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Can changes in brain energy pathways cause depression?

New research has identified mutations in the DNA code that can affect energy metabolism. It also found a link to major depressive disorder. The World Health Organization (WHO) describes depression as “the leading cause of disability worldwide.” It affects more than 300 million people around the world. Experts believe that many factors contribute to major depressive disorder (MDD).

These include genetics, environmental factors including abuse, brain physiology, and the immune system. One theory is that disturbances in energy metabolism in the brain can contribute to a person developing MDD.

Conceptually, this is relatively easy to follow. The brain has a much higher energy requirement than other organs. Any disturbance to this finely tuned system can have drastic consequences.

Health Consultations recently reported on a study in which researchers deleted the SIRT1 gene in excitatory forebrain neurons in male mice. The result was a drastic reduction in the number of mitochondria in these cells, accompanied by symptoms similar to depression.

Mitochondria, the so-called power plants of the cell, are specialized compartments that convert the food we eat into the chemical energy our cells require to function. Each cell has many mitochondria to ensure a smooth energy supply.  If we reduce their numbers or interrupt intricate metabolic pathways, cells can die due to lack of energy.

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In a recent article published in the journal Nucleic Acid Research, scientists used bioinformatics tools to identify large mutations in the genetic code of mitochondria. They found a significant molecular signature of these in a subset of brain samples with MDD. Identifying about 4,500 mutations.

Genes within mitochondria and some within the cell’s nucleus are responsible for keeping power plants running. Mutations in these genetic locations can cause mitochondrial diseases. A person can inherit these mutations, but they can also accumulate during their lifetime.

Scientists know that deletions, a type of DNA mutation in which a large part of the genetic code is missing, causes a number of mitochondrial diseases. The study’s lead author, Brooke E. Hjelm, an assistant professor of clinical translational genomics at the University of Southern California in Los Angeles, explained to the MNT that the researchers had already identified about 800 deletions in the mitochondrial genome.

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“So,” she said, “what I did was exploit a tool that is already available to the research community called MapSplice and develop a process to use it to detect and quantify mitochondrial deletions.”

While Hjelm was confident that her analysis tool would allow him to identify many deletions in her samples, she was surprised to find so many.
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In the 93 human samples, which came from 41 deceased individuals, included in the study, he discovered about 4,500 deletions. However, not all of these mutations necessarily cause the disease. If only a mutation occurs in some of the mitochondria in a person’s cell, the rest of the power plants can take the place. However, if it reaches a certain threshold, the cell may not be able to continue to function normally.

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“One thing I found particularly interesting was that many of the deletions I detected (especially those identified in many samples) had been previously identified in those with mitochondrial disease,” Hjelm explained.

‘What this means,’ he continued, ‘is that there are deletions that have previously only been seen in one or a few people with a diagnosis of mitochondrial disease, suggesting that they are rare, when in fact these deletions are likely to occur. in all of us, they are simply not present at a high enough rate to cause disease.
A subset of MDD samples have deletions

Having developed the new bioinformatics tool, Hjelm and her colleagues set out to answer the following question: Do people with diagnosed psychiatric disorders have evidence of mitochondrial dysfunction in their brains? Of the 41 people included in the study, nine had a diagnosis of MDD.

 

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