Zen and the art of mitochondrial maintenance: The machinery of death makes a healthier life
While we all aspire for a long lifespan, what is most coveted is a long period of vigor and health, or “healthspan,” that precedes the inevitable decline of advancing age. Researchers at UC Santa Barbara have discovered that instruments of death that cells use to commit suicide when things go wrong contribute to making a longer and healthier life by revitalizing the specialized cellular compartments called mitochondria.
Mitochondria generate the energy for all of our activities, from movement to thought. These power plants inside our cells descended from what were once free-living bacteria.
“We are a sort of hybrid creature that arose from two independent evolutionary lineages: mitochondria, which were once bacteria, and the rest of the cell surrounding them,” notes Joel Rothman, a professor of molecular biology whose lab conducted the research.
This dual evolutionary origin means that our DNA resides in two separate compartments in each of our cells: the nucleus, where most of our genome is located, and the mitochondria with their own DNA, as a remnant of their bacterial provenance.
“As we age, damage to the DNA in these cellular power houses accumulates, contributing to age-related decline,” notes Rothman. “Our discovery reveals a way that defective mitochondria are removed, resulting in rejuvenation of cells.”
The research, recently published in the journal eLife, shows that the biological machinery that functions as a “kill switch” for cells that are potentially harmful, for example those becoming cancerous, also eliminate the defective DNAs of mitochondria.
“There is a Yin and Yang to mitochondria,” said Pradeep Joshi, a senior scientist and co-author on the publication. “They produce the energy that sustains life. But with every breath, mitochondria also produce reactive oxygen species, harmful molecules that damage DNA and other parts of our cells.”
Thus, the longer we live, the more damage that occurs. This damage diminishes energy production by mitochondria, with negative consequences for our healthspan. As the heart, muscles, and brain demand the most from this energy supply, aging is inevitably associated with heart failure, loss of muscle function, and dementia.
According to Joshi, “aging can be considered a sort of mitochondrial disease. If we could clear out mitochondrial damage, we would improve healthspan and longevity.”
The research team discovered a system for clearing out damaged mitochondria by using a diminutive worm called C. elegans, renowned for many advances in biomedicine, including those recognized by six Nobel prizes.
The researchers found that enzymes responsible for killing cells are also required to remove damaged mitochondrial DNA. In the absence of these enzymes, defective mitochondria pile up.
Rothman and coworkers were surprised to find that, although some of the same proteins are involved, the overall process of removing the damaged mitochondria is different from that normally used to remove excess cells. “The machinery for cell death appears to be repurposed to clear out bad mitochondria,” observed Joshi. “By doing so, they restore the health to these vital power houses.”
As a human, you inherited your mitochondrial DNA exclusively from your mother and the same is true for the animals used in the study. The scientists discovered that the burden of defective mitochondria in mothers increases with age. “Unfortunately, the bad mitochondria that build up in mothers as they get older is passed down to their children,” Rothman said.
However, the good news is that it was possible to reduce both accumulation and inheritance of the defective mitochondria: the researchers found that a single gene change that makes the animals age more slowly and that extends their lifespan mitigates these problems.
“Slowing the ‘aging clock’ appears to cause defective mitochondria to accumulate more slowly, raising the possibility that anti-aging interventions could result in healthier mitochondria,” noted Rothman, who is also the founding Director of the Center for Aging and Longevity at UCSB. The research was funded in part by the National Institute on Aging.
These discoveries point to future strategies for removing debilitated mitochondria and rejuvenating cells, paving the way toward additional years of vibrant, disease-free life for all of us to enjoy.
Photo Credits and News Source: University of California - Santa Barbara.
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Artificial DNA Successfully Transcribed by Natural Enzyme, Paving the Way for Genetic Advancements
Like adding new letters to an existing language’s alphabet to expand its vocabulary, adding new synthetic nucleotides to the genetic alphabet could expand the possibilities of synthetic biology. This image shows a rendering of RNA polymerase (center) and a synthetic nucleotide (lower right).
Scientists at UC San Diego are exploring the expansion of the genetic alphabet, akin to introducing new letters to a language, by investigating the feasibility of incorporating synthetic nucleotides into the traditional four-nucleotide genetic alphabet (A, T, G, C). The findings were published in Nature Communications on December 12, 2023.
The application and risks of creating artificial DNA that can be transcribed by natural enzymes are as follows:
Applications:
1. New Medicinal Compounds: The ability to integrate synthetic nucleotides into DNA can lead to the creation of novel proteins, potentially resulting in new drugs and therapeutic agents.
2. Advanced Genetic Research: This technology can facilitate deeper understanding of genetic processes and molecular biology, opening new avenues in genetic research.
3. Synthetic Biology Innovations: Expanding the genetic code can lead to the development of new biological systems and organisms with customized features or abilities.
4. Biotechnology Advancements: It could enable the creation of more efficient biofuels, enhanced agricultural products, or new materials through synthetic biology.
5. Understanding Extraterrestrial Life: The research, initially supported by NASA, could provide insights into how extraterrestrial life might develop or be structured.
Risks:
1. Unintended Genetic Consequences: Introducing synthetic elements into the genetic code could have unforeseen effects on genetic stability, gene expression, or cellular function.
2. Biosecurity Concerns: There's a risk that this technology could be misused to create harmful organisms or biological agents.
3. Ethical and Regulatory Challenges: Manipulating the genetic code raises ethical questions about the extent of human intervention in natural processes and the need for robust regulatory frameworks.
4. Environmental Impact: If synthetic organisms were to be released into the environment, they could potentially disrupt ecosystems or outcompete natural species.
5. Technical Limitations and Errors: The precision required in this technology is high, and any errors in the transcription process could lead to detrimental effects or failed experiments.
Prof. Marvin Edeas, chairman of the scientific committee commented: "While the development of artificial DNA offers exciting potential for advancements in medicine and biotechnology, it also poses significant ethical, environmental, and biosecurity challenges that need to be carefully managed."
Photo Credits: UC San Diego Health Sciences
Blood Tests Uncover Biomarkers Linked to Suicidal Thoughts
This graphic describes the metabolomics workflow the researchers used to analyze the blood of people with depression and suicidal ideation.
Recent research from UC San Diego has identified biomarkers in blood tests that could indicate a higher risk of suicidal thoughts in individuals with depression. This pioneering study, published in "Translational Psychiatry," highlights the significant link between cellular metabolism and mental health. The findings suggest the potential for more tailored treatments and new drug targets, especially focusing on mitochondrial dysfunction. Such advancements could revolutionize the approach to mental health care, offering more personalized and effective solutions.
"The interplay between mitochondria and microbiota in medicine, particularly their impact on mental health, is a fascinating area of focus. This will be a key discussion topic at the Berlin Mitochondria Meeting this October, as highlighted by Dr. Marvin Edeas, president of the World Mitochondria Society's scientific board. This topic is particularly relevant in light of the recent UC San Diego research and findings.
For more details on this groundbreaking research, read the full article.
Photo Credits: UC San Diego Health Sciences
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Study Discovers Single-Celled Gut Protists Flourishing Without Mitochondria
Schematic evolutionary tree of the five microbial species included in the study. From left to right: Trimastix marina, Paratrimastix pyriformis, Blattamonas nauphoetae, Streblomastix strix, and Monocercomonoides exilis.
In a groundbreaking discovery by Lukáš Novák and Vladimír Hampl of Charles University, published in the journal PLOS Genetics, Oxymonadida flagellates, a group of single-celled protists that live inside the guts of termites and other animals including Blattamonas nauphoetae and Monocercomonoides exilis, challenge the conventional belief that mitochondria are indispensable.
High-quality genome analysis revealed the complete loss of mitochondria in three oxymonad species, pushing this unique event back 100 million years ago.
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Mitochondrial Loss Across Species: Genomic studies confirm the absence of mitochondria in Blattamonas nauphoetae, Streblomastix strix, and Monocercomonoides exilis, suggesting this trait is common to the entire Oxymonadida group.
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Evolutionary Insights: The timeline of mitochondrial loss places this phenomenon at around 100 million years ago, coinciding with the diversification of the oxymonad lineage.
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Metabolic Adaptations: Comparative analysis highlights the metabolic changes accompanying the transition to amitochondriality, shedding light on the unique evolutionary journey of oxymonads.
In summary, Oxymonad flagellates challenge our understanding of cellular evolution by completely shedding mitochondria, marking a significant paradigm shift in eukaryotic biology. The study's insights into the ancient origins and metabolic adaptations of these organisms provide a fascinating glimpse into the mysteries of their evolutionary past.
Photo Credits: Lukas Novak, CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)
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Mitochondrial Inhibitors Extend Lifespan in C. elegans: Insights from a Longevity Study
Doxycycline extends lifespan of C. elegans
News Release, World Mitochondria Society, Berlin - Germany – November 27, 2023
Aging, characterized as a progressive degeneration of cell and tissue functions, might be significantly influenced by mitochondrial processes.
Bonuccelli et al., from the University of Salford, United Kingdom used Caenorhabditis elegans (C. elegans) to explore the effects of mitochondrial inhibitors on aging.
Key Findings:
- Treatment with doxycycline and azithromycin (mitochondrial ribosome inhibitors) notably increased C. elegans' median lifespan.
- Improvements were observed in pharyngeal muscle function and a reduction in lipofuscin accumulation.
- ATP consumption was lowered in treated worms, indicating reduced energy expenditure.
- DPI, an inhibitor of mitochondrial complex I and II, also prolonged the median lifespan.
- Conversely, vitamin C treatment did not extend lifespan and resulted in higher ATP levels.
Conclusion: The authors suggest that mitochondrial inhibitors can effectively extend lifespan and counteract aging-related declines in C. elegans, highlighting their potential in aging research.
Photo Credits: Bonuccelli et al. Aging (Albany NY). 2023
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