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A newborn baby's heart is roughly the size of a walnut — which makes open-heart surgery challenging.
Each year, about 10,000 babies in the United States are born with critical heart defects that may require surgery to fix, often fairly soon after birth. In these infants, the two major arteries of the heart could have swapped positions or the left side of the heart may be far too small to pump properly .
Even if their surgeries go well, these babies face perilous recoveries. A complication can arise when blood flows back into the repaired heart, triggering what's known as an ischemia-reperfusion injury. This can stun the organ, triggering extensive damage that requires doctors to place the baby on a life-support machine that pumps and infuses oxygen into blood to sub in for the hampered heart and lungs. Only about 40% of newborns make it off the machine, because often, their tiny hearts don't recover.
Doctors and scientists at Boston Children's Hospital have been working to improve those odds using a creative idea: replacing the fuel source in damaged heart cells to help them bounce back from injury. That fuel source is mitochondria, the "batteries" found in most cells in the body. In this case, the mitochondria are isolated from an abdominal muscle and then injected directly into the heart.
As of April, 17 babies have undergone this procedure, and 80% made it off ECMO . It's too soon to say if the treatment improves overall survival rates, but the early data hints that it might. A clinical trial is currently underway .
James McCully (left) and his colleague Dr. Sitaram Emani of Boston Children's Hospital have developed a technique to transplant mitochondria into the hearts of children recovering from surgery. (Image credit: Courtesy of Boston Children's Hospital) "The first one or two for me were pretty nerve-wracking," said James McCully , a research associate at Boston Children's Hospital and associate professor of surgery at Harvard Medical School whose pioneering work paved the way for these procedures. His team isolates and purifies the mitochondria that a surgical team then transplants into patients.
"But you know, the heart comes back — you can actually almost see it coming back" in real time, he told Live Science. A heart deprived of energy looks pallid, while a freshly rejuvenated heart blushes a healthy pink.
Baby heart infusions are just one example of the promise of "mitochondrial transplantation." Following McCully's lead, other scientists have started investigating whether infusions of mitochondria could revitalize donated organs destined for transplantation, help stroke patients recover, and treat kids with devastating diseases. This work is still highly experimental, and its route to regulatory approval remains unclear.
But at its core is a straightforward idea: When a battery dies, you replace it.
Relic of our evolutionary past
The human body contains tens of trillions of cells , most of which contain hundreds to thousands of mitochondria. Following some back-of-the-envelope math, that means the total potential energy in each person "is the equivalent of a lightning bolt," Douglas Wallace , director of the Center for Mitochondrial and Epigenomic Medicine at Children's Hospital of Philadelphia, told attendees last year at a symposium on mitochondrial medicine .
Mitochondria, in a word, are powerful. They produce most of the chemical energy used by complex cells by churning out a molecule called adenosine triphosphate (ATP). The idea of transferring these fuel factories from one cell to another as a medical treatment emerged less than two decades ago — but cells have been doing such swaps on their own for eons.
A leading theory posits that mitochondria evolved from simple microbes. And today, they still retain distinctly microbial features. (Image credit: Behnoush Hajan/Science Photo Library via Getty Images) Dr. Jon Brestoff , an associate professor of pathology and immunology and director of the Immunometabolism Initiative at the Washington University School of Medicine in St. Louis, describes this ability to move from cell to cell as a relic of mitochondria's bacterial past . "It is hypothesized that mitochondria transfer has likely been retained throughout evolution of eukaryotic life," the huge domain of life that includes all plants, fungi, protists and animals, Brestoff told Live Science.
Mitochondria are the powerhouses of nearly all complex cells on Earth, and there are a few theories as to how they adopted that ubiquitous role. A leading idea posits that, some 1.5 billion to 2 billion years ago, one simple cell engulfed another. The bacterial cell that got swallowed carried a circular loop of DNA inside its membrane, and that captured cell later became what we now know as the mitochondrion . The new organelle enabled cells to take advantage of the abundance of oxygen on our planet by converting it into usable fuel.
Mitochondria retained bacteria-like features, such as having their own DNA and membranes. But in 2006, researchers reported that mitochondria can also exit their "host" and survive the journey into a totally different cell — a phenomenon known as mitochondrial transfer.
"That was a complete revolution in thinking," said Dr. Lance Becker , professor and Chair of the Department of Emergency Medicine at Northwell Health and the Feinstein Institutes for Medical Research. "With that notion that mitochondria might be mobile, that they might cross boundaries, that they might go from one cell to another cell, came the possibility that maybe that was something we could use to help people."
The 2006 study showed that cells that had been depleted of their own mitochondrial DNA could obtain healthy mitochondria from neighboring cells. After receiving other cells' powerhouses, the once-depleted cells were able to conduct energetically costly processes, such as cell division.
This research provided the first evidence that one cell can "donate" metabolic properties to its neighbor by sending over a fresh batch of mitochondria. Scientists once thought cells had to make all of their own mitochondria, but now, "I think cells have the ability to 'put their hand up' when they need mitochondria," Becker told Live Science.
Jon Brestoff is studying the use of mitochondrial transplantation for genetic diseases that impair the function of these cellular powerhouses. (Image credit: Courtesy of Jon Brestoff) Because those first experiments were done in lab dishes, initially, "it was unclear whether or not it was really biologically meaningful or relevant," Brestoff said. But within the past five to six years, improved tools and techniques have enabled scientists to watch mitochondrial transfer unfold within living organisms, he noted. It's been shown that cells of the same type can exchange mitochondria, as can cells of different types .
As scientists' fundamental understanding of mitochondrial transfer grew, the notion of doing the same thing therapeutically gained more traction.
"That procedure," Brestoff said, "is rooted in the biology of mitochondria transfer."
"The heart came back"
Just two years after the landmark 2006 paper, McCully's research group released data that hinted at the medicinal potential of mitochondrial transplantation.
Since then, these complementary lines of research — the foundational biology and the preclinical investigation — have continued in parallel. McCully's preclinical work helped to inspire other labs to explore the use of mitochondrial transplantation for a range of medical applications, including organ transplants and treatments for stroke and genetic disease.
McCully is "the pioneer — the guru of the field," said Dr. Giuseppe Orlando , a professor of surgery and regenerative medicine at Wake Forest University School of Medicine who is exploring mitochondrial transplantation as a way to maintain the integrity of transplant organs.
McCully's road to mitochondrial transplantation started in the 1980s. As a molecular biologist, he wanted to uncover mechanisms that protect the heart from damage, particularly when the organ's oxygen supply is compromised — such as during ischemia, or low blood flow. With an eye on older adults, he wanted to spare patients' heart tissue from the damage and cell death that can occur before and during heart surgery.
It changed color, went back to a pink hue, and just kept on going.
James McCully, a research associate at Boston Children's Hospital
McCully and his collaborators initially "didn't care about the mitochondria one iota," he said. They were more focused on the nucleus, the control center that houses most of a cell's DNA, and its influence on cellular pathways that might boost the heart's resilience to ischemia. But "what we found was that everything we did started coming back to the mitochondria," he said.
They found that ischemia triggers damage and dysfunction in mitochondria that persists even after the heart's oxygen supply is restored; this dysfunction ultimately kills cells . The damaged mitochondria swell up, leak their innards, and set off a chain reaction that causes a cell to self-destruct.
McCully and colleagues observed that biological pathways that seemed to reduce this cell death often centered on the mitochondria. "We were looking around at either pathways upstream of the mitochondria or downstream of the mitochondria," he said.
So, logically, they started looking directly at mitochondria, studying what the organelle looks like before, during and after ischemia. One day, while isolating mitochondria from a laboratory pig, the animal developed fibrillation, meaning its heart began beating very quickly, with an uncoordinated and rapid rhythm. The team tried to reset the heart's rhythm with electric shocks and medications, to no avail. But McCully had an idea.
"At that point in time, the heart's kind of [got a] gray pallor, and it looks dead," he said. "And I said, 'Go upstairs; grab some of those mitochondria that we've isolated from the non-ischemic type. Just bring them down.'" They'd previously gathered some healthy mitochondria from the same pig, in hopes of generating a "before-and-after" picture of ischemia. Instead, McCully suspended those healthy mitochondria in a solution and then injected them directly into the pig's fibrillating heart.
"And the heart came back — started beating normally. It changed color, went back to a pink hue, and just kept on going," he said.
Live Science Emani, S.M., et al. (2017) The Journal of Thoracic and Cardiovascular Surgery. Emani, S.M., et al. (2017) The Journal of Thoracic and Cardiovascular Surgery. That serendipitous experiment led to a formal test of the technique in rabbit hearts , the results of which were published in 2008. In the study, they introduced healthy mitochondria to the rabbits' hearts during ischemia, just before reperfusion — when blood is reintroduced into the oxygen-starved tissue. They found that the mitochondria improved the organs' recovery and reduced tissue death. Further research in animals suggested that mitochondria that originated from one type of tissue, like liver tissue or skeletal muscle, could be introduced to other tissue types, such as cardiac muscle.
After seeing McCully's results in various animal experiments, including more with pigs, Dr. Pedro del Nido , chair of cardiac surgery at Boston Children's and a professor of child surgery at Harvard Medical School, approached him about testing the technique in human patients — namely, in babies on a life-support machine known as ECMO.
"He saw it in the animals; he saw what was going on," McCully said. "And he deemed it as being a possible intervention to save these kids."
They sought permission from the Food and Drug Administration (FDA) to test the procedure and cleared the required regulatory hurdles. The process was made slightly easier because the mitochondria were coming from the patients' own bodies, not from a donor, McCully noted. Once given the go-ahead, they set forth with the help of Dr. Sitaram Emani , a heart surgeon at Boston Children's. The first procedure took place in 2014 .
During each procedure, Emani and the surgical team collect a small sample of skeletal muscle from the patient, and McCully then isolates whole mitochondria from the tissue and prepares them in a syringe. He refined the isolation technique so the time from collecting the muscle sample to injecting mitochondria is only 30 minutes. Lately, the team has been developing a technique they can perform in the operating room, rather than in a lab, which could cut the time to 20 minutes. Emani uses various tests, including echocardiography, to see which areas of the heart tissue move the least, and injects mitochondria straight into those areas.
"It's great to be able to see something you've done and worked on for so many years actually provide a benefit," McCully said.
Transplants for transplant organs
Dr. Giuseppe Orlando thinks that mitochondrial transplantation could serve as a potential method for fortifying donated organs that are intended for transplant patients. (Image credit: Courtesy of Dr. Giuseppe Orlando) While McCully is trying to protect infant hearts, other scientists want to do the same for other organs — including those destined for transplant surgeries.
To Orlando, mitochondria represent a potential way to make donated kidneys work better. "In transplant medicine, one of the major issues is making sure that the organs that are procured are well stored and kept viable until implantation," said Orlando, who is also president of the Cell Transplant and Regenerative Medicine Society .
Maintaining an organ's viability means preserving mitochondrial function as much as possible, but the transplantation process is tough on the organelles. "That energy plant is damaged. So it's pretty obvious that you should start thinking about a way to replace the damaged mitochondria," Orlando said.
Donated organs suffer some damage when they're unplugged from the donors' bloodstream, in part because this cuts off mitochondria's crucial oxygen supply. And then, paradoxically, the donor organs also get damaged when they're plugged into the recipient's bloodstream. That's because the fast flow of blood triggers the production of free radicals — unstable molecules that damage tissues.
While healthy organs normally produce some free radicals, reperfusion unleashes a flood. "It's more than the organ can bear and sustain," Orlando explained. This damage contributes to a phenomenon called delayed graft function, in which a transplanted kidney doesn't work right away so the patient ends up needing dialysis in the first week after surgery.
"You want to make sure that the kidney wakes up faster," Orlando said. That's where mitochondria come in.
Orlando was introduced to the idea of mitochondrial transplantation around 2019 through a collaboration with Dr. Benedetta Bussolati , a nephrologist and full professor of laboratory medicine at the University of Turin in Italy. Her lab had been studying mitochondrial transplantation in isolated kidney cells in lab experiments, and they reached out to Orlando about extending that work to lab animals.
In pigs, the researchers ran experiments in which the animals' kidneys were collected and stored in the same way human kidneys commonly would be prior to being transplanted. One set of kidneys received a placebo treatment, while another got an infusion of mitochondria from the donor pigs' muscle tissue. Upon being reperfused, the treated kidneys produced fewer free radicals and accrued less damage than the untreated kidneys did, the team reported in 2023.
They backed up this finding by analyzing RNA , a molecule that reflects which genes are active in cells. Compared with the untreated kidneys, the treated kidneys showed greater activity in genes involved in mitochondrial metabolism and lower activity in genes involved in repairing injuries.
Orlando thinks that mitochondrial transplanations could help organs "wake up" faster after being transferred from an organ donor to a recipient. (Image credit: PIERRE-PHILIPPE MARCOU via Getty Images) Some groups are exploring mitochondrial transplantation in other donor organs, like the lungs — specifically, lungs treated with " ex vivo perfusion " (EVP), an emerging approach that helps retain the viability of transplant organs. Rather than placing a donor organ in a cooler of ice, as is generally standard, EVP flushes an organ with nutrient- and oxygen-rich fluid, helping to maintain its function until the transplant surgery. In lab experiments with pig and human lungs , scientists found that introducing fresh mitochondria during EVP further improved the organs' function while reducing inflammation and free radicals.
Across different organ transplants, Orlando sees mitochondria as a potential means to improve patient outcomes and expand the pool of available organs. There are scenarios in which would-be organ donors die unexpectedly of cardiac arrest and their organs are damaged in the process; mitochondrial transplants may help make such organs fit for patients, Orlando has said .
In the near term, Orlando and his colleagues are continuing to study the basic science of mitochondrial transplantation for this clinical purpose; they've also been cleared to run a clinical trial with donor kidneys but need more funds to proceed.
Looking to the more distant future, he and other experts in the field envision a world where transplant organs can be bioengineered and stored in banks, ready and waiting for the patients who need them, Orlando said. If that vision materializes, he suggested, mitochondrial transplants might be useful for preparing banked organs for transplantation "by giving them kind of an energy boost."
Reaching the brain
If infusions of fresh mitochondria could help the heart, kidney and lungs, what about the brain? That's the question Dr. Melanie Walker and colleagues at the University of Washington School of Medicine (UW Medicine) want to answer.
Walker, a clinical professor of neurological surgery, treats patients who have had ischemic strokes, which are caused by blood clots blocking blood flow to the brain. The immediate aim of post-stroke treatment is to clear out the blocked "pipe" and restore circulation to the brain as quickly as possible, she said. But no matter how quickly this is done, some brain cells are damaged. And once the blood clot is removed, the brain may then suffer a reperfusion injury.
Standard treatments can dissolve the clot but don't protect the brain, Walker said. "What about all those cells that are maybe not quite dead — they're on the verge of maybe dying? What can we do to support those guys?" she asked.
The UW Medicine team had heard about McCully's work in Boston and wondered if something similar could be applied in stroke patients. But while heart surgery exposes the tissue in need of new mitochondria, accessing the brain is trickier. "You don't do a craniotomy to give an IV medicine," Walker told Live Science.
But Walker realized that a harmful downstream effect of stroke might provide an opportunity for treatment. Immediately after a stroke, the brain's protective shield — known as the blood-brain barrier — becomes more permeable than usual , allowing more substances to pass from the bloodstream into brain tissue. That might open a door for mitochondrial transplantation.
One method of treating ischemic strokes is to physically remove the clot using a procedure called a thrombectomy, which a surgeon is preparing for in the photo above. Dr. Melanie Walker and colleagues tried combining this approach with mitochondrial transplantation. (Image credit: BSIP via Getty Images) A 2023 mouse study spearheaded by University of Virginia researchers and co-authored by Walker backed this idea, finding that mitochondria entered the brain after stroke and integrated into brain cells. These mitochondria had been gathered from muscle tissue, as in McCully's studies, and introduced to the brain via an artery. The treatment increased ATP production while reducing cell death caused by the stroke, compared with untreated mice's brains.
This work paved the way to the first trial using mitochondrial transplant in the human brain . The small safety trial included adult patients who'd had ischemic strokes and underwent thrombectomies — surgeries to remove the clots from their blood vessels. Four received mitochondrial transplants during their procedures and 12 did not. Mitochondria were injected near the site of each patient's stroke, into the closest branch of one of the brain's major arteries.
No negative side effects were tied to the transplants, hinting that the procedure is safe in humans. "But the next question is, how do we understand if it helps? And those are harder trials to design," Walker said. That's partly because the transplants are tacked onto the clot-removal procedure, so it's difficult to separate their effects from those of the clot removal itself, she noted.
Future trials will also need to explore exactly where the transplanted mitochondria end up in the human brain, how well they function once inside brain cells, and how the dose and timing of the transplant affect patients' outcomes, the trial runners wrote in their report. For the moment, Walker said her team is focused on exploring the safety aspects of the approach and have no further trials planned at this time.
Mitochondrial diseases — and what's next
Beyond heart defects, transplant organs and stroke, researchers are looking to mitochondrial transplantation as a solution for genetic conditions that harm mitochondria directly. Brestoff and colleagues are investigating the therapy's potential for treating Leigh syndrome , a rare neurological condition caused by genetic mutations that disrupt the fuel-producing machinery in mitochondria.
"Those kids have a terrible prognosis," Brestoff said. Most children with the most common form of the syndrome, whose symptoms show up by age 2, die by age 3. There is no cure for the syndrome, and treatments to relieve its symptoms are limited . So if it works, mitochondrial transplantation could fill a big gap.
So far, the approach shows promise in lab mice with a severe form of Leigh syndrome, improving the rodents' function and extending their median lifespan by 19% to 24%, the researchers demonstrated in 2024 . They're now studying the approach in cells derived from patients with the disease.
I can get the mitochondria from you and put them into me, me into you — doesn't really matter.
James McCully, a research associate at Boston Children's Hospital
Some companies, such as Israel-headquartered Minovia Therapeutics, are already running clinical trials with patients with other types of mitochondrial disease. Minovia is running one with children with Pearson syndrome , in which missing mitochondrial DNA hinders the function of bone marrow , which normally makes blood and immune cells.
While patients with a heart or brain problem may be able to pluck mitochondria from healthy muscles, people with mitochondrial disease don't necessarily have healthy mitochondria to spare. Especially for these patients, getting mitochondria from other people — known as heterologous transplantation — likely makes the most sense. What's more, for transplantation to be used widely for any purpose, there would need to be an "off-the-shelf" mitochondrial product available, Brestoff said.
Such a product could eliminate the step in Boston Children's heart procedure where mitochondria have to be isolated from a patient while they're waiting, open on an operating table. "Getting them from the recipient can sometimes be problematic, because the recipients are sick. All the organs, all the tissue is quite distressed," McCully noted. A standardized and safety-tested mitochondrial product would therefore be a boon for the field.
Brestoff is on the scientific advisory board of LUCA Science , a company developing mitochondria as therapeutic agents, and a consultant for Cellergy Therapeutics , which is making mitochondrial products to combat conditions from muscle degeneration and aging. These companies exemplify the effort to come up with ready-made products that could someday bring the therapy to more patients.
A shift to heterologous transplantation does raise concerns about immune reactions. "You have some variations in the proteins that are present in your mitochondria that I don't have," Brestoff noted. "So it is possible that our immune systems recognize heterologous mitochondria as non-self."
But McCully doesn't expect immune reactions to be a big problem, based on his research in animals. "I can get the mitochondria from you and put them into me, me into you — doesn't really matter," he said. Early trial results from Minovia and others suggest heterologous transplantations come with minimal side effects, at least at doses tested so far.
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Another roadblock is that the FDA has not approved any organelles as therapies yet, so the standards and regulatory framework for the field are still being established, Brestoff said.
Despite that hurdle, the field has advanced significantly since its start as a niche, theoretical interest and then a highly experimental procedure for the sickest newborns. Scientists are now exploring the treatment as a solution to many common conditions, from rheumatoid arthritis to chronic pain .
Becker compared the state of the field to the early days of organ transplantation.
"It just turned out that it was revolutionary, when all of a sudden you could just give a person a kidney transplant," he said. "I think it's going to be kind of similar with mitochondria."
This article is for informational purposes only and is not meant to offer medical advice.
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