be all of failures for a party to go through. In most other systems, Death is a pretty permanent failure as well. Not as much in fantasy setting with True Resurrection, and certainly not in Mutants and Masterminds when resurrection, and regeneration can easily make death a very minor complication. (Some characters die multiple times per combat due to that high level regeneration).

So how can one keep up the stakes and make REAL consequences for failure:

1. The Villains Win- The most obvious answer- the villains are able to abscond with whatever McGuffin the PCs were trying to protect, or their superweapon goes off and blasts away a good chunk of the city, or whatever plan happens works. This can leave the party trying to "undo" whatever evil was done, and make for several upcoming missions.
2. The Party Gains a Complication: Maybe the people seeing superman fall makes people lose faith in superheroes, or a character loses his fame or security clearance after a horrible loss. Perhaps a character gains self doubt and his powers become unreliable like in Spider Man 2. Perhaps a secret identity is revealed. Giving out complications (and the hero points that go with them) can provide real world consequences while keeping the plot moving.
3. A Loved one is Kidnapped- When the PCs lose or are forced to retreat (or even if the Villains manage to escape with something), they may choose to take out an "insurance policy" against future intrusions.
4. A Device is Damaged- Perhaps a device is damaged and either becomes unreliable, or stops working altogether, until it can be repaired via another mission, or perhaps the enemy even steals it.
5. Cursed: The PC might have bad luck (roll twice, take worst roll) or become werewolves, or otherwise succumb to a curse as a result of their failure.
6. Mental Condition: The PCs might suffer emotional trauma that manifests as a psychological disorder, or depression, or something that they need to overcome before they can adventure again.
7. TPK Alternatives: Sometimes when the party loses it's because they all died in combat (or are knocked unconscious). Here are some alternatives to just ending the campaign there:
1. Death Traps: The villain locks them into a death trap to enjoy a horrendous death (that they can escape from)
2. Powerless: The villain nullifies their powers "to get them out of the way" and the PCs must find a way to restore their powers before taking on the villain again.
3. Transformed: The PCs are turned into cats or different people or something, and may need to get to their true bodies.
4. Framed: The PCs are framed for the crimes they were foiling, throwing them in jail, or an alternate prison dimension or something where they must stage a prison break and clear their names.
5. Exiled: The PCs are send to the moon, shrunk to the microverse, an alternate dimension, to the deep past/future, or somewhere they can't simply come back from, and they must find a way to return- meanwhile the villain is free to act without consequences.