Jumping 'Numts' from Mitochondria Can Be Fast and Deadly

Jumping ‘Numts’ from Mitochondria Can Be Fast and Deadly

By Martin Picard edited by Madhusree Mukerjee

Most of us remember two things from high school biology: that mitochondria are the powerhouses of cells and that we inherit stable sets of chromosomes from our two parents. Both truisms are only sort of true. Mitochondria do far more than produce energy—they also compress and transmit information about the state of a cell. And our chromosomes, although safely ensconced within the cell’s nucleus, are far from stable. A piece of genetic code from another chromosome, or even from a virus, can embed itself into the DNA chain, changing how it—and we—function.

Mitochondria descend from an ancient bacterium that was swallowed, millions of years ago, by an ancestral cell from which all life descends. As living beings, they have their own genes, called mitochondrial DNA (mtDNA). Starting in the 1960s, researchers showed—first in mice and then in yeasts and humans—that pieces of mtDNA can somehow also jump into chromosomes and named these insertions nuclear mitochondrial DNA segments, or numts (pronounced “new mites”). In 2022 Patrick Chinnery of the University of Cambridge and his colleagues cataloged numts from more than 60,000 humans and found that new ones are created once in about 4,000 births. All of us walk around with numts that we’ve inherited from ancestors in our chromosomes.

In 2024, however, Weichen (Arthur) Zhou and Ryan Mills, both at the University of Michigan, and Kalpita Karan, then at my laboratory at Columbia University, in collaboration with me and others, made an astonishing discovery. Numtogenesis, or the formation of new numts, happens not only across millennia but likely several times over during a person’s lifespan. In cultures of human cells, numtogenesis happens over days to weeks. Further, numts seem to be particularly concentrated in the brain—and may influence how long we live.

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These groundbreaking studies began at Rush University Medical Center, where a team led by neuroscientist David Bennett sequenced DNA from more than 1,000 brain samples from individuals enrolled in a long-term study of aging. Scanning these data, Zhou, Mills, Karan and their colleagues found that chromosomes in the brain cellshad many numts. Intriguingly, the prefrontal cortex, the seat of high-level rational thinking, had a particularly high concentration of these intrusions. And people with more numts in their prefrontal cortex had died earlier. People with normal cognition had lost as many as five years of life per numt. (In people with dementia caused by Alzheimer’s disease, numts didn’t seem to matter: their age at death was unrelated to how many numts they had in their prefrontal cortex.)

All previous searches for numts had been performed using immune cells from blood samples; that is why the scientific community had missed this stunning fact for decades. Blood immune cells undergo constant quality control, so only the best cells survive to be sequenced. Presumably, immune cells with numts are eliminated—or maybe numts just don’t happen in immune cells. In the brain, bad neurons cannot be so readily discarded, which may be why neurons with genome alterations from numts persisted long enough to meet the DNA sequencer.

You might wonder how these mtDNA fragments get inside the nucleus in the first place. Mitochondria, we now know, have many ways to release their DNA into the cytoplasm surrounding their host cell. Once there, mtDNA fragments can make their way into the nucleus either through pores in its wall or, if the cell divides, seep in while the envelope dissolves and reassembles. Either way, the release of mtDNA appears to be a process controlled by mitochondria.

The fact that numts can adversely affect health is perhaps not so surprising. Retrotransposons, gene fragments that jump from one chromosome to another, trigger inflammation and possibly contribute to aging. In 2017 Keshav K. Singh and others at University of Alabama at Birmingham, showed that numtogenesis speeds up in cancerous cells and may contribute to cancer formation.

But how fast can new numts arise in normal cells? To address this question in our group’s 2024 study, Karan used the Cellular Lifespan Study database developed by Gabriel Sturm, in which cells from different individuals are cultured in vitro and observed over time as they age. She found that cultured human cells accumulate one new numt every 13 days on average—a remarkable rate. Taking cells out of the body accelerates multiple hallmarks of aging, which may explain why numtogenesis happens so fast in cell cultures.

We also discovered that stress accelerates numtogenesis. Work that Sturm, Natalia Bobba-Alves, then at Columbia, I and our colleagues published in 2023 shows that “energetic” stress, caused by energy deficiency within a cell, can compromise the health of mitochondria. Karan found that when the mitochondria were dysfunctional, as occurs in people with mitochondrial diseases (and, to lesser extent, in those with diabetes and other metabolic disorders), cells in cultures accumulated numts up to 4.7 times more rapidly. Cells with defective mitochondria showed a new numt about once in every three days.

These findings suggest a new way in which stress can affect the biology of our cells: making mitochondria more likely to release pieces of mtDNA that then “infect” chromosomes. And they add one more way in which mitochondria shape our health beyond energy transformation: directly changing the sequence of our genome. Numtogenesis may serve to speed up evolution as a response to stress.

Most importantly, given that people with more numts in their brain die earlier, we must also add numtogenesis to the list of mechanisms that may contribute to how long we live. Mitochondria give us energy and life, for sure, but they may also contribute to the dimming of our inner flame of life.