Scientists have identified a faulty cellular pathway that may help explain why people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience such profound exhaustion, immune dysfunction, and crashes after exertion.
Researchers at Griffith University in Australia have found that an ion channel called TRPM3 appears to malfunction in specialized “natural killer” white blood cells. The fault disrupts the movement of calcium, an important cellular messenger, into mitochondria, the tiny structures that produce energy. The finding adds weight to the idea that ME/CFS is not simply a disorder of “fatigue,” but a complex biological illness.
“First, picture that NK [natural killer] cells are a house and that TRPM3 ion channels are doorways that allow calcium to enter this house,” Professor Sonya Marshall-Gradisnik and Dr Natalie Eaton-Fitch told Refractor. “Once inside, calcium acts as a messenger essential for numerous biological processes.”
ME/CFS is a disabling multisystem illness marked by severe exhaustion, post-exertional malaise, pain, cognitive problems, dizziness, sensory sensitivity and other symptoms that can seriously limit everyday life. There is currently no cure or approved treatment.
Although ME/CFS has often been misunderstood or dismissed, research has increasingly pointed to measurable biological changes. One recurring finding is impaired natural killer cell function. These immune cells depend on carefully controlled calcium signals to do their job, including producing immune-signaling molecules called cytokines and killing infected or abnormal cells.
The new study looked at whether previously reported mitochondrial problems in ME/CFS might be downstream of earlier faults in ion-channel and calcium signaling.
The researchers focused on TRPM3, a calcium-permeable ion channel found in natural killer cells and in tissues throughout the body, including the nervous system, gastrointestinal tract, cardiovascular system and musculoskeletal system. These broad locations are important because ME/CFS symptoms are also broad, affecting multiple body systems rather than a single organ.
When TRPM3 is activated, it helps calcium enter cells and move into internal compartments such as mitochondria. In healthy cells, that calcium movement helps coordinate immune-cell activity and supports the cell’s energy demands. In the new study, the researchers used advanced live-cell imaging to watch TRPM3-dependent calcium movement in real time in natural killer cells from 10 people with ME/CFS and 10 healthy controls.
The results showed that, compared with healthy controls, ME/CFS cells had significantly reduced TRPM3-dependent calcium movement into both the cell fluid and the mitochondria. In other words, when the researchers tried to activate this ‘doorway,’ the calcium signal did not flow normally.
“This investigation by Magawa et al. demonstrates potentially impaired mitochondrial calcium influx as a result of impaired SOCE/TRPM3 ion channel activity,” said Marshall-Gradisnik and Eaton-Fitch. “This data demonstrates that impaired TRPM3 ion channel activity may result in a reduced calcium uptake by mitochondria.”
The finding is key because mitochondria do more than simply make energy. They also help buffer calcium signals and support immune-cell activation. If calcium handling is disturbed, the result may be a messy downstream chain reaction of poor signaling, impaired immune-cell function, and potentially disturbed energy production.
That “potentially” is doing a bit of heavy lifting, however. The study did not directly measure ATP, the energy-carrying molecule produced by mitochondria. The researchers say that is the next step.
“It is important to highlight that this current investigation did not determine the downstream consequences of TRPM3 activity on mitochondrial energy production by measuring ATP,” said Marshall-Gradisnik and Eaton-Fitch. “This will be undertaken in the next series of experiments.”
One of the more intriguing findings was that, after the researchers depleted and then restored calcium stores in the cells, mitochondrial calcium influx was higher in ME/CFS cells than in controls. That might sound contradictory, given that TRPM3-triggered calcium movement was reduced. The researchers say it may point to poor calcium control rather than a simple ‘too much’ or ‘too little’ problem.
“The findings suggest that the restoration of calcium resulting [sic] in an increased influx into the mitochondria in ME/CFS compared with controls,” they said. “This may be a potential compensatory mechanism whereby the mitochondria may attempt to store additional calcium reserves, acknowledging here that NK cell activity, a known calcium-dependent process, is significantly impaired in people living with ME/CFS.”
But that compensation might come at a cost. The researchers noted that increased calcium entry into mitochondria raises the risk of calcium overload, which can be toxic to cells and may impair functions such as ATP production. When TRPM3 itself was then activated, calcium entry was reduced, again pointing to an impaired signaling cascade and poor calcium balance in ME/CFS natural killer cells.
The findings are early and based on a small cohort, but they add to the growing body of work suggesting that ME/CFS may involve ion-channel dysfunction. And, clinically, the work is not yet ready to diagnose or treat patients. For a potential biomarker to move into real-world use, it would need to show reliable sensitivity and specificity across larger cohorts and across other fatigue-related conditions. Marshall-Gradisnik and Eaton-Fitch said the team is already working through that process.
“A series of criteria are required to be fulfilled prior to clinical translation,” they said. “TRPM3 ion channel activity is the only potential biomarker to be investigated at multiple levels, being genetic (DNA), protein (expression) and function.”
The therapeutic side might also be worth watching. The researchers said previous work has shown that naltrexone, a prescription medication primarily used to treat opioid overdose, can restore TRPM3 ion-channel activity in natural killer cells from people with ME/CFS, and that a clinical trial is currently underway. They are also investigating other drug targets that may directly or indirectly influence ion-channel function.
Still, the study should not be read as proof that TRPM3 dysfunction causes all mitochondrial problems in ME/CFS, or that a treatment is imminent. The more careful interpretation is that it provides another piece of a very complicated biological puzzle.
“We know from a large body of research that ME/CFS is a multidimensional physiological condition and our research adds to the growing body of international research into the pathomechanisms of ME/CFS,” Marshall-Gradisnik and Eaton-Fitch said.
The researchers said the work provides a potential mechanistic link between TRPM3 activity, poor calcium movement within cells and downstream effects such as mitochondrial dysfunction, but added that more research is needed to validate the findings and determine whether TRPM3 dysfunction directly causes poor mitochondrial activity.
For people with ME/CFS, the key message is not that a cure is around the corner. It is that researchers are continuing to identify measurable cellular abnormalities in a condition too often reduced to tiredness or psychological distress. This study points to a possible biological chain reaction: faulty calcium ‘doorways,’ poor immune-cell signaling and mitochondria that may not receive the messages they need to work properly.
The study was published in the journal BMC Immunology.
Source: Griffith University
Fact-checked by Mike McRae
