At the MRC Mitochondrial Biology Unit at Cambridge University, Michal Minczuk is one of a growing number of scientists around the world looking to find new ways to improve mitochondrial health. This line of research could help provide much-needed treatments for people with long Covid, as well as revolutionize our understanding of everything from neurodegenerative diseases like Parkinson’s disease to the aging process.
Mitochondria, small tube-shaped structures found in hundreds, sometimes thousands, in almost all of our cells, are better known as the body’s power plants, continually converting the foods we eat into ATP, a chemical. complex that acts as a form. of energy currency for cells. Without ATP, all of our cells, from the brain to the muscles, would not have the fuel they need to keep stirring, and our organs would stop quickly.
One of the complexities of mitochondria is that they have their own DNA, separate from the DNA stored in the nuclei of our cells.
But while mitochondria are often typified as energy factories, scientists have repeatedly discovered that they do much more than just generate ATP. On the one hand, they can help keep us warm when we are cold through an alternative form of heat generation to tremors, and studies have suggested that the eye’s mitochondria even play a role in to focus light on the retina, helping us to perceive our environment. .
In fact, the more we look, the more we find that they contribute to the many components of life that keep us healthy, from the synthesis of the protein hemoglobin, which transports oxygen to the bloodstream, to the storage of calcium, and even and the whole response of the immune system. . Although mitochondria support our cells, they also play a critical role in the natural process of cell death that occurs again and again throughout our lives, identifying old and damaged cells that are they must eliminate and destroy.
Simply put, they are vital to our survival, but like much of the body’s innate machinery, we only notice them when they start to go wrong. “Mitochondria are involved in many processes, so when they don’t work well, this can precipitate different types of dysfunctions in the human body that lead to disease,” Minczuk says.
Michal Minczuk: “Little by little we are gathering the tools to be able to modify the mitochondrial genome in animal cells.” Photo: thelilyfoundation.org.uk
One of the unique complexities of mitochondria is that they have their own DNA, separate from the DNA stored in the nuclei of our cells, which comes from both parents. Mitochondrial DNA (mtDNA) is only transmitted from the mother and consists of less than 17,000 base pairs, compared to the 3.3 billion nuclei. But it still encodes specific instructions for various proteins, and over the past decade, scientists have discovered that mtDNA mutations that prevent mitochondria from functioning normally can affect our health, contributing to a variety of chronic diseases.
The most drastic cases are the so-called mitochondrial diseases where mtDNA mutations are genetically acquired. They affect about one in 4,300 people, and the consequences are serious. The life expectancy of most patients is between 10 and 35 years, and most die from general wear and tear on the body due to brain or muscle damage, or damage to organs such as the heart and kidneys. But studies have also shown that mutations can build up in mtDNA as we age, and Minczuk’s research group in the MRC mitochondrial biology unit at Cambridge University is particularly interested in the role it could play in Parkinson’s.
Some Parkinson’s patients are believed to have genetic mutations that prevent damaged mitochondria from being removed and replaced by healthy versions, a process called autophagy. As a result, the existing mitochondria in the body accumulate more and more mutations, with detrimental consequences for cells such as neurons, which are highly dependent on the energy they supply.
But the rise of new gene editing techniques may offer new treatment solutions in the coming years, initially for mitochondrial diseases, but possibly also for other diseases. This has been a challenge because Crispr technology, which uses a piece of RNA to guide an enzyme to a specific location in DNA where it cuts a mutation, cannot be used to adjust mitochondria, as it is not possible to deliver RNA in mtDNA.
However, in recent years, scientists, including Minczuk, have designed enzymes that can achieve the same effect as Crispr without requiring RNA. Although studies on rodents are still being conducted, this offers huge potential for the future.
“We’re slowly putting together the tools to be able to modify the mitochondrial genome in animal cells,” Minczuk says. “Right now we could eliminate existing mutations, changing the genetic composition of mitochondria, but we also want to be able to trigger new mutations. This would allow us to study Parkinson’s in much more detail. We could take a healthy mouse, for example, and introduce mutations observed in Parkinson’s patients and see what happens. Would that trigger the onset of symptoms? “
Covid long treatment
While mitochondrial genome piracy could change health care in the coming years, finding more immediate ways to improve mitochondrial health could help millions of people with chronic fatigue syndrome and long Covid-19, also known as ME / CFS.
At Oxford University, cardiologist Betty Raman is currently in the middle of a clinical trial to see if an amino acid cocktail known as AXA1125, produced by Massachusetts-based biotechnology Axcella Therapeutics, can help patients. long with Covid where fatigue is by far the dominant symptom. .
Prof. Betty Raman. Photography: St Cross College / Oxford University
“The drug is a powdered drink, which is consumed three times a day along with meals, and we hope it will help people with their energy and fatigue levels,” he says. “The idea is that it can give mitochondria additional fuel to produce energy and help repair damaged mitochondria. Hopefully, by the end of July, we should have some front-line results to report.”
The idea that mitochondria may be involved in the diseases of some people with Covid-19 stems from research by Raman and others on patients who are chronically exhausted from exercise after Covid-19, all and that they do not present obvious cardiac or pulmonary abnormalities. This symptom is often called post-exertion discomfort (PEM) and so do people with mitochondrial genetic diseases.
In long-term Covid patients with PEM, Raman has found that his muscles struggle to extract oxygen from the blood as efficiently as might be expected. After finding research that showed that white blood cell mitochondria were not as efficient at generating ATP in patients recovering from Covid-19, he concluded that this could be the leading cause.
But why do the mitochondria of these patients become slow when it comes to generating ATP? David Systrom, a lung care physician and critic at Brigham & Women’s Hospital in Boston, believes he has found answers through the study of patients with ME / CFS, a disease that in many cases is precipitated by viral infections such as Epstein- Barr and that has many similarities. long Covid.
When Systrom studied the mitochondrial DNA of these patients it seemed normal, but after taking a deep look and performing muscle biopsies, he identified abnormalities at the electron level, in the depths of the mitochondria.
“In both ME / CFS and Covid long, it is very likely that these are acquired forms of mitochondrial dysfunction, perhaps related to the initial infection itself or an autoimmune response to a virus or both,” says Systrom. “This impedes the mitochondrial machinery, but does not affect the DNA itself, and means the mitochondria do not generate the right amounts of ATP to meet the needs of the muscles.”
Systrom is now conducting its own clinical trial in both patients with ME / CFS and long-term Covid patients, in collaboration with Japanese pharmaceutical company Astellas, which has developed a drug that aims to restore normal mitochondrial metabolism.
Both Raman and Systrom agree that mitochondrial dysfunction is only likely to be a factor in a subset of long Covid and ME / CFS patients. However, because mitochondria are so ubiquitous throughout the body, damage inflicted on these structures through different types of organs could contribute to the wide range of different symptoms that patients often report.
A common ailment reported by people with long Covid and ME / CFS is dysautonomy, a peculiar condition that causes a rapid increase in heartbeat and dizziness when patients attempt any form of activity. Raman says this is often caused by damage to the skin’s small sensory nerves, something that has been associated with mitochondrial dysfunction.
“There is a theory that the mitochondrial problem may come first,” he says. “And because nerves are high-energy tissues, they depend especially on normal mitochondrial function and ATP production.”
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Different cell types have a different number of mitochondria, due to varying energy requirements from one organ to another. Organs with especially high energy demands such as the brain, heart, and pancreas tend to have more, which is why dysfunctional mitochondria have been linked to everything from cancer to type 2 diabetes and cardiovascular problems.
Although mitochondria are not the main driver of any of these diseases, they are believed to be a key secondary factor. “It is believed that most heart failure or heart dysfunction is mediated by the mitochondrial dysfunction that involves the heart,” Raman says. “There is a large metabolic component, and it has to do with the fact that the heart depends heavily on the continuous supply of oxygen, but also that mitochondria are sensitive structures and can be affected by a number of risk factors.”
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