Exploring the Complexities of Cell Biology
Two concepts often stick with us from high school biology lessons: mitochondria as cellular power generators and the inheritance of chromosomes from our parents. However, these ideas are somewhat simplified. Beyond energy production, mitochondria play a role in encoding and communicating cellular conditions. Similarly, the chromosomes housed within a cell nucleus are dynamic, susceptible to integration from other chromosomes or viral DNA, influencing both cellular and personal health.
Originating from an ancient bacterium engulfed by a primordial cell millions of years ago, mitochondria possess their unique DNA, known as mitochondrial DNA (mtDNA). Research starting in the 1960s, initially in mice and later in yeast and humans, revealed that mtDNA fragments could integrate into nuclear chromosomes. These integrations, called nuclear mitochondrial DNA segments or numts (“new mites”), were extensively cataloged in over 60,000 humans by Patrick Chinnery and his team at the University of Cambridge in 2022, revealing new formations in approximately one in 4,000 births. This indicates that all of us carry numts inherited from our forebears within our chromosomes.
In a significant 2024 discovery by Weichen (Arthur) Zhou, Ryan Mills at the University of Michigan, and Kalpita Karan, formerly of my lab at Columbia University, it was found that the creation of numts, a process termed numtogenesis, occurs not just over millennia but also multiple times throughout a person’s life. In human cell cultures, numtogenesis can occur within days to weeks, with a notable accumulation in the brain, potentially influencing lifespan.
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Groundbreaking research at Rush University Medical Center, led by neuroscientist David Bennett, involved sequencing over 1,000 brain samples from aging study participants. This project revealed a high concentration of numts in the chromosomes of brain cells, particularly within the prefrontal cortex, the center for higher cognitive processes. Individuals with higher numt counts in this region generally had shorter lifespans. Interestingly, the presence of numts in individuals with Alzheimer’s-related dementia did not correlate with lifespan, suggesting varying impacts based on cognitive health.
Previously, numts were primarily searched for in immune cells from blood samples, which undergo rigorous quality control, potentially overlooking their presence in less-regulated cell types like neurons. This might explain why numts in brain cells, which are not as easily replaced, have been overlooked until recent studies.
How do these mtDNA fragments penetrate the cell nucleus? Research indicates mitochondria release their DNA into the cytoplasm, from where it can enter the nucleus through its pores or during cell division when the nuclear envelope temporarily dissolves.
The health implications of numts are significant. Similar to retrotransposons, which jump between chromosomes and may induce inflammation and aging, numts have been linked to accelerated activity in cancer cells by Keshav K. Singh’s 2017 research at the University of Alabama at Birmingham. These findings suggest numts may contribute to cancer development.
In our 2024 study, Karan utilized the Cellular Lifespan Study database to determine that normal cells in culture develop a new numt every 13 days. This rapid rate, influenced by the stress of being outside the body, highlights how numtogenesis is accelerated under certain conditions.
Our 2023 research with Gabriel Sturm and Natalia Bobba-Alves showed that cellular “energetic” stress, such as energy deficits, exacerbates mitochondrial dysfunction. This dysfunction, prevalent in mitochondrial diseases and to a lesser extent in diabetes and other metabolic disorders, leads to a more rapid accumulation of numts in cultured cells, occurring as frequently as every three days.
This data not only emphasizes how stress impacts cellular biology by promoting the release of mtDNA into chromosomes but also suggests that mitochondria, known for their role in energy production, are integral in genome modification. This could be a natural evolutionary response to environmental stressors.
Given the correlation between high numt counts in the brain and reduced lifespan, it’s clear that numtogenesis is a critical factor in longevity. While mitochondria provide essential energy, they also play a role in the gradual decline of life’s vitality.
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Cameron Aldridge combines a scientific mind with a knack for storytelling. Passionate about discoveries and breakthroughs, Cameron unravels complex scientific advancements in a way that’s both informative and entertaining.