A key protein in energy regulation has been identified in a new research by scientists at the Gladstone Institute of Virology and Immunology.
Eric Verdin, senior investigator and senior author of the study, said: "Many mitochondrial proteins undergo a small chemical modification known as acetylation, which varies during feeding and fasting conditions.
"From our previous studies, we knew that the enzyme SIRT3 is involved in removing these modifications, and we speculated that SIRT3 might have a role in regulating metabolism and looked for how it might do this."
To investigate the enzyme's role in mice, the scientists used mice in which both copies of the gene had been deleted. It was seen that mice that lost both copies of the SIRT3 gene appeared to be completely normal. However, the researchers then tested the mice under fasting conditions. During fasting, expression of SIRT3 was increased in the liver, an organ that helps maintain the body's energy balance. The livers of mice without SIRT3 had higher levels of fat and triglycerides than normal mice, because the mice could not burn fat.
To find out how SIRT3 controls fat burning, the team looked at the mitochondrial proteins. They found that the enzyme called LCAD was "hyperacetylated" and contained even more acetyl groups than usual and the enzyme had reduced activity.
The mice that did not have SIRT3 also had many of the key markers of fat oxidation disorders, low energy levels and low tolerance to cold. Further analysis showed that higher levels of SIRT3 expression and activity increase the activity of this key enzyme in fat oxidation. However, a number of other proteins are acetylated in the mitochondria, an observation which suggests that other proteins may be involved.
Matthew Hirschey, postdoctoral fellow and lead author of the study, said: "We conclude that acetylation is a new mechanism for regulating fatty acid oxidation in mitochondria and that SIRT3 mediates the acetylation state.
"The implication is that SIRT3 may have a pathologic role in some metabolic disorders, such as diabetes, cardiovascular disease, or fatty liver disease. We are excited about exploring these possibilities."
The study has appeared in the journal Nature.