The finding of electron leakage during the electron transport within the mitochondrial membrane (in eukaryotes) or in the cell membrane of the prokaryotes is an important issue for the accumulation of the Reactive Oxygen Species (ROS) in the cytosol which in turn induce the probable aging of cells. In eukaryotes, mitochondrion is known to be the major site of the ROS generation in different pathological processes which may further cause cell damages as evident through the ischemia-reperfusion (I/R) injury, respiratory diseases, cell apoptosis, and even the onset of cancer. Thus, the mitochondrial leakage and the physiological effect of leaked protons and electrons grow up with future interest in energy metabolism. Current review focused on the physiological impact of electron/ proton leakage particularly in the eukaryotic cells based on the previous reports; emphasized on the prospects of the eukaryotic mitochondrion as a modulator of proton and electron leakage; and finally attempted to assess the regulatory mechanisms of such electron/ proton leakage.