The preprint of (1)
Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights
have supplemental tables which show increased and decreased levels of proteins in serum from ME/CFS patients.
I selected some proteins and asked artificial intelligence AI what it meant.
I used artificial intelligence (AI) via https://www.google.com/ to get some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information.
Me: What is the function af EIF1AY, EIF1B, EIF2S1, EIF2S2, EIF3B, EIF4A2, EIF4B, EIF4E and EIF4G2?
AI: The proteins encoded by the genes you listed are all eukaryotic translation initiation factors (eIFs), which play essential roles in the process of protein synthesis, specifically in the initial phase (translation initiation).
Here are the specific functions of each:
EIF1AY (Eukaryotic translation initiation factor 1A, Y-linked): Encodes the Y-chromosome isoform of eIF1A. It is a key component of the 43S pre-initiation complex (PIC) and helps stabilize the binding of mRNA to the 40S ribosomal subunit. It, along with EIF1, facilitates scanning of the mRNA to locate the correct start codon (AUG) and promotes the assembly of the 48S complex.
- EIF1B (Eukaryotic translation initiation factor 1B): Involved in the assembly of the ribosomal pre-initiation complex and accurate start codon recognition, ensuring that translation begins at the correct location on the mRNA. It is a paralog of EIF1 and may have some functional redundancy with it.
- EIF2S1 (Eukaryotic translation initiation factor 2 subunit alpha): The alpha subunit of the EIF2 complex. EIF2 forms a ternary complex with GTP and the initiator Met-tRNA, which then binds to the 40S ribosomal subunit. The phosphorylation state of EIF2S1 is a critical regulatory point for general protein synthesis, allowing the cell to respond to various stresses (e.g., amino acid starvation, ER stress) by globally inhibiting translation while selectively promoting the translation of specific stress-response mRNAs.
- EIF2S2 (Eukaryotic translation initiation factor 2 subunit beta): The beta subunit of the EIF2 complex. It plays a critical role in the regulation and function of EIF2, specifically by catalyzing the exchange of GDP for GTP, which is necessary to recycle the EIF2 complex for subsequent rounds of translation initiation.
- EIF3B (Eukaryotic translation initiation factor 3 subunit B): EIF3 is a large complex that interacts with both mRNA and other eIFs (like EIF4G) to promote the association of the 43S initiation complex with the mRNA cap structure. EIF3B is one of the many subunits of this complex.
- EIF4A2 (Eukaryotic translation initiation factor 4A2): A member of the EIF4A family of ATP-dependent RNA helicases, which are part of the EIF4F complex. It is responsible for unwinding secondary structures in the 5' untranslated region of the mRNA to facilitate ribosome scanning.
- EIF4B (Eukaryotic translation initiation factor 4B): Binds to mRNA and enhances the RNA helicase activity of EIF4A, aiding in the unwinding of mRNA secondary structures to promote efficient translation initiation.
- EIF4E (Eukaryotic translation initiation factor 4E): The cap-binding protein subunit of the EIF4F complex. It recognizes and binds to the 5' m7G cap structure of mRNA, a crucial step for the recruitment of the ribosome to the mRNA.
- EIF4G2 (Eukaryotic translation initiation factor 4G2): Also known as DAP5, it is a scaffold protein in the EIF4F complex, linking EIF4E (at the cap) and EIF4A, and interacting with other factors like PABP to form a closed-loop mRNA structure. Unlike its paralog EIF4G1, EIF4G2 functions as a general repressor of translation in some contexts.
Me: What is the cause of decreased levels of EIF1AY, EIF1B, EIF2S1, EIF2S2, EIF3B, EIF4A2, EIF4B, EIF4E and EIF4G2 in serum from ME/CFS patients in the study "Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights"?
AI: The study "Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights" observed decreased levels of several eukaryotic translation initiation factors (EIFs) in the serum of ME/CFS patients, which the researchers interpret as a potential indication of generalized downregulation of protein synthesis or a hypometabolic state.
The precise, singular "cause" of these decreased circulating levels within the context of the study's findings is not fully established as a direct mechanism (e.g., a single genetic mutation or exposure). Instead, the study posits that these reduced levels are likely a consequence of the underlying disease pathology, which may involve:
- Systemic Energy Deficiency: ME/CFS is often characterized by significant energy impairment. A broad reduction in translation factors in circulation may reflect a cellular effort to conserve energy by globally reducing the energetically expensive process of protein production across many tissues in the body.
- A "Metabolic Trap": Some theories suggest that cells in ME/CFS patients enter a state of hypometabolism or a "metabolic trap" where key processes, including protein synthesis, are downregulated or stalled. The observed serum protein profile would be consistent with this systemic reduction in cellular activity.
The study used proteomics to identify these changes as biomarkers and mechanistic insights, suggesting a systemic issue with how patients' bodies manage energy and cellular processes, rather than identifying a singular upstream cause for the low EIF levels themselves.
Me: Can you put decreased ME/CFS serum levels of LONP1 into the context?
AI: Decreased serum levels of LONP1 (Lon peptidase 1, mitochondrial) fit within the context of the other decreased protein synthesis components as a key indicator of widespread mitochondrial dysfunction and a potential driver of the systemic metabolic stress seen in ME/CFS patients.
Here is how LONP1 connects these observations:
Function of LONP1
LONP1 is a crucial, multi-functional protein located primarily within the mitochondrial matrix. It acts as:
- An ATP-dependent protease that degrades misfolded, oxidized, or otherwise damaged proteins inside the mitochondria, thereby maintaining protein quality control.
- A chaperone that helps properly fold newly imported mitochondrial proteins and facilitates the assembly of functional protein complexes, including those involved in the respiratory chain.
- A DNA-binding protein that interacts with mitochondrial DNA (mtDNA) and regulates its copy number and transcription by degrading the transcription factor TFAM when it is not bound to DNA.
Context in ME/CFS
The simultaneous decrease in circulating EIFs (translation initiation factors), aaRSs (aminoacyl-tRNA synthetases), and LONP1 points to a comprehensive failure in the body's ability to produce, maintain, and regulate proteins, particularly within the energy-producing mitochondria:
- Mitochondrial Quality Control Failure: Lower levels of LONP1 mean that damaged or misfolded proteins within the mitochondria likely accumulate. This directly impairs the function of the respiratory chain complexes (which generate ATP) and disrupts mitochondrial homeostasis.
- Impaired Protein Synthesis Loop: The observed reduction in EIFs and aaRSs indicates a problem with the cytoplasmic machinery that initiates protein synthesis and charges tRNAs. Because LONP1 is essential for the maturation and regulation of several mitochondrially-encoded proteins (which are crucial subunits of the respiratory complexes), its decrease exacerbates this problem from within the mitochondria.
- Metabolic Feedback Loop and Stress Response: A decline in mitochondrial function and the accumulation of damaged mitochondrial proteins (due to low LONP1) trigger the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt). This stress signaling pathway further contributes to the global downregulation of cytosolic protein synthesis, including the EIFs and aaRSs, to conserve energy.
- Systemic Energy Deficit: The entire pattern suggests a deep, systemic energy deficiency. Cells in ME/CFS patients appear unable to maintain the high metabolic activity required for normal protein turnover and synthesis, reflecting a broader "hypometabolic state" where the body powers down essential processes to survive, leading to the low levels of all these related proteins in the serum.
In essence, decreased LONP1 levels in ME/CFS serum serve as a significant indicator of core mitochondrial dysfunction that likely contributes to the fatigue and post-exertional malaise symptoms characteristic of the disease.
Me: Can you put increased ME/CFS serum levels of GLUD1, MRM1, NIF3L1, RIDA and UNG into the context?
The increased levels of GLUD1, MRM1, NIF3L1, RIDA, and UNG in the serum of ME/CFS patients, as observed in the mentioned study, provide context for the body's stress response to the underlying metabolic dysfunction and mitochondrial issues.
Unlike the decreased levels of protein synthesis components (EIFs, aaRSs, LONP1), which suggest a broad metabolic slowdown, the increased levels of these specific proteins point toward cells attempting to compensate, repair damage, or manage severe oxidative stress and metabolic bottlenecks.
Here is how these increased proteins fit into the ME/CFS context:
1. GLUD1 (Glutamate dehydrogenase 1)
GLUD1 is a mitochondrial enzyme that converts glutamate to alpha-ketoglutarate, a key intermediate in the Citric Acid (TCA) cycle for energy production.
- Context: Increased GLUD1 levels suggest the body is attempting to drive fuel into the TCA cycle using amino acids (glutamate) as an alternative energy source to compensate for impaired carbohydrate or fatty acid metabolism, a common finding in ME/CFS. It indicates a metabolic shift to try and maintain ATP production.
2. MRM1 (Mitochondrial RNA methyltransferase 1)
MRM1 is involved in modifying mitochondrial ribosomal RNA, which is essential for the function of the mitochondrial ribosome and the synthesis of proteins within the mitochondria.
- Context: Increased MRM1 levels could be a compensatory response to the observed mitochondrial stress and the decreased levels of other mitochondrial components (like LONP1). The cell may be trying to boost the efficiency of the remaining mitochondrial protein synthesis machinery to counteract the general dysfunction.
3. NIF3L1 (Noc-like protein NIF3L1)
NIF3L1 is an evolutionarily conserved protein with roles in regulating the cell cycle and potentially acting as a stress response protein.
- Context: Its increased presence suggests a general cellular stress response. It may play a role in sensing the metabolic distress or activating pathways that arrest the cell cycle to prevent division during energy crises or high oxidative stress.
4. RIDA (Reactive intermediate deaminase A)
RIDA is a housekeeping enzyme that prevents the accumulation of toxic reactive intermediates in metabolic pathways. It helps mitigate stress caused by certain metabolic byproducts.
- Context: The elevation of RIDA suggests an increased level of oxidative stress or the production of toxic metabolic intermediates in ME/CFS patients. The body may be upregulating this enzyme as a defensive measure to detoxify the cell and minimize damage caused by the disrupted metabolism.
5. UNG (Uracil-DNA glycosylase)
UNG is a critical enzyme in DNA base excision repair, responsible for removing misincorporated uracil from DNA, thus protecting genome integrity.
- Context: Increased UNG levels strongly indicate elevated DNA damage within the cells, likely due to the high levels of reactive oxygen species (ROS) and oxidative stress observed in ME/CFS patients. The body increases UNG to try and repair this damage and maintain genomic stability.
Overall Context: A Tipping Point of Stress
Taken together, the profile presents a complex picture:
- Decreased Proteins: Indicate a hypometabolic state and system-wide energy conservation/shutdown of expensive processes like bulk protein synthesis.
- Increased Proteins: Indicate an active, yet potentially overwhelmed, stress response characterized by:
- Attempted compensation via alternative fuel sources (GLUD1).
- Efforts to maintain mitochondrial function (MRM1).
- Defense against accumulated toxins and oxidative stress (RIDA, UNG, NIF3L1).
The circulating proteome thus reflects a body under siege, where normal function is downregulated while crisis-management pathways are upregulated in an attempt to cope with profound energy failure and systemic damage.
Me: The ME/CFS serum proteins mentioned in this AI thread are mostly intracelluar proteins. Are serum proteins a safe way to base your answers on the function of the cells?
AI: That is an astute observation and a highly relevant question in the field of clinical proteomics.
It is generally a valid concern that most proteins discussed in the study are primarily intracellular, yet were measured in the serum (extracellular space). This observation significantly influences how one interprets the function of the cells based on these measurements.
Here is a breakdown of why these serum measurements can be informative, but require careful interpretation:
1. Serum Proteins vs. Cellular Function: The Leakage Hypothesis
Typically, the presence of large amounts of intracellular proteins in the serum is not indicative of normal cellular function but rather of cellular damage, lysis (breakdown), or altered membrane permeability.
In the context of the ME/CFS study, the presence of proteins like LONP1 (mitochondrial matrix), GLUD1 (mitochondrial matrix), and RIDA (cytosol) in the serum suggests a "leakage" from damaged or dying cells throughout the body.
2. How the Study Interprets This "Leakage"
The study authors frame these findings not just as random leakage, but as a systematic "snapshot" of a broad, systemic pathological state:
- Evidence of Widespread Cell Stress/Damage: The presence of many different intracellular proteins points to widespread, generalized cell stress and potentially increased cell death (apoptosis or necrosis) across multiple tissues. This is a key symptom of a systemic disease like ME/CFS.
- A "Window" into the Internal Environment: While the proteins are measured externally (in serum), their origin is internal. Measuring which specific intracellular proteins are highly elevated or depressed in the serum provides strong evidence about the type of damage occurring internally—e.g., mitochondrial damage (LONP1, GLUD1), DNA repair stress (UNG), and protein synthesis shutdown (EIFs).
3. The Limitation: Extracellular Function vs. Intracellular Abundance
It is important to remember that the concentration of a protein in the serum is not always a direct, linear proxy for its activity within a living, functional cell.
- A decreased level of EIF1AY in the serum might mean fewer cells are producing it or those cells are more intact and leaking less.
- An increased level of RIDA might mean many cells are dying and releasing their contents, or that surviving cells are vastly overproducing RIDA in a futile compensatory effort before they leak it out.
Conclusion: A Safe Way to Base Answers?
Yes, but with caveats.
You can safely base answers on the implications of these findings within the study's specific context:
- The serum data provides a reliable biomarker signature of the disease state.
- It provides strong evidence for systemic damage, mitochondrial stress, and widespread metabolic distress in ME/CFS patients.
However, interpreting the absolute levels of these leaked intracellular proteins requires recognizing that they reflect a state of dysfunction and cellular crisis, rather than the healthy, homeostatic function of a normal cell. The study used a sophisticated approach to correlate these circulating proteins with known biological pathways, allowing them to infer what is happening inside the cells of these patients.
Me: It sounds as these patients are really ill. ME/CFS has been considered a functional disorder. Is it outdated knowledge?
AI: Yes, based on a substantial and growing body of biomedical evidence, classifying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) as purely a functional disorder is considered an outdated view by major health organizations and the leading scientific consensus.
Here is the current understanding:
- Official Classification as a Neurological Disease: The World Health Organization (WHO) has classified ME/CFS as a neurological disease (specifically in the category of "other disorders of the nervous system," ICD-10 G93.3; and as a "post-viral syndrome" in ICD-11) since 1969. It is not classified as a mental or behavioral disorder.
- Strong Biological Evidence: Decades of biomedical research have demonstrated a clear biological basis for the disease across multiple body systems:
- Immune System Dysfunction: Abnormalities in immune cells, reduced natural killer (NK) cell function, and altered cytokine levels are consistently found.
- Mitochondrial and Metabolic Issues: The kind of proteomic findings you mentioned (disrupted protein synthesis, mitochondrial damage indicators, alternative fuel use) highlight significant energy metabolism issues.
- Neuroinflammation and Autonomic Dysfunction: Brain imaging has revealed neuroinflammation, and many patients experience dysautonomia (problems with heart rate, blood pressure, digestion regulation).
- Post-Exertional Malaise (PEM): The hallmark symptom, a severe and delayed crash after exertion, has distinctive physiological findings that are not psychological in nature.
- Harm of Misclassification: Leading medical bodies, such as the US National Academy of Medicine (formerly the Institute of Medicine), have issued reports concluding that ME/CFS is a serious, complex, multisystem disease, not a psychological one. The continued misconception among some health professionals that it is psychosomatic has historically led to misdiagnosis, delayed treatment, and significant patient harm, as treatments based on behavioral theories (like unsupported versions of graded exercise therapy) were found to be potentially harmful.
In conclusion, the scientific community largely considers ME/CFS to be a legitimate, severe biological illness, not a functional or psychosomatic disorder. The robust molecular evidence, such as the proteomic findings in the study you cited, directly supports this modern understanding.
Reference:
1) Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights