Skoltech researchers and their international colleagues found that the nuclear protein Sirtuin 6 is the key regulator of mitochondrial activity in the brain. Sirtuin 6 is involved in many important processes, such as DNA protection, fat and glucose metabolism, and energy supply to the cell. Since aging and neurodegenerative diseases display similar processes in neurons, the team’s findings will help develop new prevention and treatment approaches for these conditions. The study, supported by a Russian Science Foundation grant, came out in Cell Death and Disease.

Cellular aging comes with genome instability caused by the “wear” of DNA repair systems. This disrupts the functioning of proteins that are encoded in DNA and control cellular functions. Deterioration of the cell’s “energy stations” — mitochondria — has the most noticeable and critical effect on the cell, which, like a phone with a depleted battery, barely copes with its basic functions and finally dies. Both aging and degenerative diseases, such as Alzheimer’s and Parkinson’s, involve similar effects and have similar underlying mechanisms.

Researchers from the Skolkovo Institute of Science and Technology in Moscow and their international colleagues focused on the function of the mammalian nuclear protein, Sirtuin 6, which can chop off a small bunch of atoms from DNA “packers” in order to control DNA folding and unfolding and, therefore, gene activity. Sirtuin 6 ensures the integrity of hereditary material and chromosomes’ end sections called telomeres (chromosome shortening is one of the hypothetical causes of aging), regulates cell metabolism, and plays an important role in fending off diseases associated with aging and death of neurons. The authors set out to determine exactly how Sirtuin 6 affects mitochondrial function in the mouse brain.

In their experiment, the researchers used mice with a broken Sirtuin 6 gene and hence amounts of Sirtuin 6 below normal. They isolated RNA from mouse brains and deciphered its sequence to understand exactly which genes are at work in neurons. They also analyzed the amount of substances associated with mitochondrial activity.

The team discovered that a lack of Sirtuin 6 leads to pathological changes. Nearly 3,000 genes were affected, and those associated with mitochondria suffered the most damage. This was also confirmed by disruptions in mitochondrial metabolism: The samples contained fewer agents of oxidative phosphorylation that helps store the nutrients’ energy in the form of adenosine triphosphate (ATP) — the basic “energy currency” of living organisms. Cell respiration became less efficient, too. The authors noted a direct link between the lack of Sirtuin 6 and the death of mitochondria: Both protein levels and the amounts of mitochondria dropped about 20% in the mouse brain cells. The reason for all these dramatic consequences is the abundance of contacts between Sirtuin 6 and other proteins, especially the cell’s ubiquitous YY1 transcription factor, which Sirtuin 6 literally works in tandem with, and Sirtuin 3 and Sirtuin 4 — its relatives and “substitutes” in the mitochondria.

“Our findings clearly show that a decrease in Sirtuin 6 levels in the brains of elderly people might be among the main causes of age-related neurodegenerative diseases. Now we have to figure out the details. Currently, we are testing a hypothesis about DNA packaging being behind all this, since Sirtuin 6 cuts off a bunch of atoms from DNA ‘packers’ and thus controls DNA folding and unfolding. This paper is the first step in our large-scale study supported by an RSF grant and focusing on DNA packaging in healthy individuals and patients with various brain diseases. We have already obtained experimental data on DNA packaging in the human brain and are now thoroughly analyzing it,” Skoltech Assistant Professor Ekaterina Khrameeva, who led the RSF-supported project, commented.

Photo combined. First author and project team member Dmitrii Smirnov and project lead Ekaterina Khrameeva. Credit: Ekaterina Khrameeva