MCT1 Identified as Gatekeeper of Cardiac Lactate Energy Pathway

A transporter protein called MCT1 keeps the heart fueled under stress by importing lactate directly into mitochondria, and deleting it in mice abolishes mitochondrial lactate oxidation, accelerates heart failure and raises mortality, according to a new study published in Nature by researchers at the University of Utah Health.

The paper, titled "MCT1-dependent mitochondrial lactate import sustains cardiac metabolism," resolves a long-standing puzzle in cardiac metabolism: how the heart burns two carbohydrate fuels at once. In most human tissues, consuming more glucose suppresses lactate use, and the reverse holds true as well. The heart breaks that rule, and the Utah team, led by assistant professor of biochemistry Gregory Ducker, PhD, has now identified the mechanism in experimental mice.

The answer lies in spatial separation inside the cell. Heart muscle oxidizes glucose in the cytosol while simultaneously oxidizing lactate inside the mitochondria. Because the two reactions occur in different compartments, neither fuel crowds out the other, and the heart can draw energy from whatever is available. "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.

What does MCT1 actually do?

MCT1 was traditionally understood as a plasma membrane transporter. The researchers found it in an unexpected location: the inner mitochondrial membrane of both mouse and human cardiomyocytes. There it shuttles lactate into the mitochondrial matrix, where it can be burned for energy.

Genetic mutations in MCT1 break this pipeline. "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 stated. The measured consequence in mice was not subtle — losing the transporter collapsed the heart's energy balance and shortened survival under stress.

The pathway appears largely dispensable in daily life. It becomes critical only when the heart is under strain. "This appears to be a critical backup system for heart function," Ducker said. "In an emergency, we would really, really rely on this."

Where does the therapeutic angle point?

The findings establish a new requirement for lactate as fuel for the injured heart and suggest targets for re-energizing cardiac muscle 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."

Co-senior author Stavros Drakos, MD, PhD, professor of medicine at University of Utah Health, framed the clinical logic in terms of waste reuse. "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," Drakos said. "By optimizing this process, we could potentially improve heart muscle function in patients suffering from heart failure or heart attacks."

How firm are the findings?

The core results come from laboratory work and mouse experiments, and the study reports MCT1 in the mitochondria of human cardiomyocytes as well, which strengthens the translational case. The authors' summary claim is broad but measured: "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 distance between mouse ablation experiments and a human therapy remains considerable. No compounds, trial timelines or dosing strategies appear in the study. What the work supplies is a mechanistic map — a named transporter, a defined compartment and a documented failure mode — that drug developers studying heart failure and post-infarction recovery can now build against.