How the Heart Stays Strong with MCT1-Dependent Mitochondrial Lactate Import

Maintaining energy flow to the heart is a complex process which can break down during common but severe cardiovascular disease conditions such as heart failure. Researchers previously knew that heart muscle seems to do an unusual metabolic trick to always get enough energy, which is using two carbohydrate energy sources—glucose and lactate—at the same time.

In most human tissues, using more glucose makes it harder to use lactate, and vice versa, but the heart is different. Working with experimental mice, scientists headed by a team at the University of Utah have now found a unique cell-level difference that helps keep heart muscle fueled up, which is the ability to burn glucose in the cell cytosol while burning lactate in the mitochondria. This spatial separation allows both energy-generating reactions to happen simultaneously, helping keep the heart fueled up no matter the energy source.

While mostly dispensable to daily life, this process is crucial to preventing heart failure when the heart is stressed. “This appears to be a critical backup system for heart function,” says Gregory Ducker, PhD, assistant professor of biochemistry at University of Utah Health. “In an emergency, we would really, really rely on this.”

The findings could point to new potential therapeutic strategies for some serious heart disorders. Ducker is senior author of the researchers’ published paper in Nature, titled “MCT1-dependent mitochondrial lactate import sustains cardiac metabolism,” in which they stated, “Thus, the existence of a parallel lactate-based pathway for carbohydrate oxidation can sustain cardiac energetics and maintain myocardial structure and function under diverse stress conditions.”

The heart is the hardest-working muscle in the body, beating constantly no matter what the body’s energy reserves look like. The heart’s energy demands can be met through the use of both glucose and lactate as fuel. “The heart possesses a dynamic capacity to oxidize a variety of fuels, including glucose and lactate, to meet its energetic demands under diverse dietary, exertion, and injury stressors,” the authors wrote.

Laboratory work and experiments in mice reported by Ducker and colleagues now suggest how the heart can use both fuel sources at the same time. Their research found that the separation between glucose and lactate metabolism depends on a molecule called MCT1, which moves lactate to the inside of the mitochondria. “We further observe that MCT1, traditionally localized to the plasma membrane, also resides in the inner mitochondrial membrane of mouse and human cardiomyocytes,” they wrote. Genetic mutations in MCT1 prevent lactate from entering the mitochondria and disrupt the heart’s energy balance, leading to heart failure when stressed. “Genetic ablation of MCT1 abolishes mitochondrial lactate oxidation, disrupts adaptation to neurohormonal, hemodynamic or ischemic stress and accelerates the development of heart failure with enhanced mortality,” the investigators further stated.

These results uncover a new requirement for lactate to fuel the injured heart and suggest new therapeutic targets to re-energize the heart during heart failure. “Our findings help point to new areas in which we could target the heart muscle to benefit and repair itself by allowing it to use lactate better,” Ducker said. “That’s the long-term goal: to help the heart muscle heal.”

The discovery of a new pathway through which the heart muscle can use lactate to generate energy opens promising opportunities for developing new treatments for serious heart conditions, including heart failure and heart attacks.

“Rather than simply releasing lactate into the bloodstream as a waste product, we may be able to enhance the heart’s ability to use it as a valuable source of energy,” says Stavros Drakos, MD, PhD, Professor of Medicine at University of Utah Health and co-senior author of the study. “By optimizing this process, we could potentially improve heart muscle function in patients suffering from heart failure or heart attacks.”

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