Mitochondria fling DNA into our brain cells; may cause harm

As direct descendants of ancient bacteria, mitochondria have always come across as a little strange. Now US researchers have discovered that mitochondria in our brain cells frequently fling their DNA into the nucleus, where the DNA becomes integrated into the cells’ chromosomes. Furthermore, these insertions may be causing harm.

Mitochondrial DNA behaves like a virus

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

In the past few decades, researchers discovered that mitochondrial DNA has occasionally ‘jumped’ out of the organelle and into human chromosomes. As explained by the University of Michigan’s Ryan Mills, who co-led the new research with Columbia University’s Associate Professor Martin Picard, “The mitochondrial DNA behaves similar to a virus in that it makes use of cuts in the genome and pastes itself in, or like jumping genes known as retrotransposons that move around the human genome.”

These insertions are called nuclear-mitochondrial DNA segments, or NUMTs (pronounced ‘new-mites’), and have been accumulating in our chromosomes for millions of years, which means that “all of us are walking around with hundreds of vestigial, mostly benign, mitochondrial DNA segments in our chromosomes that we inherited from our ancestors”, Mills noted. Furthermore, research in just the past few years has shown that ‘NUMTogenesis’ is still happening today.

“Jumping mitochondrial DNA is not something that only happened in the distant past,” said Kalpita Karan, a postdoc in the Picard lab who conducted the research with Weichen Zhou, a research investigator in the Mills lab. “It’s rare, but a new NUMT becomes integrated into the human genome about once in every 4000 births. This is one of many ways, conserved from yeast to humans, by which mitochondria talk to nuclear genes.”

The realisation that new inherited NUMTs are still being created made Picard and Mills wonder if NUMTs could also arise in brain cells during our lifespan.

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

To examine the extent and impact of new NUMTs in the brain, the team worked with Columbia’s Assistant Professor Hans Klein, 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 regions of the brain using banked tissue samples from nearly 1200 older adults. Their analysis, published in the journal PLOS Biology, showed that nuclear mitochondrial DNA insertion happens in the human brain —mostly in the prefrontal cortex — and likely several times over during a person’s lifespan.

“We used to think that the transfer of DNA from mitochondria to the human genome was a rare occurrence … [so] it’s stunning that it appears to be happening several times during a person’s lifetime,” Picard said.

“We found lots of these insertions across different brain regions, but not in blood cells, explaining why dozens of earlier studies analysing blood DNA missed this phenomenon.”

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

Stress accelerates NUMTogenesis

So 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 cultured and aged in a dish over several months, enabling exceptional longitudinal ‘lifespan’ studies. These cultured cells gradually accumulated several NUMTs per month, and when the cells’ mitochondria were dysfunctional from stress, the cells accumulated NUMTs four to five times more rapidly.

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

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

Image credit: iStock.com/wir0man