Heart muscle appears to carry a backup fuel line: a transporter called MCT1 pipes lactate straight into the mitochondria of heart cells, and in mice that route kept hearts from failing under stress. A University of Utah team led by Gregory Ducker and Stavros Drakos reported the result in Nature on October 28. Mice engineered to lack the transporter in the heart were the ones that struggled, which is how the protective role was shown.
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The work was done in mice and in human heart tissue samples, and it points to a possible heart-failure target rather than a treatment.
A second door into the mitochondria
Most tissues cannot burn glucose and lactate at the same time. Heart muscle can, according to a summary of the Utah work, because it burns glucose in the cell’s cytosol while lactate is burned inside the mitochondria, and keeping the two jobs separated lets both run at once. MCT1 is the molecule that moves lactate across to the mitochondrial side. Ducker, a biochemistry professor at University of Utah Health and senior author, called it a critical backup system for heart function, one the organ would rely on heavily in an emergency.
The paper, published as “MCT1-dependent mitochondrial lactate import sustains cardiac metabolism” with A. A. Cluntun as first author, rests on earlier groundwork. A 2024 preprint from the same group, posted on bioRxiv, showed MCT1 sitting on the inner mitochondrial membrane of heart cells, not only on the outer cell surface where it is usually found, and confirmed it in mitochondria isolated from human hearts.
What happened when the shortcut was removed
The preprint describes the experiments in detail, and the published version may differ in places. Using mice in which MCT1 could be deleted from the heart on demand, the researchers found that lactate-derived labeling of the cycle that feeds mitochondrial energy production fell, while glucose-derived labeling did not change. Young knockout mice looked normal: no structural or functional abnormalities by one year of age and no change in exercise capacity. The weakness only appeared under load.
When the hearts were stressed, either with angiotensin II and phenylephrine infusions or by surgically narrowing the aorta, the knockout mice developed more pronounced thickening of the heart muscle and a faster decline in ejection fraction, the share of blood pumped out with each beat. After ischemia-reperfusion injury, which mimics a heart attack, their hearts showed larger areas of dead tissue, and while normal mice recovered pumping function by about seven weeks, the knockouts did not recover over the study period. Failing knockout hearts also had elevated NADH and depleted ADP and other purine nucleotides, a chemical signature of mitochondria that cannot keep up.
The preprint also tested a drug. Hearts lacking Mpc1, the gene for the mitochondrial pyruvate carrier, still oxidized glucose carbon, and the MCT1 inhibitor AZD3965 blocked that oxidation only in the Mpc1-knockout animals, indicating that MCT1 acts as a redundant route for carbohydrate entry into mitochondria. A third group of mice lacking MCT4, a lactate exporter, served as a comparison. The authors propose that importing lactate lets its carbon feed the cycle without disturbing the redox balance in the cytosol, where glucose is being burned at the same time.
From mouse hearts to a drug target
The same project, which the NIH funds through a grant to Ducker listed on a research-project page, reports that human heart samples from people with heart failure carried more MCT1 in their mitochondria. That suggests failing hearts lean harder on the route, but the tissue came through the Utah Cardiac Recovery Program, and the animal work was approved by the university’s animal-care committee. It is an observation in tissue, not evidence that boosting it helps a patient.
Drakos, a professor of medicine at University of Utah Health and co-senior author, said the findings suggest it may be possible to enhance the heart’s ability to use lactate as a valuable energy source. His lab studies cardiac recovery in heart failure, including through the Utah Cardiac Recovery Program, and previous work there linked loss of the mitochondrial pyruvate carrier to hypertrophy and heart failure. Drakos’s lab previously reported that expression of the pyruvate carrier rises alongside recovery in heart-failure patients supported by a mechanical pump, and that inhibiting MCT4 reduced thickening of the heart in cells and mice. Both researchers describe lactate use and MCT1 as potential therapeutic targets for heart failure and heart attack.
The distance to a therapy is long. Everything described here was shown in mice or in tissue samples, and no experiment tested whether raising MCT1 activity protects a failing heart. The funders are the National Institutes of Health, the Department of Veterans Affairs, the American Heart Association and the Burroughs Wellcome Fund, and the open question for the next round of experiments is whether the route can be turned up, rather than only shown to matter when it is removed.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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