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Half a century after its initial discovery, researchers have now elucidated the functioning of a crucial molecular machine located within mitochondria, the cellular organelles often referred to as the ‘powerhouses’ of the cell. This mechanism allows for the conversion of sugars into essential fuel, a process fundamental to life on Earth.
Scientists from the Medical Research Council (MRC) Mitochondrial Biology Unit at the University of Cambridge have characterized the structure of this molecular transporter, revealing its function as a lock that facilitates the movement of pyruvate—a byproduct of sugar metabolism—into mitochondria.
Identified as the mitochondrial pyruvate carrier, this significant molecular entity was first theorized in 1971. However, it has taken until now for researchers to visualize its atomic structure using cryo-electron microscopy, a sophisticated imaging technique that magnifies objects to approximately 165,000 times their actual size. The groundbreaking findings have been published in Science Advances.
Dr. Sotiria Tavoulari, a Senior Research Associate at the University of Cambridge and one of the first to decipher the carrier’s composition, explained, “The sugars we consume are the primary source of energy for bodily functions. Once broken down, they generate pyruvate. To maximize the energy yield from pyruvate, it must be delivered into the mitochondria, where it enhances energy production significantly, boosting the synthesis of adenosine triphosphate (ATP) by up to 15 times.”
Maximilian Sichrovsky, a PhD student at Hughes Hall and co-first author of the study, added, “While it may seem simple to transport pyruvate into mitochondria, the mechanisms underlying this process remained elusive until now. Through advanced cryo-electron microscopy, we have not only visualized the transporter but also clarified its operational dynamics. This understanding is critical and may pave the way for new therapeutic interventions across a spectrum of medical conditions.”
Mitochondria consist of two membranes: an outer membrane that is porous, allowing pyruvate to pass through effortlessly, and an inner membrane that is impermeable to pyruvate. To transport pyruvate into the mitochondrion, the carrier first opens an outer gate to let the pyruvate in, subsequently closing before opening an inner gate that allows the pyruvate to enter the mitochondrial space.
Professor Edmund Kunji from the MRC Mitochondrial Biology Unit likened the process to the functioning of canal locks on a molecular level: “The mechanism is comparable to a lock on a canal. A gate opens to let a boat in, then closes before opening another gate for the boat to continue its journey smoothly.”
This carrier’s vital role in mitochondrial energy production confirms its potential as a target for drug development in various health issues, including diabetes, fatty liver disease, Parkinson’s disease, certain cancers, and even hair loss.
While pyruvate serves as a key energy source, cells are also capable of deriving energy from fats and amino acids. Inhibiting the pyruvate carrier could force the body to seek alternative energy supplies, offering new avenues for treating certain ailments. For instance, in fatty liver disease, obstructing pyruvate’s entry into mitochondria might prompt the body to metabolize excess fat stored in liver cells, which can be harmful.
Moreover, certain cancer cells, particularly in specific prostate tumors, exhibit a strong reliance on pyruvate metabolism. These cells often produce increased numbers of pyruvate transporters to meet their energy demands. Targeting the carrier could starve these tumors of the energy necessary for their proliferation.
Earlier research has also hinted that blocking the mitochondrial pyruvate carrier may reverse hair loss. The metabolic activation required for hair follicle growth depends on lactate production. In circumstances where the mitochondrial pyruvate carrier is inhibited, pyruvate is redirected to lactate formation instead.
Professor Kunji remarked on the implications of this research: “Drugs that inhibit the carrier’s function could fundamentally alter mitochondrial operations, potentially benefiting various conditions. With electron microscopy, we can visualize precisely how these drugs interact within the carrier, acting like a ‘wrench’ that disrupts its normal function. This opens new horizons for structure-based drug design aimed at developing improved, targeted therapies, which could significantly impact treatment strategies.”
This research was made possible through support from the Medical Research Council and involved collaborations with experts from the Medical College of Wisconsin, the National Institutes of Health, and the Free University of Brussels.
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