Cystic fibrosis (CF) is a genetic disease that affects organs like the lungs, pancreas, and liver by disrupting the flow of salt and water across cell membranes. Adenosine triphosphate (ATP), the body’s energy currency, is central to nearly all cellular processes, including the function of the defective CF protein. Understanding the relationship between ATP production and CF pathology is important. Researchers now consider how the overall energy supply within cells influences the disease’s severity, moving beyond viewing CF solely as a channel defect.
The Basics of Cystic Fibrosis and the CFTR Protein
CF is caused by mutations in the CFTR gene, which makes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein is a chloride ion channel embedded in the outer membrane of epithelial cells lining various passages, such as those in the lungs and digestive tract. The primary function of CFTR is to regulate the transport of chloride ions and, indirectly, water across these cell membranes.
When the CFTR protein is functional, it allows chloride ions to move out of the cell, which helps to draw water onto the cell surface, creating a thin, slippery layer of mucus. In people with CF, a defective CFTR protein either does not reach the cell surface, is not produced in sufficient quantities, or does not open correctly.
This malfunction traps chloride ions inside the cell, causing insufficient water to hydrate the surface. The resulting dehydrated mucus becomes thick and sticky, which clogs the airways and ducts, leading to the characteristic symptoms of lung infections, breathing difficulties, and digestive problems.
ATP’s Role in CFTR Channel Function
The CFTR protein belongs to a family of molecules known as ATP-binding cassette (ABC) transporters. Unlike most other ABC transporters that actively pump substances across a membrane, CFTR functions as a gate, or channel, for chloride ions. However, its operation remains entirely dependent on ATP, making it an ATP-gated anion channel.
The CFTR channel is structured with two nucleotide-binding domains (NBDs), NBD1 and NBD2, which are the sites where ATP physically interacts with the protein. For the channel to open and allow chloride to pass through, ATP must bind to these domains. This binding event causes the two NBDs to come together in a “head-to-tail” formation, which transmits a conformational change that physically opens the channel pore.
Channel closure is triggered by the subsequent hydrolysis of the bound ATP into adenosine diphosphate (ADP) and inorganic phosphate. This cycle of ATP binding (opening) and hydrolysis (closing) regulates the channel’s gating cycle. Therefore, a CFTR protein that reaches the cell surface requires a constant supply of ATP to function as an effective gate for ion transport.
Mitochondrial Dysfunction and Altered Cellular Energy Supply
While the direct use of ATP to power the CFTR channel is well-established, research focuses on the cellular machinery responsible for generating ATP: the mitochondria. Mitochondria produce the vast majority of the cell’s energy through oxidative phosphorylation. Studies show that cells lacking functional CFTR exhibit mitochondrial dysfunction, meaning these cellular powerhouses are compromised.
In cells derived from people with CF, researchers observe reduced efficiency in the mitochondrial electron transport chain, specifically with decreased activity in Complex I and Complex IV. This impairment limits the cell’s capacity for oxidative phosphorylation, resulting in a quantifiable reduction in the overall production of ATP. This energy deficit is reflected in an elevated ratio of ADP to ATP within the mitochondria, indicating a failure to efficiently convert stored energy into usable fuel.
This bioenergetic stress suggests that the problem in CF cells is not just a faulty chloride channel, but also a generalized energy crisis affecting multiple cellular functions. The CFTR defect appears to exert a detrimental influence on mitochondria, either through direct interaction or by disrupting cellular signaling pathways. This compromise in energy production further compounds the issue of the defective CFTR channel that requires energy to work.
How Bioenergetic Changes Exacerbate CF Symptoms
Chronic energy deprivation and mitochondrial dysfunction directly contribute to the severity of CF symptoms, moving beyond the simple effect of thick mucus. A damaging consequence of impaired mitochondrial function is the increased generation of reactive oxygen species (ROS), unstable molecules that cause cellular damage. This heightened ROS production overwhelms the cell’s natural defenses, leading to chronic oxidative stress.
Oxidative stress and energy deficit impair the ability of immune cells, such as neutrophils and macrophages, to function properly and clear bacteria from the lungs. The inability of the immune system to effectively combat pathogens trapped in the thick mucus leads to persistent, chronic infections, which are the main cause of lung damage in CF.
Furthermore, the energy-deprived state means cells have less ATP for energy-intensive tasks like tissue repair and regulating the inflammatory response. This results in prolonged and excessive inflammation.
The cycle of infection, inflammation, and reduced cellular energy creates a self-perpetuating system that drives the destruction and scarring of lung tissue. Impaired ATP production stemming from mitochondrial dysfunction acts as a co-factor, transforming the initial CFTR defect into a life-threatening, multi-organ disease. Therapeutics that improve mitochondrial health and cellular bioenergetics may offer a path to slow the progression of symptoms independent of the CFTR protein itself.