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, often referred to as the cell's powerhouse, play a more significant role than just energy production. They function as signaling hubs, capable of reprogramming cellular activity through epigenetic changes. Mild mitochondrial stress during early life in organisms like yeast, fruit flies, and worms can lead to increased resilience and longevity—a phenomenon known as mitohormesis.
In a recent study conducted at the Salk Institute, researchers explored how mitohormesis works in cells and mice. They discovered that inducing mitochondrial reactive oxygen species (ROS) only during embryonic development in mice provides cardioprotective benefits. The mechanism behind this protective effect involves the release of citrate from stressed mitochondria, which initiates a cascade of events leading to long-term epigenetic changes that promote beneficial adaptations.
The study, published in Science Advances, suggests that mitohormesis could be a powerful therapeutic target for preventing heart and other age-related tissue pathology, potentially even promoting healthy aging. However, high levels of mitochondrial ROS are typically damaging, which is why mitochondria have evolved antioxidant systems to neutralize these species. At lower levels, however, ROS act as essential signaling molecules.
The research team, led by senior author Gerald Shadel, found that a small amount of mitochondrial stress during embryonic development in mice led to an increase in the number of mitochondria later in life. Crucially, these mitochondria produced fewer ROS, and the liver had activated several cellular antioxidant systems. When the mice were later treated with a chemotherapy drug known to cause heart failure, those that had endured embryonic mitochondrial stress were protected from the drug's cardiac toxicity.
To understand the mechanism behind this cardioprotective effect, the researchers studied mouse embryonic fibroblasts. They induced mitohormesis by blocking the mitochondrial antioxidant system, leading to an accumulation of superoxide, a type of ROS. This superoxide inhibited a key enzyme in the energy production process, causing citrate to accumulate.
Citrate then left the mitochondria and was converted to acetyl-CoA, a molecule that triggers epigenetic changes, resulting in long-lasting cellular protection and resilience to future stress.
This discovery sheds new light on the previously overlooked role of superoxide as a mitochondrial ROS capable of signaling. Understanding how citrate acts as a second messenger for superoxide accumulation could inform the development of more effective antioxidant therapeutics, moving beyond the limitations of current treatments.
The findings also open the door for future research into how mitohormesis affects healthy aging and whether inducing mitohormesis after embryonic development or with citrate can delay aging in more human-relevant tissue models.
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