Sirtuins and mitochondria: new data
The SIRT5 protein has a huge impact on mitochondrial metabolism
LifeSciencesToday based on the materials of the Buck Institute: SIRT5 Regulation Has Dramatic Effect on Mitochondrial MetabolismThe family of proteins-deacetylases of sirtuins has attracted the close attention of scientists in recent years, since their connection with life expectancy, diabetes, cancer and the regulation of metabolism has been established.
The results of a new study published in the journal Cell Metabolism (Rardin et al., SIRT5 Regulates the Mitochondrial Lysine Succinylome and Metabolic Networks) allowed researchers from the Buck Institute for Research on Aging to conclude that mitochondrial sirtuin SIRT5 actively regulates proteins involved in metabolism.
Using a new quantitative proteomic method developed at the Buck Institute, the laboratory of Professor Bradford Gibson, PhD, in collaboration with the group of Eric Verdin from the Gladstone Institute, it was possible to identify hundreds of mitochondrial proteins that undergo modification (lysine succinylation) and subsequent regulation by sirtuin SIRT5. These findings have far-reaching implications for understanding metabolism in both normal and pathological conditions.
"Before you start studying any process, you need to know the players involved in it," says Professor Gibson. The SIRT5 protein is synthesized in mitochondria – cellular organelles responsible for energy production and homeostasis present in all cells of our body. Based on quantitative differences between mice without the Sirt5 gene and control animals, Professor Gibson and his colleagues found that SIRT5 selectively removes sites of succinyl modifications in more than 140 different proteins involved in major metabolic pathways, including fatty acid oxidation, oxidative phosphorylation and the formation of ketone bodies.
"Protein succinylation in many pathways is widespread in mitochondria, and SIRT5 appears to be the only mitochondrial enzyme responsible for regulating this structural modification," explains lead author Matthew Rardin, a postdoctoral fellow in Professor Gibson's laboratory.
"We found that lysine succinylation has a huge effect on enzyme activity," adds Professor Gibson. Succinylation involves the transfer of a four–carbon negatively charged succinyl group to the primary amine of lysine residues - one of the 20 amino acids that make up all proteins. Under physiological conditions, this modification changes the structure of usually positively charged lysine residues and their electric charge.
SIRT5 selectively removes sites of succinyl modifications in more than 140 different proteins involved in major metabolic pathways, including fatty acid oxidation, oxidative phosphorylation and ketone body formation, and, apparently, is the only mitochondrial enzyme responsible for regulating this structural modification. (Fig. Cell)"If proteins are hypersuccinylated, metabolic pathways, including fatty acid accumulation in the liver and decreased synthesis of ketone bodies, are disrupted," Dr. Rardin continues.
Thus, the study showed that HMGCS2, an enzyme that limits the rate of formation of ketone bodies, important for energy production during fasting, has at least 15 succinylation sites. Moreover, they showed that succinylation of certain residues of HMGCS2 lysine near its binding pocket to the substrate suppresses the activity of the enzyme. Thus, the function of SIRT5 seems to be the removal of these succinyl modifications and the restoration of the enzymatic activity of HMGCS2, as well as other mitochondrial enzymes.
"Although all the effects of lysine succinylation on mitochondrial function remain unknown, we have compiled a large list of proteins whose succinylation appears to be actively regulated by SIRT5," Gibson says. "Our list of proteins and sites will be an extremely valuable resource for scientists studying the impact of these structural changes on many important metabolic pathways in normal and pathological conditions."
This study is part of a large project to study the role of sirtuins in mitochondrial biology and metabolism. In a paper published earlier this year in Proceedings of the National Academy of Sciences (Rardin et al., Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways), the same group investigated the activity of sirtuin SIRT3, close to SIRT5, regulating lysine acetylation in mitochondria. Unlike succinylation, which charges lysine residues negatively, acetylation only neutralizes their positive charge.
Taken together, these two works highlight the huge number of intersections between acetylation and succinylation of lysine. Professor Gibson and his colleagues believe that SIRT3 and SIRT5 are fine–tuning operators of several metabolic pathways, the instrument of which is the selective regulation of these two modifications. Many proteins are regulated by both SIRT3 and SIRT5, often at the same sites, and these modifications probably have important functional effects similar to what scientists have demonstrated on HMGCS2.
"We were surprised by such a high degree of intersections, especially since previous work showed a slight substrate overlap between these two sirtuins," Gibson says.
Scientists remind that it is too early to assess the functional role of both SIRT3 and SIRT5.
"We hope that someday the data we have collected will help us better understand the role of sirtuins in pathological processes ranging from neurodegeneration to diabetes, especially in those in which mitochondria are known to play a key role," concludes Professor Gibson. "This is just the beginning."
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