Can changes in brain energy pathways cause depression?

Mental Health
New research has identified mutations in the DNA code that may affect energy metabolism. It also found a link to major depressive disorder.
Girl with depression
Could mutations in mitochondria cause depression?

The World Health Organization (WHO) describe 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 may contribute to a person developing MDD.

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

Medical News Today recently reported on a study in which researchers deleted the gene Sirt1 in forebrain excitatory neurons in male mice. The result was a stark reduction in the number of mitochondria in these cells, accompanied by depression-like symptoms.

Mitochondria, the so-called powerhouses of the cell, are specialized compartments that convert the food we eat into the chemical energy that our cells require to function. Each cell has many mitochondria to ensure a smooth supply of energy.

If we reduce their number or disrupt the intricate metabolic pathways, cells may die due to energy starvation.

In a paper published recently in the journal Nucleic Acid Research, scientists used bioinformatic tools to identify large mutations in the mitochondria’s genetic code. They found a significant molecular signature of these in a subset of brain samples with MDD.

Identifying nearly 4,500 mutations

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

Scientists know that deletions, a type of DNA mutation wherein a large stretch of genetic code is missing, cause a number of mitochondrial diseases.

Lead study author Brooke E. Hjelm — an assistant professor of clinical translational genomics at the University of Southern California in Los Angeles — explained to MNT that researchers had already identified around 800 such deletions in the mitochondrial genome.

“So,” she said, “what I did was I exploited a tool that is already available to the research community called MapSplice and developed a process so that it could be used to detect and quantify mitochondrial deletions.”

While Hjelm was confident that her analysis tool would allow her to identify many deletions in her samples, she was surprised to find quite so many.

In the 93 human samples — which came from 41 deceased individuals — included in the study, she discovered nearly 4,500 deletions.

However, not all of these mutations necessarily cause disease. If a mutation only occurs in a few of the mitochondria in a person’s cell, the rest of the powerhouses can take up the slack. If it reaches a certain threshold, however, the cell may not be able to carry on functioning normally.

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

“What this means,” she continued, “is that there are deletions that had previously only been seen in one or a few [people] with a diagnosed mitochondrial disease suggesting they are rare, when in fact these deletions likely occur in all of us, they just aren’t 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 conditions have evidence of mitochondrial dysfunction in their brains?

Of the 41 people included in the study, nine had a diagnosis for MDD.

Hjelm found a large number of “high-impact” deletions, as she calls them in the study paper, in brain tissue from two of the individuals with MDD.

What we are seeing in our data is that a subset of [people] with MDD have a large mitochondrial deletion in their brain […].”

Brooke E. Hjelm

How exactly might deletions cause depression?

According to Hjelm, “The basic principle would be that your brain cells (neurons) require energy to function and communicate with one another properly, and because these cells aren’t getting energy from enough healthy mitochondria, they can’t relay messages from one region to another or respond to external stimuli the way they should.”

She also shared some of the questions that remain, which includes gaining a better understanding of “which brain regions are susceptible to this and […] what proportion of [people] with depression have this particular mitochondrial issue.”

Determining who carries deletions in their mitochondrial genome will be a significant hurdle that the team will need to overcome. As removing brain tissue for diagnosis is not practical, Hjelm indicated that new brain imaging techniques or biomarker tests would be required.

Ultimately, Hjelm hopes that this will allow healthcare professionals to use a personalized medicine approach and tailor treatments that are most likely to address the underlying molecular causes of MDD in these people.

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