Scientist brings expertise on ‘subcellular soul’ to Center for Innovation in Brain Science

Meagan J. McManus, PhD, is definitely a “glass is half-full” kind of person.

“I can’t turn it off,” McManus said of her ever-present optimism.

Which is the best attitude to have if you’re a researcher since grant proposals get rejected, journal submissions get denied and hypotheses turn out to be wrong.

“As a scientist, you sign up for a life of rejection,” said McManus, an associate professor of pharmacology at the University of Arizona College of Medicine – Tucson and a researcher with the Center for Innovation in Brain Science.

That doesn’t faze her, though, thanks to the growth mindset her parents instilled in her and her older sister.

“We were always taught that everything is working together for good, and I feel that especially in science,” McManus said. “I learn best from failure. A failed hypothesis is pointing you to a greater truth.”

Joining the team

McManus is new to the U of A. Though she’s only been in Tucson a handful of months, she has already discovered the beauty of Sabino Canyon and the distinct signature scent of the Southwest.

“Everything smells better in the desert,” said McManus, who spent 15 years in Philadelphia before Roberta Diaz Brinton, PhD, the inaugural director of the center and a Regents Professor of Pharmacology at the U of A College of Medicine – Tucson, persuaded her to move west.

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The two bonded over lunch at a neuroscience conference, finding common ground in their shared passions for mitochondria, women’s brain health… and chips, McManus said with a laugh.

Brinton, an internationally recognized leader in Alzheimer’s research and aging, created the center, a hybrid academic-biotech research unit dedicated to developing cures for age-associated neurodegenerative diseases. McManus’s research dovetails with Brinton’s work, focusing on mitochondrial resilience in brain aging.

McManus’s lab developed probes for positron emission tomography that are able to track distress signals from mitochondria. The development could identify who is vulnerable to diseases like Alzheimer’s and Parkinson’s long before symptoms appear.

“If we can detect who’s at risk early, we can identify people who will benefit most from mitochondrial treatments,” McManus explained. “Many past mito therapies likely failed because we only treated patients after their neurons were damaged and symptoms emerged. If we can catch the problem sooner, we have a real chance to protect the mitochondria and preserve brain function in aging.”

And that’s something to be excited and optimistic about. 

More than the powerhouse

In case you need a quick Biology 101 refresher on mitochondria: they generate the energy needed for life, but they’re much more than powerhouses. Along with producing over 90% of our bodies’ adenosine triphosphate, or ATP, mitochondria manage everything from body heat generation and calcium buffering to synthesizing vital hormones, like cortisol and estrogen. McManus likens mitochondria to the motherboard of a cell. 

“They’re like the subcellular soul,” she said.

Everything in your environment — psychological stress, electromagnetic fields, temperature, nutrition and toxins — is monitored and interpreted by mitochondria, which then respond by altering the nucleus to optimize cellular survival. 

And in McManus’s case, they even altered her career path.

A new calling

McManus, who was born and raised in Albany, Georgia, was on track to work in naturopathic medicine and plant-derived pharmaceuticals. After college graduation, she planned to run the medicinal plant section of the University of Georgia’s new ecology center in Costa Rica during a gap year before heading to medical school. Instead, her father, a medicinal chemist, urged her to check out the pharmacology department. It was in Jim Franklin’s neuroscience lab, studying the role of mitochondria in neuronal cell death, where McManus’s professional life changed. 

The more McManus learned, the more she was hooked.

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“I got excited because everything started to click,” McManus said. “If energy is life, we are only as healthy as our mitochondria. The brain is the most energetically demanding organ, so when our mitochondria fail with aging, the brain suffers first and we become more vulnerable to neurodegenerative disease.”

After designing a project focused on neurodegenerative disease that showed how mitochondria-targeted therapeutics could prevent Alzheimer’s in mice, she met and started working alongside her scientific hero-turned-mentor Douglas C. Wallace, a geneticist and evolutionary biologist considered one of the founders of the field of human mitochondrial genetics. In fact, Wallace, the director of the Center for Mitochondrial and Epigenomic Medicine at Children’s Hospital of Philadelphia, was the first to show that mutations in mitochondrial DNA can cause human disease. 

“Doug Wallace has been studying this for decades,” McManus said. “He had the insight to see that mitochondria were playing a critical role in every chronic disease long before the rest of us caught up.”

While McManus works to staff her new U of A lab, she’s hoping to start running some clinical trials. First, funding needs to be secured, which is never easy. McManus, of course, can’t help but focus on the positive and how far the research has come. 

“It's beautiful to see mitochondria gaining new appreciation, and I think that's largely due to recent technological advances,” she said. “We’re finally able to track mitochondria in the living brain now, and that's going to open so many new opportunities for preventative medicine. It’s a really exciting time to be a mitochondriac.”