Study shows frequent mitochondrial DNA insertion in the brain cells

As direct descendants of ancient bacteria, mitochondria have always been a bit alien.

Now a study shows that mitochondria may be even stranger than we thought.

Mitochondria in our brain cells often throw their DNA into the nucleus, the study showed, where the DNA is integrated into the cells’ chromosomes. And these insertions can cause damage: Among the nearly 1,200 study participants, those with more insertions of mitochondrial DNA in their brain cells were more likely to die sooner than those with fewer insertions.

“We used to think that the transfer of DNA from the mitochondria to the human genome was a rare event,” says Martin Picard, mitochondrial psychobiologist and associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler. Columbia Aging Center. Picard led the study with Ryan Mills of the University of Michigan.

“It’s amazing that it seems to happen several times in a person’s lifetime,” Picard adds. We found many of these insertions in different brain regions, but not in blood cells, which explains why dozens of previous studies of blood DNA missed this phenomenon. “

Mitochondrial DNA behaves like a virus

Mitochondria live in all our cells, but unlike other organelles, mitochondria have their own DNA, a small circular strand containing about three dozen genes. Mitochondrial DNA is a remnant of the organelle’s ancestors: ancient bacteria that settled in our single-celled ancestors about 1.5 billion years ago.

In recent decades, researchers discovered that mitochondrial DNA has occasionally “jumped” out of the organelle in human chromosomes.

The mitochondrial DNA behaves similar to a virus in that it uses cuts in the genome and sticks itself in, or as jumping genes known as retrotransposons that move through the human genome.”

Ryan Mills, University of Michigan

The insertions are called nuclear-mitochondrial segments – NUMTs (“pronounced new mites”) – and have been accumulating in our chromosomes for millions of years.

“As a result, we are all walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors,” says Mills.

Mitochondrial DNA insertions are common in the human brain

Research in recent years has shown that “NUMTOgenesis” is still happening today.

“Mitochondrial DNA skipping is not something that only happened in the distant past,” says Kalpita Karan, a postdoc in the Picard lab who conducted the study along with Weichen Zhou, a study researcher in the Mills lab. “It’s rare, but a new NUMT is integrated into the human genome about once in 4,000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes.”

The realization that new hereditary NUMTs are still being produced made Picard and Mills wonder whether NUMTs could also arise in brain cells during our lifetime.

“Inherited NUMTs are usually benign, probably because they arise early in development and the harmful ones are eradicated,” says Zhou. But if a piece of mitochondrial DNA inserts itself into a gene or regulatory region, it could have important consequences for that person’s health or longevity. Neurons may be particularly sensitive to damage caused by NUMTs because when a neuron is damaged, the brain usually does not make a new brain cell to take its place.

To investigate the extent and impact of new NUMTs in the brain, the team collaborated with Hans Klein, assistant professor at the Center for Translational and Computational Neuroimmunology at Columbia, who had access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The researchers looked for NUMTs in different parts of the brain using stored tissue samples from more than 1,000 older adults.

Their analysis showed that the insertion of nuclear mitochondrial DNA occurs in the human brain – usually in the prefrontal cortex – and probably several times throughout a person’s life.

They also found that people with more NUMTs in their prefrontal cortex died earlier than those with fewer NUMTs. “This suggests for the first time that NUMTs may have functional consequences and potentially influence lifespan,” Picard says. “NUMT accumulation can be added to the list of genome instability mechanisms that may contribute to aging, functional decline and longevity.”

Stress accelerates NUMTOgenesis

What causes NUMTs in the brain, and why do some regions accumulate more than others?

To get some clues, the researchers looked at a population of human skin cells that can be grown and aged in a dish for several months, allowing for exceptional longitudinal studies of “lifespan.”

These cultured cells gradually accumulated several NUMTs per month, and when the cells’ mitochondria stopped functioning due to stress, the cells accumulated NUMTs four to five times faster.

“This shows a new way in which stress can affect the biology of our cells,” says Karan. “Stress makes mitochondria more likely to release pieces of their DNA, and these pieces can then ‘infect’ the nuclear genome,” Zhou adds. It’s just one way mitochondria shape our health, aside from energy production.

“Mitochondria are cellular processors and a powerful signaling platform,” says Picard. “We knew they can control which genes are turned on or off. Now we know that mitochondria can even change the nuclear DNA sequence itself.”

Additional information

The study, titled “Somatic nuclear mitochondrial DNA insertions are common in the human brain and accumulate over time in fibroblasts,” was published August 22 in PLOS Biology.

All authors: Weichen Zhou (University of Michigan), Kalpita R. Karan (Columbia), Wenjin Gu (Michigan), Hans-Ulrich Klein (Columbia), Gabriel Sturm (Columbia and University of California, San Francisco), Philip L. De Jager (Columbia), David A. Bennett (Rush University Medical Center), Michio Hirano (Columbia), Martin Picard (Columbia) and Ryan E Mills (Michigan).

This work was supported by grants from the US National Institutes of Health (R01AG066828, R21HG011493, and P30AG072931), the Baszucki Brain Research Fund, and the University of Michigan Alzheimer’s Disease Center Berger Endowment.