Mitochondria Send Their DNA to Our Brain Cells, Study Finds

Mitochondria, direct descendants of ancient bacteria, have always been somewhat strange. Now, a study shows that mitochondria may be even stranger than previously thought.

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

The mitochondria in our brain cells frequently send their DNA into the nucleus, where the DNA integrates with the cell’s chromosomes. And these insertions can be harmful: Among the nearly 1,200 study participants, those with the most mitochondrial DNA insertions in their brain cells were more likely to die earlier than those with the fewest.

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

“It’s surprising that this phenomenon seems to occur multiple times during a person’s lifetime,” Picard adds. “We found many such insertions in different brain regions, but not in blood cells, which explains why dozens of previous studies analyzing blood DNA have not detected this phenomenon.”

Mitochondrial DNA behaves like a virus

Mitochondria live inside all of our cells, but unlike other organelles, they 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 took up residence inside our single-celled ancestors about 1.5 billion years ago.

Over the past few decades, researchers have discovered that mitochondrial DNA occasionally “jumps” out of the organelle and into human chromosomes.

“Mitochondrial DNA behaves similarly to a virus in that it uses cuts in the genome and sticks to it, or like jumping genes called retrotransposons that move around the human genome,” Mills says.

These insertions are called nuclear-mitochondrial segments (NUMT, 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, segments of mitochondrial DNA in our chromosomes, which we inherited from our ancestors,” Mills says.

Mitochondrial DNA insertions are common in the human brain

Research conducted in recent years has shown that “NUMTogenesis” is still ongoing today.

“Mitochondrial DNA jumping is not something that happened a long time ago,” says Kalpita Karan, a postdoctoral fellow in the Picard lab who conducted the study with Weichen Zhou, a researcher in the Mills lab. “It’s rare, but a new NUMT integrates into the human genome about once every 4,000 births. It’s one of many ways, conserved from yeast to humans, that mitochondria communicate with nuclear genes.”

The observation that new inherited NUMTs are always being created led Picard and Mills to wonder whether NUMTs might also appear in brain cells throughout our lives.

“Inherited NUMTs are usually benign, probably because they appear early in development and the harmful cells are cleared out,” Zhou says. But if a piece of mitochondrial DNA inserts itself into a gene or regulatory region, it can have significant consequences for a person’s health or lifespan. Neurons may be particularly susceptible to damage from NUMTs because when a neuron is damaged, the brain typically doesn’t produce a new brain cell to replace it.

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

Their analysis showed that nuclear mitochondrial DNA insertion occurs in the human brain, primarily in the prefrontal cortex, and likely multiple times during a person’s lifetime.

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

Stress accelerates NUMtogenesis

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

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

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

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

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