Early mitochondrial stress reveals potential mechanism for lasting heart protection

Mitochondria are popularly known as the “powerhouse of the cell,” but these cellular structures do much more—including acting as signaling hubs. Some signals that mitochondria send can reprogram the activity of the entire cell by switching “on” or “off” different genes through epigenetic changes. Mitochondria’s signals can be so effective that, in yeast, fruit flies and worms, mild stress in mitochondria early in life can make the entire organism more resilient and live longer through a process called mitohormesis.

A new Salk Institute study asks how mitohormesis works in cells and mice. The authors found that inducing mitochondrial reactive oxygen species (ROS)—byproducts of mitochondria’s energetic function—only during mouse embryonic development is cardioprotective.

They then uncovered the molecular mechanism behind this lasting effect: Stressed mitochondria release citrate, initiating a cascade of downstream events that leads to long-term epigenetic changes promoting beneficial mitohormetic adaptations.

The study, published in Science Advances, suggests that mitohormetic signaling may be a powerful therapeutic target to stave off heart and other age-related tissue pathology and perhaps even promote healthy aging.

What do we know about mitohormesis?

“Mitohormesis has a rich history in model organisms used to study longevity mechanisms in the aging research field, with other researchers and us finding that—paradoxically—mitochondrial stress, which is usually considered detrimental to health, can actually extend lifespan and have other benefits,” says senior author Gerald Shadel, Ph.D., professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk.

At high levels, mitochondrial ROS can damage both mitochondria and the cells they inhabit. Consequently, mitochondria have developed antioxidant systems to neutralize these species. However, at lower levels, ROS are essential signaling molecules.

In 2018, following earlier observations in yeast that ROS-mediated mitohormesis extends lifespan, Shadel’s lab demonstrated mitohormesis in mammals, using a mouse strain the researchers developed in which a mitochondrial antioxidant enzyme can be reversibly inhibited.

The study analyzed mouse livers, finding that a small amount of mitochondrial stress during embryonic development led the mice to have more mitochondria later in life. Crucially, these mitochondria also produced fewer ROS, and the liver had activated several of its cellular antioxidant systems.

Their new study uses the same approach—this time moving from analyzing the liver to probing beneficial effects on the heart.

How does mitohormesis work?

“As an MD/Ph.D. student, I am always looking to connect foundational biological processes with human disease, and I have been especially interested in the ties between mitochondrial and cardiovascular health,” says first author Matthew Donnelly, a graduate student researcher in Shadel’s lab. “To that end, we decided to test whether mitohormesis would protect against a heart failure model in mice—and we found that it does.”

The team repeated their 2018 experiment: knocking down the mitochondrial antioxidant system when the mice were in embryonic development, then restoring it before birth. The mice then grew into adulthood before being treated with doxorubicin, a chemotherapy drug with known mitochondria-damaging side effects that can induce heart failure.

Mice that endured embryonic mitochondrial stress were protected from doxorubicin’s cardiac toxicity. The researchers then investigated the mechanisms behind this cardioprotective effect.

This mechanistic question prompted the team to move from studying mice to mouse embryonic fibroblasts. With these cells, they repeated their protocol of blocking the mitochondrial antioxidant system to induce mitohormesis.

The researchers found that this led to the accumulation of the ROS called superoxide, which, in turn, inhibited a key enzyme in the energy production process, disrupting a chain of chemical reactions and causing citrate to accumulate.

Citrate then left the mitochondria and was converted to acetyl-CoA, a molecule that helps enact epigenetic change; in this case, the epigenetic changes drove long-lasting cellular protection and resilience to future stress.

Could mitohormesis-based interventions promote healthy aging?

The findings reveal an unappreciated aspect of mitochondrial ROS signaling, which may help explain the shortcomings of antioxidant therapeutics and illuminate a promising future for mitohormetic therapies. Superoxide has long been overlooked as a mitochondrial ROS capable of signaling because it is unable to leave the mitochondria on its own.

Uncovering that citrate acts as a “second messenger” for superoxide accumulation has important implications for how mitochondria signal to the rest of the cell and could inform antioxidant therapeutic approaches.

“Antioxidant therapies have been developed to mitigate damaging effects of ROS, but they have largely failed in clinical trials,” says Shadel.

“A better therapeutic approach than just targeting one reactive oxygen species at a time might be to enact a more nuanced global program like mitohormesis that affects both mitochondria and several antioxidant systems simultaneously. Hopefully our findings will spur the development of more effective alternatives in the future.”

Since mitohormesis delays aging and extends lifespan in model organisms, the study also sets the stage for future research into how mitohormesis affects healthy aging.

Future studies could explore whether inducing mitohormesis after embryonic development or with citrate can delay aging in mammals by globally protecting tissues and organs against age-related declines and whether these findings extend beyond mice into more human-relevant tissue models.

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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