Proceedings of th National Academy of Sciences
Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program.

The mitochondria, organelles that produce the largest amounts of adenosine triphosphate and mitochondrial reactive oxygen species in living cells, are equipped with a universal mechanism that can completely prevent reactive oxygen species production. This mechanism consists of mild depolarization of the inner mitochondrial membrane to decrease the membrane potential to a level sufficient to form adenosine triphosphate but insufficient to generate mitochondrial reactive oxygen species production. In short-lived mice, aging is accompanied by inactivation of the mild depolarization mechanism, resulting in chronic poisoning of the organism with mitochondrial reactive oxygen species productions. However, mild depolarization still functions for many years in long-lived naked mole rats and bats.

The mitochondria of various tissues from mice, naked mole rats and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species: hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates - mitochondrial adenosine triphosphate, is electrophoretically transported by the adenosine triphosphate / adenosine diphosphate antiporter to the catalytic site of bound hexokinase or bound creatine kinase without adenosine triphosphate dilution in the cytosol. One of the kinase reaction products, adenosine diphosphate, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H+-adenosine triphosphate synthase with adenosine diphosphate until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level - id est, mild depolarization of mitochondria. This ∆ψ decrease is sufficient to completely inhibit mitochondrial reactive oxygen species generation. In 2.5 years old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in naked mole rats and bats for many years. As a result, reactive oxygen species mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived naked mole rats and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.