Mitochondria (red) are organelles found in most cells. They generate a cell’s chemical energy. Credit: NICHD/U. Manor
A new study from Karolinska Institutet, published in Science Translational Medicine, shows that people with type 2 diabetes have lower levels of the protein that breaks down and converts creatine in the muscles. This leads to impaired function of the mitochondria, the ‘powerhouses’ of the cell.
Creatine is a popular supplement for improving exercise performance as it can make muscles work harder and longer before they become fatigued. Previous studies however showed a possible link between high blood creatine levels and increased type 2 diabetes risk. This has raised questions about whether creatine supplementation may contribute to that risk.
New research based on studies in both humans and mice shows that people with type 2 diabetes have lower protein levels in their muscles that metabolises and converts creatine – a protein called creatine kinase.
“This reduced protein level leads to impaired creatine metabolism in the muscle. This may explain why people with type 2 diabetes accumulate creatine in their blood,” says principal investigator Anna Krook, Professor at the Department of Physiology and Pharmacology at Karolinska Institutet.
Scientists don’t know exactly what high creatine levels in the blood mean for the body, but it is known that it does have an effect outside the cells.
“The findings indicate that impaired creatine metabolism is a consequence of type 2 diabetes, rather than a cause of the disease,” says Anna Krook.
Impairs mitochondrial function
The study also shows that low levels of creatine kinase are not only linked to higher creatine levels in the blood, but also impair the function of mitochondria in the muscle. Mitochondria, which convert nutrients into energy, function less well in muscle cells with reduced creatine kinase, leading to both lower energy production and increased cell stress.
“This is quite consistent with the fact that people with type 2 diabetes have poorer energy metabolism. In the future, one possibility could be to regulate creatine kinase as part of the treatment of metabolic diseases such as obesity and diabetes,” says Anna Krook.
An unexpected finding of the study was that changes in creatine kinase levels affected the appearance of mitochondria and also their ability to produce energy, regardless of the amount of creatine available.
“This suggests that although the main role of creatine kinase is to process creatine, it affects mitochondrial function in other ways,” explains David Rizo-Roca, the study’s first author.
“Our next step is to find the molecular mechanisms behind these effects,” he says.
Fever temperatures accelerate immune cell metabolism, proliferation and activity, but in a particular subset of T cells, it also causes mitochondrial stress, DNA damage and cell death, Vanderbilt University Medical Center researchers have discovered.
The findings, published in the journal Science Immunology, offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer.
The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, Professor of Immunobiology and corresponding author of the new study. Most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37°C.
“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology.
Graduate student Darren Heintzman was interested in the impact of fevers for personal reasons: Before he joined the Rathmell lab, his father developed an autoimmune disease and had a constant fever for months on end.
“I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said.
Heintzman cultured immune system T cells at 39°C. He found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity.
“If you think about a normal response to infection, it makes a lot of sense: You want effector (helper) T cells to be better at responding to the pathogen, and you want suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said.
But the researchers also made an unexpected discovery: that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die?
The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress.
“There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better – they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.
Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signalling mechanisms that led to DNA damage and activation of the tumour suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.
The researchers found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined.
“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what it does. If temperature changes shift the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. This is fundamental textbook kind of stuff.”
The findings suggest that heat can be mutagenic, when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die.
“Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation.
“People ask me, ‘Is fever good or bad?’” Rathmell added. “The short answer is: A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.”
Having more positive experiences in life is associated with lower odds of developing brain disorders like Alzheimer’s disease, slower cognitive decline with age, and even a longer life. But how feelings and experiences are translated into physical changes that protect or harm the brain is still unclear.
Now, a study from Columbia researchers suggests that the brain’s mitochondria may play a fundamental part. The new study shows that the molecular machinery used by mitochondria to transform energy is boosted in older adults who experienced less psychological stress during their lives compared with individuals who had more negative experiences.
“We’re showing that older individuals’ state of mind is linked to the biology of their brain mitochondria, which is the first time that subjective psychosocial experiences have been related to brain biology,” says Caroline Trumpff, assistant professor of medical psychology, who led the research with Martin Picard, associate professor of behavioural medicine at Columbia University Vagelos College of Physicians and Surgeons and in the Robert N. Butler Columbia Aging Center.
“We think that the mitochondria in the brain are like antennae, picking up molecular and hormonal signals and transmitting information to the cell nucleus, changing the life course of each cell,” says Picard. “And if mitochondria can change cell behaviour, they can change the biology of the brain, the mind, and the whole person.”
Study details
The new research used data collected by two extensive studies of nearly 450 older adults in the United States. Each study collected detailed psychosocial information from the participants for two decades during their lives. Study participants donated their brains after death for further analysis, which provided data on the state of the participants’ brain cells.
Trumpff created indices that converted patients’ reports of positive and negative psychosocial factors into a single score of overall psychosocial experience. She also scored each participant on seven domains that represent distinct genetic networks active in mitochondria.
“The use of multivariate mitotype indices is an important innovation because we could more easily interpret the biological state of the mitochondria with networks of related genes than an analysis of thousands of individual genes,” Picard says.
Study results
The results showed that one mitochondrial domain – which assessed the organelle’s energy transformation machinery – was associated with psychosocial scores.
“Greater well-being was linked to greater abundance of proteins in mitochondria needed to transform energy, whereas negative mood was linked to lower protein content,” Trumpff says. “This may be why chronic psychological stress and negative experiences are bad for the brain, because they damage or impair mitochondrial energy transformation in the dorsolateral prefrontal cortex, the part of the brain responsible for high-level cognitive tasks.”
The researchers also analysed mitochondria in specific cell types in the brain and found that the associations between mitochondria and psychosocial factors were driven not by the brain’s neurons, but its glia cells, which may be playing more than their traditionally assumed “supportive” roles.
“This piece of the study, made possible by our collaboration with the Columbia Center for Translational and Computational Neuroimmunology, is what I think makes it particularly significant,” Picard says. “To ask questions at this level of cellular resolution in the brain is unprecedented in the mitochondrial field.
“Neurons have been the focus of neuroscience, but we’re waking up to the fact that other cells in the brain may be driving disease.”
Do mitochondria change mood, or does mood change mitochondria?
Though the current study cannot determine if the participant’s psychosocial experiences altered their brain mitochondria or if innate or acquired mitochondrial states contributed to those experiences, other studies suggest that the relationship between mitochondria and mood works both ways.
In animal studies, the evidence is very strong, Picard says, that chronic stress affects mitochondrial energy transformation. And in people, a recent study conducted by Picard and collaborator Elissa Epel at UCSF found the first evidence that mood may affect mitochondria in humans: In that study, positive mood predicted greater mitochondrial energy production in the participants’ blood cells on subsequent days, but mitochondrial activity did not predict mood on subsequent days.
A growing body of work in animals and humans also indicates that mitochondria themselves can alter behaviour.
“It’s possible that these mechanisms reinforce one another,” Trumpff says. “Chronic stress could alter an individual’s mitochondrial biology in ways that subsequently affects their perception of social events, creating more stress. The emerging picture in the literature is that all these pathways are interactive.”
Next steps
Though the brain’s energy transformation machinery was greater in participants with higher psychosocial scores, the researchers do not yet know if that leads to greater energy transformation. Trumpff and Picard are currently doing those studies with hundreds of brains from the same cohorts of participants.
The team is also exploring a way to measure the brain’s mitochondrial health, which could be used in doctors’ offices in the future.
“Mitochondria are the source of health and life, but we don’t have ways to quantify health, only disease,” Picard says. “We need a science of health. We need tests that show how healthy and resilient someone is.
“This would be valuable clinically to monitor changes in health before the appearance of disease, and it could transform medical research by giving scientists something to target other than decades of accumulated protein deposits or other forms of long-term damage.”
These coloured streaks are mitochondrial networks within fat cells. Researchers from UC San Diego discovered that a high-fat diet dismantles mitochondria, resulting in weight gain. Credit: UC San Diego
While lifestyle factors like diet and exercise play a role in the development and progression of obesity, scientists have come to understand that obesity is also associated with intrinsic metabolic abnormalities. Now, researchers from University of California San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the all-important energy-producing structures of our cells.
In a study published January 29, 2023 in Nature Metabolism, the researchers found that when mice were fed a high-fat diet, mitochondria within their fat cells broke apart into smaller mitochondria with reduced capacity for burning fat. Further, they discovered that this process is controlled by a single gene. By deleting this gene from the mice, they were able to protect them from excess weight gain, even when they ate the same high-fat diet as other mice.
“Caloric overload from overeating can lead to weight gain and also triggers a metabolic cascade that reduces energy burning, making obesity even worse,” said Alan Saltiel, PhD, professor in the Department of Medicine at UC San Diego School of Medicine. “The gene we identified is a critical part of that transition from healthy weight to obesity.”
Obesity occurs when the body accumulates too much fat, which is primarily stored in adipose tissue. Adipose tissue normally provides important mechanical benefits by cushioning vital organs and providing insulation. It also has important metabolic functions, such as releasing hormones and other cellular signaling molecules that instruct other tissues to burn or store energy.
In the case of caloric imbalances like obesity, the ability of fat cells to burn energy starts to fail, which is one reason why it can be difficult for people with obesity to lose weight. How these metabolic abnormalities start is among the biggest mysteries surrounding obesity.
To answer this question, the researchers fed mice a high-fat diet and measured the impact of this diet on their fat cells’ mitochondria, structures within cells that help burn fat. They discovered an unusual phenomenon. After consuming a high-fat diet, mitochondria in parts of the mice’s adipose tissue underwent fragmentation, splitting into many smaller, ineffective mitochondria that burned less fat.
In addition to discovering this metabolic effect, they also discovered that it is driven by the activity of single molecule, called RaIA. RaIA has many functions, including helping break down mitochondria when they malfunction. The new research suggests that when this molecule is overactive, it interferes with the normal functioning of mitochondria, triggering the metabolic issues associated with obesity.
“In essence, chronic activation of RaIA appears to play a critical role in suppressing energy expenditure in obese adipose tissue,” said Saltiel. “By understanding this mechanism, we’re one step closer to developing targeted therapies that could address weight gain and associated metabolic dysfunctions by increasing fat burning.”
By deleting the gene associated with RaIA, the researchers were able to protect the mice against diet-induced weight gain. Delving deeper into the biochemistry at play, the researchers found that some of the proteins affected by RaIA in mice are analogous to human proteins that are associated with obesity and insulin resistance, suggesting that similar mechanisms may be driving human obesity.
“The direct comparison between the fundamental biology we’ve discovered and real clinical outcomes underscores the relevance of the findings to humans and suggests we may be able to help treat or prevent obesity by targeting the RaIA pathway with new therapies,” said Saltiel “We’re only just beginning to understand the complex metabolism of this disease, but the future possibilities are exciting.”
Researchers have found an anti-ageing function in a protein deep within human cells. They discovered that a protein called ATSF-1 controls a fine balance between the creation of new mitochondria and the repair of damaged mitochondria. Their findings were published in Nature Cell Biology.
Mitochondria create toxic by-products during their energy production process, which contributes to the rate at which the cell ages.
Associate Professor Steven Zuryn and Dr Michael Dai at the Queensland Brain Institute made the discovery of a key repair protein. “In conditions of stress, when mitochondrial DNA has been damaged, the ATSF-1 protein prioritises repair which promotes cellular health and longevity,” Dr Zuryn said.
As an analogy, Dr Zuryn likened the relationship to a race car needing a pitstop.
“ATSF-1 makes the call that a pitstop is needed for the cell when mitochondria need repairs,” he said.
“We studied ATFS-1 in C. elegans, or round worms and saw that enhancing its function promoted cellular health, meaning the worms became more agile for longer. They didn’t live longer, but they were healthier as they aged.”
“Mitochondrial dysfunction lies at the core of many human diseases, including common age-related diseases such as dementias and Parkinson’s. Our finding could have exciting implications for healthy ageing and for people with inherited mitochondrial diseases.”
Understanding how cells promote repair is an important step towards identifying possible interventions to prevent mitochondrial damage.
“Our goal is to prolong the tissue and organ functions that typically decline during ageing by understanding how deteriorating mitochondria contribute to this process,” Dr Dai said. “We may ultimately design interventions that keep mitochondrial DNA healthier for longer, improving our quality of life.”
Red mitochondria in airway cells become coated with green SARS-COV-2 proteins after viral infection: Researchers discovered that the virus that causes COVID-19 damages lungs by attacking mitochondria. Credit: Stephen Archer
Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).
Ultimately, mitochondria became the powerhouses within all human cells.
This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria – more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.
SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.
How COVID-19 affects lungs
People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:
First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).
Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.
We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.
This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.
It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage – an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction – were making lung injury and hypoxaemia (low blood oxygen) worse.
Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.
We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.
Attacking mitochondria
Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.
How SARS-CoV-2 targets mitochondria to kill lung cells and prevent oxygen sensing. Credit: Brooke Ring, provided by Stephen Archer
Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).
In our experiments, we didn’t need to use a replicating virus to damage the mitochondria – simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.
We are now developing drugs that may one day counteract COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.
Our team’s infectious diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition – fatigue and neurologic dysfunction – could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.
Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.
The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.
Pandemic pivot
The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field – virology – in an effort to make a small contribution to the COVID-19 puzzle.
Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.
Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.
Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.
“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.
Our discovery will hopefully be translated into new medicines to counter future pandemics.
Researchers at Karolinska Institutet in Sweden have linked resistance to treatment for VHL syndrome-induced kidney cancer to low mitochondrial content in the cell. When the researchers increased the mitochondrial content with an inhibitor, the cancer cells responded to the treatment. Their findings, which are published in Nature Metabolism, may lead to more targeted cancer drugs.
Mitochondria are the most oxygen-demanding component of the cell, but it was not known how mitochondria adapt in a low-oxygen environment and how they are linked to cancer therapy resistance.
“We’ve shown for the first time how the formation of new mitochondria is regulated in cells that lack oxygen and how this process is altered in cancer cells with VHL mutations,” explained Associate Professor Susanne Schlisio, group leader at the Karolinska Institutet.
A gene called von Hippel-Lindau (VHL) prevents healthy cells from turning cancerous. The 2019 Nobel Prize in Physiology or Medicine was awarded to the discovery that VHL was part of the cell’s oxygen detection system. Normally, VHL breaks down another protein called HIF – but when VHL is mutated, HIF accumulates and causes a disease called VHL syndrome in which the cells react as if they were lacking oxygen. This syndrome greatly increases the risk of tumours, both benign and malignant. VHL syndrome-induced kidney cancer has a poor prognosis, with a five-year survival rate of just 12%.
Researchers analysed the protein content of cancer cells from patients with different variants of VHL syndrome, to see how they differed from another group of individuals with a special VHL mutation called Chuvash, a mutation involved in hypoxia-sensing disorders without any tumour development. Those with the Chuvash VHL-mutation had normal mitochondria in their cells, while those with VHL syndrome mutation had few.
To increase the amount of mitochondrial content in VHL related kidney cancer cells, the researchers treated these tumours with an inhibitor of a mitochondrial protease called “LONP1.” This resulted in the cells becoming susceptible to the cancer drug sorafenib, which they had previously resisted. In mouse studies, this combination treatment led to reduced tumour growth.
The study’s first author Shuijie Li, postdoctoral researcher in the Schlisio’s group, suggested that the findings could be applied to more than just VHF syndromic kidney cancers.
“We hope that this new knowledge will pave the way for more specific LONP1 protease inhibitors to treat VHL-related clear cell kidney cancer,” Dr Li said. “Our finding can be linked to all VHL syndromic cancers, such as the neuroendocrine tumours pheochromocytoma and paraganglioma, and not just kidney cancer.”
There is convincing evidence that micronutrients, such as iron, selenium, zinc, copper, and coenzyme Q10, can impact the function of cardiac cells’ energy-producing mitochondria to contribute to heart failure according to a review published in the Journal of Internal Medicine.
Research has established a relationship between poor cardiac performance and metabolic perturbations, including deficits in substrate uptake and utilisation, reduction in mitochondrial oxidative phosphorylation and excessive reactive oxygen species production. Together, these disturbances result in depletion of cardiac adenosine triphosphate (ATP) and loss of cardiac energy. Delivering more energy substrates such as fatty acids to the mitochondria will be worthless if the mitochondria can’t turn them into fuel.
Micronutrients are required to efficiently convert macronutrients to ATP. However, studies have shown that up to 50% of patients with heart failure have deficiencies in one or more micronutrients. “Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation,” the authors argued. Their findings suggest that micronutrient supplementation could represent an effective treatment for heart failure.
“Micronutrient deficiency has a high impact on mitochondrial energy production and should be considered an additional factor in the heart failure equation, moving our view of the failing heart away from ‘an engine out of fuel’ to ‘a defective engine on a path to self-destruction’,” said co–lead author Nils Bomer, PhD, of the University Medical Center Groningen, in The Netherlands.
An accompanying editorial suggests a large trial to see if there is indeed a clinical benefit.
A new study revealed that lupus may be triggered by a defective process in the development of red blood cells (RBCs) which leaves mitochondria remnants. The study was published in Cell.
The researchers found that in a number of lupus patients, maturing red blood cells fail to get rid of their mitochondria, which are normally excluded from red blood cells. This abnormal retention of mitochondria can trigger the cascade of immune hyperactivity characteristic of this disease.
“Our findings support that red blood cells can play a really important role in driving inflammation in a subgroup of lupus patients. So this adds a new piece to the lupus puzzle, and could now open the door to new possibilities for therapeutic interventions,” said the study’s senior author, Dr Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine
Lupus is a chronic disorder with no cure that features intermittent and sometimes debilitating attacks by the immune system on the body’s own healthy tissues, including skin, joints, hair follicles, heart and kidneys. A common underlying factor in lupus is the abnormally elevated production of immune-activating proteins called type I interferons. Treatments aim to suppress immune activity, including interferon-driven inflammation.
Previous research found defective mitochondria in the immune cells of lupus patients. In the current study, the researchers focussed on red blood cells, which should lack mitochondria. Many lupus patients had red blood cells with detectable levels of mitochondria, and more common in patients with worse symptoms. By contrast, healthy controls had no mitochondria-containing red blood cells.
Lead author of the study, Dr. Simone Caielli, assistant professor of immunology research at the Drukier Institute and the Department of Pediatrics at Weill Cornell Medicine, then studied how human red blood cells normally get rid of mitochondria as they mature, as prior studies had mainly examined this in mice, and why this process could be defective in lupus patients.
Subsequent experiments showed these abnormal red blood cells cause inflammation. Normally, when red blood cells age or display signs of damage they are removed by macrophages, with binding antibodies helping removal. When the macrophages ingest them, the mitochondrial DNA in the red blood cells triggers a powerful inflammatory pathway called the cGAS/STING pathway, in turn driving type I interferon production. These findings show that “those lupus patients with mitochondria-containing red blood cells and evidence of circulating anti-RBC antibodies had higher interferon signatures compared to those who didn’t,” Dr Caielli said.
The researchers are now investigating how the mitochondria is retained in these cells. Identifying lupus patients with these cells could help predict when they are likely to undergo lupus flares and to develop therapies.
Elite athletes have temporary mitochondrial impairment following intense workouts, according to new research, which suggests they may need to be mindful about overtraining.
Mitochondria are organelles that are responsible for most of the useful energy derived from the breakdown of carbohydrates and fatty acids, which is converted to ATP by the process of oxidative phosphorylation. Mitochondrial capacity is a term used to describe the body’s ability to generate energy, and is one factor associated with increased athletic performance during endurance exercise. Previous research found that untrained recreational athletes had a decrease in mitochondrial capacity after sprinting exercises.
In this study, the researchers worked with a small group of male elite athletes, many of whom were national title holders or had international recognition for their performance in cycling and triathlon. The athletes participated in a four-week training programme in their primary sport, which consisted of two to four days of low-to-moderate–intensity endurance workouts, followed by three days of more intense training. These intense workouts included high-intensity interval training in the morning, followed by a seven-hour break and then a moderate-intensity cycling session in the afternoon. Each volunteer did between 12 and 20 hours of activity per week. The athletes, though used to heavy training, were not accustomed to this specific workout schedule.
The researchers were surprised to observe that the highly trained participants’ mitochondrial capacity was impaired after the month-long training period. “We thought that elite athletes should be more resistant against [these] kind of alterations,” said Filip Larsen, PhD, of the Swedish School of Sport and Health Sciences and corresponding author of the study.
However, elite athletes may be able to prevent temporary mitochondrial impairment by listening to their bodies, the researchers suggested. By paying attention to changes such as “mood disturbances, reductions in maximal heart rate [during exercise] and muscles that feel heavy and unresponsive” top athletes may be able to pull back and avoid overtraining situations that could contribute to reduced mitochondrial content and function, Larsen explained. “Exercise is good for you, but too much unaccustomed training might have mitochondrial consequences.”
The study also found that reduced mitochondrial capacity did not affect exercise performance, suggesting that oxygen delivery from the heart to the muscles plays a more important role than mitochondrial function in performance. Expression of three proteins with strong antioxidant properties were also found to be increased in the muscles after intense training.
Journal information: Daniele A. Cardinale et al, Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes, Journal of Applied Physiology (2021). DOI: 10.1152/japplphysiol.00829.2020
