Mild Depolarization of the Mitochondrial Membrane as a Mechanism of Slowed Aging in Long-Lived Mammals

Every cell contains hundreds of mitochondria, cell structures that evolved long ago from symbiotic bacteria. They carry remnants of the original bacterial DNA, and continually fuse and divide like bacteria. Mitochondria participate in many core cellular processes, but arguably their most important function is to produce the chemical energy store molecule adenosine triphosphate (ATP), needed to keep the cell running. This is an energetic process, and produces free radicals such as reactive oxygen species (ROS) as a side-effect. ROS damage cellular machinery, provoking the activity of repair mechanisms. This damage is actually used as a signal, such as when it triggers the beneficial response to exercise: mitochondria work harder, moderately more ROS is generated, and muscle cells have evolved to repair and build tissue in response.

Too much ROS, too great a level of oxidative damage, is harmful, however. It overwhelms repair and maintenance mechanisms, giving rise to the state of oxidative stress. This is characteristic of old tissues and age-related disease, and early theories of aging focused strongly on oxidative damage as a primary mechanism by which aging leads to age-related disease. The picture is more nuanced than this, however, and where oxidative stress falls in the chain of first causes and downstream consequences continues to be debated.

In today's open access research, scientists point out certain aspects of mitochondrial biochemistry that might contribute to the exceptional longevity of bats and naked mole-rats in comparison to mice and other similarly sized mammals. The mitochondria of naked mole-rats and bats preserve a mild depolarization response that minimizes ROS production, and they do this more effectively than mice. It is possible to argue that in the case of bats the metabolic demands of flight, and in the case of naked mole-rats oxygen-poor underground environments, have led to mitochondria that are more resilient to processes of aging. It is still hard to pick out what is cause and what is consequence, however, and it is hard to assess affect size in terms of the degree to which exceptional species longevity results from one mechanism versus another mechanism. Mitochondria are only one of a number of mechanisms of longevity studied in naked mole-rats, and relative contributions are debated.

Newly confirmed biochemical mechanism in mouse, bat and naked mole rat cells is a key component of the anti-ageing program

Naked mole rats, an east African rodent of a size comparable to moles or mice, show a strongly delayed process of ageing and live up to 30 years. Scientists now confirmed a mechanism in mouse, bat and naked mole rat cells - a "mild depolarization" of the inner mitochondrial membrane - that is linked to ageing: Mild depolarization regulates the creation of mitochondrial reactive oxygen species (mROS) in cells and is therefore a mechanism of the anti-ageing program. In mice, this mechanism falls apart at the age of 1 year, while in naked mole rats this does not occur until ages of up to 20 years.

Mitochondrial reactive oxygen species (mROS) such as hydrogen peroxide are by-products of cell respiration and, in higher doses, associated with various diseases and ageing processes. There are different mechanisms at the inner and outer mitochondrial membranes that regulate the mROS production. Key function of cell respiration is energy production in the form of ATP (adenosine triphosphate) through coupling of mitochondrial respiratory chain complexes with ATP synthase. Different mitochondrial intermembrane space enzymes (hexokinases I + II and creatine kinase) have now been confirmed to slightly lower the membrane potential of the inner mitochondrial membrane ("mild depolarization"). This means that the differences in the electric load between the inner and the outer space of the mitochondria are lowered and the energy production through ATP synthesis is reduced to some extent. At the same time this leads to the cessation of mROS production.

The research team was able to show that both biochemical mechanisms do not operate in the same intensity and efficiency in different species and tissues and at different ages: The researchers examined the hexokinases I + II and creatine kinase mechanisms in various tissues (lung, kidney, brain, skeletal muscles, heart, and others) in mice (Mus musculus), naked mole rats (Heterocephalus glaber), and Seba's short-tailed bats (Carollia perspicillata). They found interesting differences: Mild depolarization significantly starts decreasing after 1 year of age in mice with negligible levels after 24 months in skeletal muscles, diaphragm, heart, brain, and spleen. In lung and kidney tissue, mild depolarization decreases to a lesser extent with ageing. "The crumbling of the anti-ageing program in the cells starts after only a third of the average life span in mice, while the naked mole rats and Seba's short-tailed bats maintain mild depolarisation and hence the suppression of mROS production up to high ages. This contributes to the extraordinary longevity of these species."

Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program

The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): 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 ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol.

One of the kinase reaction products, ADP, 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+-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation.

In 2.5-y-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 NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.

Comments

Strangely, there is no comment on an article that has the prospect of extending human life three times. I do not know if I read it correctly, but I have not noticed how to achieve depolariation of mitochondrial membranes.

I will try meldonium, the Russian medicine Милдронат used by tennis player Maria Sharapova for 10 years. It is said to slow down the performance of mitochondria.

Posted by: Jan Omasta at March 25th, 2020 11:38 AM

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