Acute gastric mucosal lesions (AGML) are primary gastrointestinal affection and many people suffer from this disease. Although there are several causes in this disease, reactive oxygen species from mitochondria (mitROS) would like to be related deeply. Surprisingly, not only non-steroidal anti-inflammatory drugs (NSAIDs) but also gastric acid with moderate pH induces mitROS, and resulted in inducing cellular apoptosis. In addition, previous our study showed manganese superoxide dismutase (MnSOD) overexpressed gastric mucosal cells, which scavenge mitROS specifically, suppressed generating lipid peroxidation attributed from mitROS and cellular death. Therefore, mitROS from NSAIDs and gastric acid are likely to cause AGML, and control of mitROS suppresses AGML and other gastrointestinal disease.