overview: Human cells with compromised mitochondria consume more energy. This hypermetabolism enhances the short-term viability of cells, but it also dramatically increases the rate of cellular senescence.
sauce: Columbia University
Why do cells, and therefore humans, age? The answer may have a lot to do with mitochondria, the organelles that power cells. The idea is not new, but direct evidence in human cells has so far been lacking. until now.
In a study published on January 12, communication biology, A team led by researchers from Columbia University found that human cells with damaged mitochondria respond by gearing up and expending more energy.
This adaptation, called hypermetabolism, enhances short-term cell viability, but at a high cost. This means that the rate at which cells age is dramatically increased.
“While the findings were made in cells from patients with rare mitochondrial diseases, they may also be relevant to other conditions that affect mitochondria, such as neurodegenerative diseases, inflammatory conditions and infections,” he said. Researcher and Associate Professor of Behavioral Sciences Martin Picard, Ph.D. He graduated from Columbia University’s Vagelos College of Physicians and Surgeons in Medicine (Psychiatry and Neurology).
“Furthermore, hypermetabolism may be the main reason why most cells deteriorate with age.”
Hypermetabolic cells age faster
It was generally believed that mitochondrial defects (impaired conversion of food sources into usable energy) slowed the rate of cellular metabolism in order to conserve energy.
However, when we analyzed the metabolic activity and energy expenditure of cells from patients with mitochondrial diseases, we found that cells with damaged mitochondria doubled their energy expenditure.
Furthermore, a reanalysis of data from hundreds of patients with various mitochondrial diseases showed that mitochondrial defects also increased energy costs at the systemic level.
This energy boost keeps cells moving, but also breaks down their telomeres (caps that protect the ends of chromosomes) and activates the stress response and inflammation. The net effect is to accelerate biological aging.
“When cells expend more energy to make proteins and other substances essential for short-term survival, they may be stealing resources from processes that ensure long-term survival, such as maintaining telomeres.” the study.
hypermetabolism, fatigue, aging
This hypermetabolic state may explain why patients with mitochondrial disease experience fatigue and exercise intolerance, among other symptoms.
“To compensate for the extra energy use in your cells, your body ‘tells’ you to conserve energy, not to over-exercise. We might see the same dynamics as in ,” says Picard.
While the study does not represent a new treatment for patients with currently untreatable mitochondrial diseases, it does strengthen current recommendations for patients to move more.
“It may seem counterintuitive, because the more active you are, the more energy you burn, which can make your symptoms worse,” says Sturm.
“But exercise is known to increase the efficiency of the organism. less.”
Improved bioefficiency, which reduces intracellular energy expenditure and ameliorate fatigue and other symptoms, may partially explain the health benefits of exercise in patients with mitochondrial diseases and other healthy people.
When looking for new treatments for mitochondrial diseases, researchers should focus on hypermetabolism, says Picard. “Although mitochondrial defects impair a cell’s ability to produce energy, energy deficiencies may not be the primary cause of disease. Our research shows that these defects increase energy expenditure.” We may need to target hypermetabolism to move the needle therapeutically, and more research is needed to know if that works.”
Hypermetabolism is also common in other diseases. If increased cellular energy expenditure is responsible for accelerating the aging process, targeting hypermetabolism could be a way to ameliorate fatigue, improve people’s quality of life, and even slow biological aging. There is a possibility.
Funding:
This study was supported by the National Institutes of Health (R01AG066828), the Baszucki Brain Research Fund, the J. Willard and Alice S. Marriott Foundation, the Muscular Dystrophy Association, the Nicholas Nunno Foundation, the JDF Fund for Mitochondrial Research, and the Schumann Mitochondrial Diseases Fund.
The authors declare no competing interests.
See also
About this Aging and Cell Metabolism Research News
author: Helen Gary
sauce: Columbia University
contact: Helen Gary – Columbia University
image: Image credit to Martin Picard/Columbia University
Original research: open access.
“OxPhos deficiency causes hypermetabolism and shortens lifespan in patients with cellular and mitochondrial diseases” by Martin Picard et al. communication biology
overview
OxPhos deficiency causes hypermetabolism and shortens lifespan in patients with cellular and mitochondrial diseases
Patients with primary mitochondrial oxidative phosphorylation (OxPhos) deficiency present with fatigue, multisystem disorders, are often lean, and die prematurely, although the mechanistic basis for this clinical picture remains unclear. am.
By integrating data from 17 cohorts of patients with mitochondrial disease (n= 690) We found evidence that these disorders increase resting energy expenditure. hypermetabolism.
We longitudinally examine this phenomenon in patient-derived fibroblasts from multiple donors. Genetic or pharmacological disruption of OxPhos approximately doubles cellular energy expenditure.
This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiencies, with the exception of uncoupling as a common mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines, including GDF15.
In parallel, OxPhos defects accelerate telomere erosion and epigenetic senescence with each cell division, consistent with evidence that excessive energy expenditure accelerates biological aging.
To investigate potential mechanisms of these effects, we generate longitudinal RNASeq and DNA methylation resource datasets.
Taken together, these findings highlight the need to understand how defects in OxPhos affect the cost of living for energy and the link between hypermetabolism and aging in patients with cellular and mitochondrial diseases. .
