Within each of the body’s tiny cells are dozens to tens of dozens of even tinier mitochondria. These organelles (“little organs”) convert fuel from the food we eat into energy. At least that’s how it’s supposed to work — for some the situation is far different. Every year 800 babies are born in America with some form of inherited mitochondrial disease. Any organ may be affected — brain, muscles, heart, liver, nerves, eyes, ears and kidneys — at any age.
Debilitating and potentially fatal, mitochondrial disorders mimic many other illnesses, making them notoriously tricky to diagnose. And because they’re caused by an array of inborn errors of metabolism, all of which are rare, they’re not easy to study.
Related research has shown, however, that even people born with healthy mitochondria may develop impairment. In fact, mitochondrial dysfunctions are often hidden in other conditions including Huntington’s and Alzheimer’s, muscular dystrophy, and even autism.
Mayo Clinic researchers are pursuing a range of investigative approaches to better understand and predict the impact of mitochondrial malfunctions, with the goal of helping patients. Here, we touch on four of these scientists and their research efforts. Mitochondria not only power us up, they’re at the center of intracellular communications and stress responses. They help determine which cells should grow and which should die. And, because they generate most of our body heat, they deserve our gratitude when north winds blow. On Mayo Clinic’s Minnesota campus, Eugenia Trushina, Ph.D. leads a laboratory investigating mitochondrial dynamics in the brain.
Cells have lots of types of organelles, but mitochondria are special, having evolved from bacteria that came to live symbiotically inside larger cells — one changing the other to our ultimate advantage. “Because mitochondria were originally an independent species, they have very unique behavior,” she says.
They also have their own DNA.
A mitochondrion sends DNA-coded instructions to its nucleus, and vice versa. To complicate the picture even more, while a cell has just one nucleus with one genome, it has many mitochondria, each of which carries multiple genome copies. And these copies typically vary within a cell. Inside the same person, some mitochondrial genomes might be healthy, but others defective, and different cells can have different proportions of affected mitochondria within them.
Using patient samples to make sense of it all
“Right now, it’s really difficult for some patients with rare genetic diseases to finally get an answer about what condition they have,” explains Devin Oglesbee, Ph.D., who co-directs the Mayo Clinic Mitochondrial Disease Biobank, which opened in 2009. “We’re trying to expand their options.”
Blood-derived samples from a large number of patients and their family members — people with and without mitochondrial disorders — are banked along with non-identifying donor information like age, sex, diagnosis and medication. Each sample remains in its subzero vault until a researcher requests it, months, years or even decades later. Both the Mitochondrial Disease Clinic and the North American Mitochondrial Disease Consortium (originally spearheaded by investigators at Columbia University in New York) contribute to the effort.
Born and educated in Oregon, Dr. Oglesbee first joined Mayo Clinic as a postdoctoral fellow, later becoming co-director of the Biochemical Genetics Laboratory, which focuses on creating methods to detect and monitor inborn errors of metabolism (including the development of screening tests for newborns). Now, he and his collaborators can use banked samples to look for biomarkers — specifically metabolites — that show up at levels outside the normal range in patients with mitochondrial disorders.
Metabolites are small compounds like sugars, lipids, amino acids etc. that are involved in the chemical reactions taking place within our cells. Basically, our DNA makes proteins, and those proteins generate metabolites. Scientists can take a sort of snapshot of the metabolites in a sample and compare it to the profiles of other samples. Biomarkers are the compounds that stand out; they can be used to detect and diagnose disease, often before symptoms appear, and they can help point to the most effective treatments.
“At Mayo Clinic, we’re capable of just immediately translating those new discoveries into a marker for patients,” Dr. Oglesbee says. For example, a clinical test is now available for a metabolite called growth differentiation factor 15 or GDF15 — a new arrow in the quiver for evaluating patients with potential mitochondrial disorders.
“There has also been a lot of work,” continues Dr. Oglesbee, “on using these biobanked specimens for regenerative medicine.” In one such approach, Timothy Nelson, M.D., Ph.D., is generating stem cells from patients with mitochondrial disorders with the goal of identifying therapies to halt or reverse the progression of diseases arising from faulty genes.
Stress and energy balance
Acute cases of mitochondrial disease can be straightforward to diagnose, but most children and adults present to their pediatricians or GPs with multiple, complex symptoms that don’t seem to add up. As a physician in the Mitochondrial Disease Clinic, Eva Morava-Kozicz, M.D., Ph.D. knows that her patients have often beaten a long, rocky and confusing path to reach her door.
“The children — they’re between life and death,” she says, “and the adults have this chronic, invalidating disease that affects all organs and all systems, even the brain. It’s just really a very, very unfair disease.”
Dr. Morava focuses on describing new mitochondrial disorders, including, recently, a disease associated with hearing loss. “Of course, I wish that meant that by discovering it I could take it away,” but at least now this particular combination of symptoms should raise suspicion of the gene defect, and a targeted diagnostic approach is in the making. She also studies stress-related mood disorders using mice with lower than normal mitochondrial complex 1 activity. Complex 1 is the enzyme catalyzing the first reaction of mitochondrial respiration — the conversion of fuel from food into energy for our cells. Her interest in mood disorders began when treating a 16-year-old patient who’d been admitted to a psychiatric hospital after being diagnosed with a conversion disorder (anxiety that’s been “converted” into physical symptoms).
“She did have psychosis, it was true,” says Dr. Morava, “but she also couldn’t walk.”
Because muscle and nerve cells have especially high energy needs, muscular and neurological problems are common features of mitochondrial disorders, and it turned out that this patient had a riboflavin-responsive complex I deficiency. After being supplemented with this B vitamin, she recovered. It’s not unusual for a clinician to mistakenly conclude that a mood disorder has led a patient to, as Dr. Morava explains, “make-believe that they have a metabolic disorder,” when, actually, the metabolic disorder led to the mood disorder.
Before joining Mayo Clinic, Dr. Morava, who was born and educated in Hungary, spent a decade in the Radboud University Medical Center. There she began a collaboration with a neuroscientist who later became her husband, Tamas Kozicz, M.D., Ph.D. Now together at Mayo Clinic, they and their teams are working to figure out why the complex-1-deficient mice are more vulnerable to stress.
These mice have only mild mitochondrial dysfunction, but when stressed, they exhibit clinical symptoms that include mood disorders. In essence, the mice have to balance their power use because there’s not quite enough energy to go around. When stressed, that balance is upset and they become crippled by anxiety.
When caring for patients, “there are a lot of dietary interventions we use to improve quality of life,” says Dr. Morava, “and there are some treatable metabolic disorder types.” Avoiding stressors can help, as can certain supplements, depending on the genetic defect. Some medications can alleviate symptoms, while others can make them worse; antidepressants, for instance, actually have metabolic side effects, and thus can exacerbate symptoms.
Mitochondrial diseases like the ones Dr. Morava treats arise from defects in genes for mitochondrial proteins. But because mitochondria are gatekeepers — critical cellular checkpoints that contribute to health — their dysfunction impacts other disorders ranging from stroke to cardiomyopathy to diabetes.
Mitochondria are dynamic; they split, they join, and they reposition themselves strategically within cells experiencing metabolic or environmental stresses. In muscle cells, they interconnect like a wire grid distributing power throughout a city. In nerve cells, they’re more like energy transport vehicles, moving along axons like interstates.
To track mitochondria during the early stages of Alzheimer’s disease, Dr. Trushina uses live cell imaging assays and three-dimensional electron microscopy reconstruction. These techniques are like traffic cameras, following mitochondria as they move within nerve cells to match energy demand to energy supply.
“A motor neuron can have an axon that’s one meter long, and mitochondria have to travel from the cell body…to the distal parts of axons to dock at the sites of synapse, at the sites where energy’s needed…and then they have to travel all the way back to the cell body for repair or degradation,” explains Dr. Trushina, “so it’s quite a journey.”
Originally from Russia, Dr. Trushina first came to Mayo Clinic as a postdoc to study the molecular mechanisms of Huntington’s disease. Early on, she happened across a compound that had been earmarked to treat high cholesterol, and was struck by an idea: even though the compound didn’t work as a cholesterol drug, it did protect neurons from mis-timed cell death. Because mitochondria regulate cell death through an event termed mitochondrial outer membrane permeabilization (a.k.a., cell suicide), maybe, she thought, mitochondria could be a therapeutic target for neurodegenerative diseases.
After monitoring mitochondrial traffic for more than a decade, Dr. Trushina and her team have developed promising analogues of that original, neuroprotective compound. These small molecules not only reduce levels of the sticky amyloid beta peptides that build up to form plaques in the synapses between nerve cells in the brains of Alzheimer’s patients, they actually avert cognitive decline.
The symptoms of Alzheimer’s only reveal themselves when the disease has already caused irreversible damage. Clinicians need good methods to diagnose patients earlier, and effective treatments to keep amyloid plaques from getting a foothold. Working to meet these requirements, Dr. Trushina is profiling metabolites, searching out early biomarkers of mitochondrial dysfunction at the same time that she’s bringing Alzheimer’s drugs to clinical trials.
Because mitochondria play such important roles in our cells, their optimal function is foundational for health, while their dysfunction is associated with most chronic conditions, including aging. When it all comes down to it, “everything converges on mitochondria,” says Dr. Trushina.
To that end, Mayo Clinic has established the Mitochondrial Care Center, in which researchers and physicians work together to develop future therapies and care approaches for patients with mitochondrial conditions. In addition to the researchers in this article, the center includes co-directors Eduardo Chini, M.D.,Ph.D. and Ralitza Gavrilova, M.D.,as well as Ian Lanza, Ph.D. who focuses on mitochondrial physiology; Wolfdieter Springer, Ph.D., whose drug-target studies span several related diseases including Parkinson’s; and Joao Passos, Ph.D. who researches mitochondria and its relation to senescent cells and aging.
– Megan McKenzie, May 2019