Jumping ‘Numts’ from Mitochondria Can Be Fast and Deadly

Leaping of ‘Numts’ from mitochondria can be rapid and deadly

Who Martin Picard edited by Madhusree Mukerjee

MMost of us remember two things from high school biology: that mitochondria are the powerhouse of cells and that we inherit stable sets of chromosomes from both of our parents. Both truisms are simply true. Mitochondria do much more rather than producing energy – they also compress and transmit information about the state of a cell. And our chromosomes, although safely nestled in the cell’s nucleus, are far from stable. A piece of genetic code from another chromosome, or even from a virus, can be inserted into the DNA strand, changing how it—and we—work.

Mitochondria descend from an ancient bacterium that was engulfed millions of years ago by an ancestral cell from which all life descends. As living organisms, they have their own genes, called mitochondrial DNA (mtDNA). Beginning in the 1960s, researchers showed—first in mice and then in yeast and humans—that fragments of mtDNA can also somehow jump onto chromosomes, and named these insertions nuclear mitochondrial DNA segments or numts (pronounced “new mites”). 2022 by Patrick Chinnery of the University of Cambridge and his colleagues the cataloged numts They found that new ones emerge from more than 60,000 humans and every 4,000 births. We all walk around with the numts on our chromosomes that we have inherited from our ancestors.

In 2024, however, Weichen (Arthur) Zhou and Ryan Mills, both at the University of Michigan, and Kalpita Karan, then in my lab at Columbia University, in collaboration with me and others, did something amazing. the discovery. Numtogenesis, or the formation of new numts, occurs not only over millennia, but possibly several times during a person’s lifetime. In human cell culture, numtogenesis occurs over days or weeks. Also, numts seem to be particularly concentrated in the brain and may affect how long we live.

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These pioneering 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 people enrolled in a long-term study of aging. By examining these data, Zhou, Mills, Karan and their colleagues found that the chromosomes in brain cells contained many numt. Curiously, the prefrontal cortex, the seat of higher rational thought, had a particularly high concentration of these intrusions. And people with more numts in the prefrontal cortex died earlier. People with normal knowledge lost five years of life. (In people with dementia caused by Alzheimer’s disease, it didn’t seem to matter: the age of death had nothing to do with how many numts they had in the prefrontal cortex).

All previous searches were done using immune cells from blood samples; therefore, the scientific community missed this amazing fact for decades. Immune blood cells are therefore subject to constant quality control only the best cells survive to be sequenced. Presumably, immune cells are eliminated or may not occur in immune cells. In the brain, bad neurons cannot be so easily dismissed, which may be why neurons with alterations in the numts genome survived long enough to find the DNA sequencer.

You may be wondering how these mtDNA fragments get inside the nucleus. Mitochondria, we now know, have many forms release their DNA into the surrounding cytoplasm of their host cell. Once there, fragments of mtDNA can enter the nucleus through pores in its wall or, if the cell divides, become internalized as the envelope dissolves and reassembles. Regardless, mtDNA release appears to be a process controlled by mitochondria.

The fact that numts can be harmful to health is perhaps not so surprising. Retrotransposons, pieces of genes that jump from one chromosome to another, cause inflammation and may contribute to aging. Numtogenesis was demonstrated in 2017 by Keshav K. Singh and others at the University of Alabama at Birmingham. is accelerated in cancer cells and can contribute to cancer.

But how fast can new numts be generated in normal cells? To answer this question in our team’s 2024 study, Karan used this Cellular Life A research database developed by Gabriel Sturm, where cells from different individuals are grown in vitro and observe over time as you get older. He found that cultured human cells accumulate a new numt every 13 days on average, a remarkable rate. Removing cells from the body accelerates several features of aging, which may explain why numtogenesis occurs so rapidly in cell cultures.

We also found that stress accelerates numtogenesis. The work published in 2023 by Sturm, Natalia Bobba-Alves, then at Columbia, and my colleagues shows that “energetic” stress is caused by a lack of energy in a cell. commitment mitochondrial health. Karan found that when the mitochondria were dysfunctional, as occurs in people with mitochondrial diseases (and to a lesser extent in those with diabetes and other metabolic disorders), cells in culture accumulated nums 4.7 times faster. Cells with defective mitochondria showed a new number approximately 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 fragments of mtDNA that then “infect” chromosomes. And mitochondria add another way to shape our health beyond energy transformation: directly changing the sequence of our genome. Numtogenesis may serve to accelerate evolution in response to stress.

Importantly, given that people with more numts in the brain die earlier, we must also add numtogenesis to the list of mechanisms that may contribute to how long. Mitochondria give us energy and life, sure, but they may also help put out the flame within our lives.