A recent study reveals that mitochondria in our brain cells often release their DNA into the nucleus, where it may integrate into chromosomes and potentially cause damage.
Mitochondria, which originated from ancient bacteria, have always had a somewhat alien nature.
A new study suggests that mitochondria might be even more peculiar than we previously thought.
The research found that mitochondria in brain cells frequently eject their DNA into the nucleus. There, this DNA can integrate into the cell’s chromosomes. This phenomenon could be detrimental; among nearly 1,200 participants in the study, those with higher mitochondrial DNA insertions in their brain cells had an increased likelihood of dying sooner compared to those with fewer insertions.
“We previously believed that mitochondrial DNA transferring to the human genome was a rare event,” says Martin Picard, a mitochondrial psychobiologist and associate professor at Columbia University Vagelos College of Physicians and Surgeons and the Robert N. Butler Columbia Aging Center. Picard led the research with Ryan Mills from the University of Michigan.
“It’s astonishing that this seems to happen multiple times throughout a person’s life,” Picard adds. “Our findings indicate many of these insertions in various brain regions, but they weren’t present in blood cells, explaining why numerous past studies that analyzed DNA from blood overlooked this phenomenon.”
Mitochondrial DNA acts similarly to a virus
Mitochondria reside in all our cells; however, unlike other organelles, they possess their own DNA, a small circular strand containing around 36 genes. Mitochondrial DNA is a legacy from the ancient bacteria that merged with our single-celled ancestors approximately 1.5 billion years ago.
Over the last few decades, scientists have recognized that mitochondrial DNA sometimes “jumps” from the organelle into human chromosomes.
“Mitochondrial DNA behaves much like a virus as it uses cuts in the genome to insert itself, or resembles jumping genes known as retrotransposons that traverse the human genome,” explains Mills.
These insertions are identified as nuclear-mitochondrial segments—abbreviated as NUMTs (“pronounced new-mites”)—and they have been accumulating in our chromosomes for millions of years.
“Consequently, we all carry hundreds of mostly harmless vestiges of mitochondrial DNA in our chromosomes, inherited from our ancestors,” Mills states.
Mitochondrial DNA insertions are prevalent in the human brain
Recent research has established that “NUMTogenesis” continues to occur today.
“Jumping mitochondrial DNA isn’t just a phenomenon of the distant past,” remarks Kalpita Karan, a postdoctoral researcher in the Picard lab who collaborated with Weichen Zhou, a research investigator in the Mills lab. “It’s rare, but a new NUMT integrates into the human genome approximately once in every 4,000 births. This is one of many ways, conserved from yeast to humans, that mitochondria communicate with nuclear genes.”
The understanding that new inherited NUMTs are still forming led Picard and Mills to inquire whether NUMTs could also emerge in brain cells throughout a person’s life.
“Inherited NUMTs are generally harmless, likely because they arise early in development and the detrimental ones are filtered out,” notes Zhou. However, if mitochondrial DNA integrates into a gene or its regulatory region, it could significantly affect an individual’s health or lifespan. Neurons could be especially vulnerable to damage from NUMTs, as the brain typically does not replace damaged neurons with new ones.
To explore the presence and effects of new NUMTs in the brain, the researchers collaborated with Hans Klein, an assistant professor in the Center for Translational and Computational Neuroimmunology at Columbia, who provided access to DNA sequences from participants in the ROSMAP aging study (led by David Bennett at Rush University). The team investigated NUMTs across various brain regions using preserved tissue samples from over 1,000 older adults.
Their analysis confirmed that nuclear mitochondrial DNA insertion occurs in the human brain—predominantly in the prefrontal cortex—and likely happens several times over a person’s lifetime.
Moreover, the researchers found that individuals with a higher number of NUMTs in their prefrontal cortex tended to die earlier than those with fewer NUMTs. “This is the first indication that NUMTs may have functional implications and could possibly influence lifespan,” says Picard. “The accumulation of NUMTs can be added to the list of genomic instability mechanisms that contribute to aging, functional decline, and lifespan.”
Stress accelerates NUMTogenesis
What triggers NUMTs in the brain, and why do certain regions accumulate more than others?
To investigate, the researchers examined a population of human skin cells that can be cultured and aged in a dish for several months, allowing for remarkable longitudinal “lifespan” studies.
These cultured cells gradually developed several NUMTs each month, and when their mitochondria were stressed, the cells accumulated NUMTs four to five times faster.
“This unveils a new way that stress can influence our cellular biology,” Karan explains. “Stress increases the likelihood of mitochondria releasing pieces of their DNA, which can then ‘infect’ the nuclear genome,” Zhou adds. This is just one way mitochondria affect our health beyond mere energy production.
“Mitochondria are like cellular processors and an important signaling platform,” says Picard. “We already knew they could regulate gene expression. Now we realize that mitochondria can actually alter the nuclear DNA sequence itself.”
