The article “Jumping ‘Numts’ from Mitochondria Can Be Fast and Deadly” by Martin Picard, published online in Scientific American on January 3, 2025, sheds new light on a significant biological phenomenon with profound implications for both health and evolutionary biology.

Mitochondria have their own DNA, but over evolutionary time, they have transferred most of their genes to the host genome. Now research teams led by Martin Picard at Columbia University and Ryan Mills at the University of Michigan have found that this process is continuing to the present day, sometimes with profound implications for our health. 1, 2, 3

Mitochondrial DNA (mtDNA) fragments, known as nuclear mitochondrial DNA segments (numts), integrate into the nuclear genome at a surprisingly high rate, approximately once every 4,000 births.4 This process, called numtogenesis, does not just occur in the distant evolutionary past but continues actively throughout an individual’s life, particularly in brain cells where it might accelerate aging and reduce lifespan.

The significance of this finding lies in its potential to alter our understanding of genetic stability and disease, and of mitochondria themselves. By inserting into critical parts of our genome, Numts disrupt gene function,4 potentially leading to conditions, such as cancer or neurodegenerative diseases. The research also suggests that stress can amplify this DNA transfer, highlighting a new pathway through which environmental factors impact genetic health.

This discovery emphasizes the dynamic interplay between mitochondrial and nuclear genomes. It also reveals another way that mitochondria influence our lives: by changing the genome of our cells. Perhaps most importantly, it demonstrates the need for further investigation into how these interactions shape human health and longevity.

An interview with Martin Picard

  1. What made you begin your research into Numts?
    We reviewed the literature on the many ways in which mitochondria influence gene expression and cellular behaviors. This highlighted a plurality of mechanisms.5 One of them is the transfer of mtDNA pieces to the nucleus, which could destabilize the genome, a hallmark of aging. This process is known to occur on the scale of millennia. So the initial thought was that this might be a mechanism of aging, just like the activation of “retrotransposons” that already live in our genomes cause aging.6 What if mitochondria—and particularly defective mitochondria in primary mitochondrial diseases or acquired mitochondrial defects—spit out pieces of DNA that disrupt the nucleus as a mechanism to speed up evolution but, in the process, end up driving the aging process?
  2. How did you or others isolate this phenomenon?
    We took a two-pronged approach. First, we used our Cellular Lifespan Study7 system where we can track the same cells over months in vitro, and we asked whether there were new Numts over this short time scale. The answer was a clear yes. It was particularly noted in cells that came from children with primary mitochondrial disorders, as predicted. Second, we had to check if this mattered to people: does it happen in the human body across a person’s lifetime? In blood, new Numts don’t accumulate. So we looked in the brains of about 1000 people who died of various causes. There, we found several new Numts that were “private” and unique to each person, meaning that there is almost no chance that they were inherited. So they must have arisen during a person’s lifetime.
  3. If Numts are part of a larger process of the interaction between mtDNA and nuclear DNA, can you explain more about how the two genomes are designed how they interact with each other?
    The mitochondria shipped pieces of their genome to the nuclear genome during evolution, explaining how it went from a full bacterial genome initially (with hundreds of genes) to only 37 now in our mitochondria. So as a result, the two genomes encode mitochondrial proteins and must be functionally coupled to make well-functioning, specialized mitochondria8 in each cell type.
  4. Where do you see the research going from here, and how many labs, institutes or companies are working on these issues?
    This study puts the process of Numt insertions,  called Numtptogenesis, on the list of mechanisms of aging and possibly other diseases. In the brain, we found that people with more Numts in the prefrontal cortex, especially, died earlier than people with fewer new Numts. So maybe they regulate how long or how healthy we can live. There are many labs working on Numtogenesis as an evolutionary mechanism, and maybe our findings provide a rationale to studying this process in non-immune cells to understand its relevance to health.
  5. Clearly, this is a frontier. What do you expect we will know more about in a year?
    I hope we see researchers with whole-genome sequencing data on non-blood tissues explore and quantify the presence of Numts so we can see to what extent these results extend to other organs and health or disease phenotypes. For example, this may be relevant to mitochondrial diseases.

Comment by Alex Sercel

“The key advance of this work is measuring numtogenesis on a short timescale in tissue culture and in the somatic tissues of individuals over their lifespan instead of looking at the rate of Numt inheritance between generations. Genetic changes, such as Numts, are only observed in subsequent generations if they occur in the sperm or egg and are non-lethal to an individual’s progeny. Said differently, damaging numts are likely to be screened out by natural selection and are less likely to be seen in population-genetics studies.

“This work shows that Numts can occur more frequently than previously thought and may arise in all tissues of the body, specifically long-lived cells like neurons in the brain. The Numts that manifest in a person’s organs over the lifespan bear the potential to damage their cells and tissues because these genetic changes have not been subject to the selective pressures that filter out harmful mutations between generations,” Alex Sercel, PhD, MitoWorld’s Director of Scientific Affairs and a former Postdoctoral Scholar in the Picard Lab at Columbia University Irving Medical Center.

References

  1. Xue L, Moreira JD, Smith KK, Fetterman JL (2023) The Mighty NUMT: Mitochondrial DNA flexing its code in the nuclear genome. Biomolecules 13(5):753. doi: 3390/biom13050753
  2. Zhou W, Karan KR, Gu W, et al. (2024) Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts. PLoS Biol 22(8): e3002723.
    https://doi.org/10.1371/journal.pbio.3002723
  3. Picard M (2025) Jumping ‘Numts’ from mitochondria can be fast and deadly. Scientific American.
    https://www.scientificamerican.com/article/jumping-numts-from-mitochondria-can-be-fast-and-deadly/
  4. Wei W, Schon KR, Elgar G, et al.(2022) Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature 611: 105–114.
    https://doi.org/10.1038/s41586-022-05288-7
  5. Picard M, Shirihai OS (2022) Mitochondrial signal transduction. Cell Metabolism 34: 1620–1653.
    https://doi.org/10.1016/j.cmet.2022.10.008
  6. Gorbunova V, Seluanov A, Mita P et al.(2021) The role of retrotransposable elements in ageing and age-associated diseases. Nature 596: 43–53.
    https://doi.org/10.1038/s41586-021-03542-y
  7. Sturm G, Monzel AS, Karan KR, et al.(2022) A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations. Sci Data 9: 751.
    https://doi.org/10.1038/s41597-022-01852-y
  8. Monzel AS, Enríquez JA, Picard M (2023) Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nat Metab5: 546–562.
    https://doi.org/10.1038/s42255-023-00783-1