The main findings of this study were as follows: (1) the Rubicon–p22phox complex is translocated to the outer mitochondrial membrane; (2) the Rubicon–p22phox interaction enhances both cytosolic ROS and mtROS; (3) Rubicon inhibits mitochondrial metabolism and biogenesis; (4) Mito-TIPTP increases mitochondrial function by alleviating the binding of Rubicon to p22phox; and (5) Mito-TIPTP increases the survival of colitis-induced mice by blocking Rubicon–p22phox binding and restoring the mitochondria. The gene discussed is CYBA; the disease is colitis.