focus and context, part IIa: ADHD and rejection

The following post is in part an answer to a question in a randform comment.


ADHD is a socalled disorder. Among its symptoms are a “unusual way” of focusing/concentrating. The symptoms of ADHD are gradually. Thus weak forms of ADHD may not necessarily be seen as disorder, but as a normal condition.

Although the clinical investigations are not yet sufficient there exist strong indications that neurophysiological components play an imminent role in ADHD. And these may also be play a role in understanding rejection.

In particular the concentration level of a certain neurotransmitter called Dopamine seem to be smaller in ADHD patients than in non-ADHD patients, moreover the reuptake of Dopamine seems to be faster in ADHD patients. Since Dopamine steers the neural activity of a lot of neurons (“dopaminergic neurons”), the faster reuptake (and may be also the general lower level) of Dopamine seems to lead to a faster decrease of neural activity/stimulation (see plasticity). Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area (VTA). The production of Dopamine can be influenced by components including genetic disposition and nutrition.

Among others SPECT scans found people with ADHD to have reduced blood circulation (indicating low neural activity), and a significantly higher concentration of dopamine transporters in the striatum. Medications (such as methylphenidate) thus focused on treating ADHD by blocking the dopamine transporter and thus reducing dopamine reuptake in certain areas of the brain, such as those that control and regulate attention. As explained above dopamine is a stimulant, thus methylphenidate increases neural activity.

The level and reuptake of Dopamine seems to be accompagnied by emotional states, such as motivation (ADHD patients can actually “hyperfocus” if motivated), but as it seems also be connected to negative experiences/responses:

In der klinischen Praxis kann in diesem Zusammenhang immer wieder beobachtet werden, dass diese Patienten sich primär an negative und traumatisierende Erlebnisse erinnern. Nur massive Traumata vermögen bei ihnen Spuren im Gedächtnis zu hinterlassen. Fatalerweise sind es dann in erster Linie diese schmerzhaften Erinnerungen, welche das Grundgerüst des Selbstgefühls bilden.
source

translation (without guarantee of correctness):
In the clinical practice one can repeatedly observe, that patients recall primarily negative and traumatising experiences. Only massive Traumata may leave Traces in their memory. Badly enough these painful memories are then predominantly the memories which form the basic framework which forms self-assurance.

As a result ADHD patients have a tendency to easier develop comorbidities such as anxiety disorder, depression etc.

Emotional memories are partially triggered by activity in the Nucleus accumbens.
Major inputs to the nucleus accumbens include prefrontal association cortices, basolateral amygdala, and dopaminergic neurons which are located in the already above mentioned ventral tegmental area (VTA). Due to its role in the development of positive emotions the Nucleus accumbens is also called the “pleasure or reward center” of the brain.

However research suggests that in addition to its prominent role in appetitive learning, the nucleus accumbens (NAC) may also be involved in fear conditioning.

I couldn’t find a study with regard to this, but it is thus not far fetched to assume that a different activation pattern of the Nucleus accumbens may also be due to a different (way of/rate of) change of the dopamine level (this may also be a feedback mechanism). On a first guess this could imply that the positive activation of the Nucleus accumbens may be less easy for people with e.g. a faster/differently changing Dopamine level (such as ADHD patients), in particular this different dopamine regulation may (again this is guessing) even lead to a rather complete inactivation of the Nucleus accumbens and thus enforce negative emotions, like the above mentioned fear conditioning. Moreover if the Nucleus accumbens is inactivated it could be rather resistent to positive stimulation. As a simple reference: It is generally not easy to cheer someone up who is grumpy.

Concluding -it may be at least for a certain group of people very important to avoid negative experiences. This could explain also why some people may appear to “hyperreact” when e.g. being critized or rejected. And – it may be sensible to focus on investigating the mechanisms of rejection as these may dominate the mechanisms of reward. This may also be useful with regard to understanding Traumata which may be the result of a severe form of rejection such as in betrayal and abuse.

In short -it is important to understand why people feel rejected. In particular the experience of rejection is not only an individual feature, but is certainly influenced by other factors, like general societal (e.g. stress) factors, or like cultural conditions, which include religious constructions, conceptions of honor, but also arrangements on how to “institutionally” avoid that people feel rejected. These arrangements may reach as far as from pink slip parties to hospices.

addition Aug. 11, 2020:
There is a popular science read at the magazine Quanta (“Mitochondria May Hold Keys to Anxiety and Mental Health”) about the role of -in particular- mitochondria in the brain in conjunction with neural dysfunctions:

“mitochondria are often anchored at key positions within neurons, such as near the synapses, apparently to help their function. Mitochondrial effects might also be exerted through the brain’s non-neuronal glial cells, such as the oligodendrocytes that sheath neurons in myelin and the astrocytes that support neurons’ health.”

Amongst others it is hypothesized that a:

“deficit of cellular energy production in critical neural circuits might explain an overall lack of motivation and self-esteem seen in anxiety-prone people.”

So in particular:

When Sandi put rats in competition to establish a social hierarchy, she saw that the animals with less anxiety were more likely to acquire dominant rank. Further study showed that these less anxious animals had greater mitochondrial function in the nucleus accumbens, a part of the brain vital to motivated behavior and the production of effort.

The stress hormone cortisol seems to play here an important role:

Specialized receptors carry the cortisol into the nuclei of cells, where it activates about 1,000 genes to help cells prepare for the “fight or flight” response. But the receptors also ferry some of the incoming cortisol into the mitochondria, where it interacts with the mitochondrial DNA and makes energy production more efficient.

Some thoughts on that:
Since we talked about dopamine here it should be mentioned that dopamine is produced in socalled Dopaminergic cell groups. It seems to be currently somewhat well-known that mitochondrial defects are connected with the death of dopaminergic neurons. This connection could thus be a key factor in the question on how mitochondria could be involved in the above described mechanisms of dopamine circulation in the brain and thus in dopamine’s possible role in mental states like anxiety.
The conrete forms of interaction between mitochondria and dopamine seem however not yet so clear. In particular this article from 2008: suggests that “Deleterious effects of dopamine (DA) involving mitochondrial dysfunction have an important role in DA-associated neuronal disorders, including schizophrenia and Parkinson’s disease.”
Here is now a newer study (“PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function “) which highlights the role of PINK1 -a mitochondrial kinase:

We found that in neuronal progenitors, PINK1 regulates mitochondrial morphology, mitochondrial contact to the endoplasmic reticulum (ER) and the phosphorylation of Miro1. A compensatory metabolic shift towards lipid synthesis provides mitochondria with the components needed for membrane renewal and oxidative phosphorylation, maintaining the mitochondrial network once mature.

Cholesterol is increased by loss of PINK1, promoting overall membrane rigidity. This alters the distribution of phosphorylated DAT at synapses and impairs dopamine uptake. PINK1 is required for the phosphorylation of tyrosine hydroxylase at Ser19, dopamine and calcium homeostasis and dopaminergic pacemaking.

We suggest a novel mechanism for PINK1 pathogenicity in Parkinson’s disease in addition to but not exclusive of mitophagy. …

At this place it should be mentioned that next to dopamine there are two more monoamine neurotransmitters one could look at, namely norepinephrine and in particular Serotonin, which is actually more well-known than dopamine to be related to -as Wikipedia says: “modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.”

18 Responses to “focus and context, part IIa: ADHD and rejection”

  1. Al Aziz Says:

    Thank you for interesting explanation. So you say that high-rank officials who does
    not like to be critized should better take the pills you mentioned, since they probably have this sickness you describe?

    Some say that criminals with hard childhood, who were rejected and sick should be excused. Do you want to say the same? I think murderers shouldn’t be excused.

  2. nad Says:

    @Al Aziz

    Please see this randform post.

    I feel a bit under time prasure thus I’ll answer later to your question:
    Some say that criminals with hard childhood, who were rejected and sick should be excused. Do you want to say the same? I think murderers shouldn’t be excused.

  3. Al Aziz Says:

    why do you not answer my question?
    Do you have anxiety disorder? :)

  4. Chi An Chenk Says:

    Interesting to hear about the PINK1 connection! While it would certainly also be interesting to hear why Mr. Zuckerberg furthers this PINK1 research and while some folks may eventually hear more about your dopamine and depression theories, I think that – given your own last words in the supplement of today that you owe us an explanation about the role of serotonin.

  5. nad Says:

    @Chi An Chenk
    I do not really write blog posts anymore, so in particular I don’t think I will write anything on serotonin in the foreseeable future. I had made the recent addendum in the above post because I had a recent increased interest in biochemical pathways due to some discussions we had here about the medical treatment of someone who might be a so-called covid-19 long-hauler.
    One of the possible long-hauler symptoms is anxiety and thus the dopamine pathways may give some hints. For “our” long-hauler it seemed though that overarching symptoms of anxiety were luckily mostly only prevalent in certain situational environments, so that for that particular patient other problems, like a Tinnitus or a FEV1 distinctively below 50%, were clearly more important. Since the patient’s notional covid-19 symptoms occurred in February (i.e. no testing) and since – as described in the Atlantic article – a many-months-later antibody test was quite typically negative the patients symptoms are basically regarded as non-covid-19 symptoms and are accordingly treated. Our recent discussions thus centered about the question whether a high dose of “shock” or “stress” medication of prednisolone, which is amongst others immunosuppressive could lead to a massive re-onset of covid-19 symptoms due to a hypothesized Sars-2 virus latency.

    My interest in PINK1 and those discussions about mitochondrial involvement was thus amongst others motivated by the fact that Sars-2 seems to heavily interact with the phosphorylization of kinases. The article “The Global Phosphorylation Landscape of SARS-CoV-2 Infection” doesn’t show PINK1 in a list of kinases whose activities are heavily disrupted by Sars-2, but who knows, may be I just need to look more carefully into their database. At this place it should be mentioned that apparently PINK1 is not only in the brain:

    PINK1 is highly expressed in the brain but it is also expressed throughout the rest of the body and has been associated with disease mechanisms in several tissues41, 42 including the progression of some cancers14, 43.

    So concluding: I don’t know but I just found the connection of PINK1 to dopamine regulation (and thus anxiety), it’s tight connection with cortisone production (and thus inflammation reactions), it’s main location around mitochondria and ER and its connection to oxidative phosphorylation (Fatigue) in mitochondria rather appalling. But I am not a doctor and all of this is highly hypothetical – I just try to form some sort of a rough idea of what might be going on with long-haulers.

  6. Besserwisser Says:

    Regardless whether you think that PINK1 plays a role in the Corona disease or not – you should acknowledge that it seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    This is beautifully explained in the article: “Clearance of Damaged Mitochondria Through PINK1 Stabilization by JNK and ERK MAPK Signaling in Chlorpyrifos-Treated Neuroblastoma Cells”:

    The simple interpretation of these results is that JNK and ERK1/2 signaling regulates PINK1/Parkin-dependent mitophagy in the mitochondria of CPF-treated cells. Overall, this study proposes a novel molecular regulatory mechanism of PINK1 stabilization under CPF exposure.

    and to be more precise this was shown by ROS-regulating JNK and ERK1/2:

    We observed that PINK1 stabilization was selectively regulated by ROS-mediated c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling activation but not p38 signaling. In the mitochondria of CPF-exposed cells, pretreatment with specific inhibitors of JNK and ERK1/2 significantly decreased PINK1 stabilization and Parkin recruitment and blocked the LC3-II protein level.

    and as far as I can tell neither JNK nor ERK1/2 (also called MAPK3/1) (both are mitogen activated kinase not to confused with MAPs) ) are in the list of proteins that interact with Sars-2

  7. nad Says:

    Besserwisser wrote:

    ..it seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    Well “controlled” is quite a strong word. The article uses “regulated” and I understand this as -yes- there seems to be a strong kind of influence, but as far as I understood this sentence “pretreatment with specific inhibitors of JNK and ERK1/2 significantly decreased PINK1 stabilization and Parkin recruitment ..” means also that this influence has its limitations.

    But anyways thanks for pointing out those references. It actually helps to give a first direct indication of exactly that what I had suspected, namely that Sars-2 may damage PINKs functioning. That is in the article you referenced, which provides the SARS-CoV-2 protein interaction map” it is written about ORF6:

    “ORF6 of SARS-CoV antagonizes host interferon signalling by perturbing nuclear transport^33, and the NUP98–RAE1 interaction with ORF6 may perform the same function for SARS-CoV-2.”

    reference 33. is:
    Frieman, M. et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 81, 9812–9824 (2007).
    I understand this as that in particular the open reading frame Nr. 6 (ORF6) of Sars and Sars-2 are identical or at least so similar that the corresponding proteins function in the same way.
    But if this is so then this apparently means that ORF6 may “induce ER stress and JNK-dependent apoptosis” according to the article: A SARS-CoV protein, ORF-6, induces caspase-3 mediated, ER stress and JNK-dependent apoptosis.
    The authors also mention the STAT blocking but furthermore a suggestive effect on JNK activation:

    One of the possible causes of ORF-6 inducing ER stress is that ORF-6 blocks STAT1 translocation to the nucleus and sequesters host nuclear import factor KPNA2 into rough ER/Golgi membrane. …. Also, ER stress can activate JNK through IRE1, TRAF2 and ASK1 pathways. Since both ORF-6 and ORF-7a are ER-localized proteins, we hypothesized that ER stress induced by these two proteins will lead to Caspase-3 and JNK activation.

    So this is still just a hypothesis but I actually think that there may be even more connections. Like it might be that parkin recruitment and thus “ubiquitylation” (and thus mitophagy) of damaged mitochondria is eventually directly impaired by Sars-2. I am not sure if you want to hear more about this very vague hypothesis, finally I am hypothizing about things I barely understand.

    addition made on Oct 10, 2020: The phosphorylation landscape article remarks that MAPK1/3 is probably also affected by Sars-Cov-2:

    Kinases predicted to be downregulated include several cell cycle kinases (CDK1/2/5 and AURKA), cellgrowth-related signaling pathway kinases (PRKACA, AKT1/2,MAPK1/3, and PIM1), and the cytoskeleton regulators (PAK1),among others.

    Figure S2A displays for MAPK1 and MAPK3 a considerably small negative change in “predicted kinase activities across different time points post-infection.” This looks however differently for Figure S3E.

  8. Blasentee Says:

    I had a recent increased interest in biochemical pathways due to some discussions we had here about the medical treatment of someone who might be a so-called covid-19 long-hauler.

    What’s up with that? Is the patient still alive? Did the colesterin help?

  9. Thorsten Trinkvogt Says:

    Regardless whether you think that PINK1 plays a role in the Corona disease or not – you should acknowledge that it seems that PINK 1 is anyways controlled by JNK and ERK1/2.

    Nad – Please keep up your writings and don’t feel irritated by critique!
    All efforts should be welcome in order to fight this Corona crisis!

    Likewise literature should be open – I find it is not so good that Springer requires registration for reading Corona articles (example ). But of course some people need to have an income.

    Did you meanwhile find out whether the ORF6 of Sars-2 and Sars is the same? I think the gene sequences are open source.

  10. human transmission Says:

    Do you know in how far the above medical discussions can be applied to other RNA viruses like those caused by Viral hemorrhagic fevers? Those bloud fevers may have not only caused the great pestilence but may have even caused the bubonic plague and you probably know that recently even the sofar controllable Chaparemammarenavirus seems to have a new mutant which is human transmissable.

  11. nad Says:

    @Blasentee

    What’s up with that? Is the patient still alive? Did the colesterin help?

    You really meant Coleresterin? You probably were referring to prednisolone, which is a corticosteroid, like cortisol and thus related to stress and immune response. Cholesterin or Cholesterol seems to be a kind of “pre-cortisol”. At Quanta Magazine there is a nice image explaining how cortisol is made from cholesterol. (From this article.) As I pointed out above it seems that PINK1, which mainly seems to operate between mitochondria and around the boundary of the endoplasmic reticulum seems to play quite a role here (again see e.g. article PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function).

    Quanta Magazine has also a new article on Covid19: How to Understand COVID-19 Variants and Their Effects on Vaccines. In this article a description of a rather terrifying Covid19 response is linkedto: Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. It is described about the 45 year old patient that after being diagnosed with Covid19 on day 0:

    On day 154, he died from shock and respiratory failure.

    He suffered from diffuse alveolar hemorrhage, abdominal pain, fatigue, dyspnea, hypoxemia, cellulitis, continued respiratory decline when he finally died following a fungal infection during intubation. His nasopharyngeal swab tests displayed over the course of the roughly 5 months a reoccuring positive test result. I understand this that he may have been reoccuringly infectious over the course of 5 months.

    So to answer your question: The patient has luckily not died yet and there were at least intermediately improvements concerning the repiratory functions and fatigue, but the patient is not well yet and the question about virus latency has not been settled.

  12. Nebentubuhler Says:

    again see e.g. article PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function

    I just want to mention that one could get the impression that you want to promote german science by again highlighting the article:
    “PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function”
    as its authors seem to be all from Munich or Tübingen.
    There are a lot of articles related to PINK1.

  13. nad Says:

    Thorsten Trinkvogt wrote:

    Did you meanwhile find out whether the ORF6 of Sars-2 and Sars is the same? I think the gene sequences are open source.

    I haven’t checked yet. But in the article: “Interferon antagonism by SARS-CoV-2: a functional study using reverse genetics” it is found that they are not the same:

    Although genes encoding intereferon antagonists are highly conserved between SARS-CoV and SARS-CoV-2, the protein 6 gene is less conserved. In cells infected with SARS-CoV or SARS-CoV-2, protein 6 interacts with KPNA1, KPNB1, and Nup93 (SARS-CoV-2 only) and prevents the activation of ISRE promoter elements through STAT1 translocation.13, 14 Our findings complement studies by Miorin and colleagues14 and Lei and colleagues,16 showing that charged residues at the CTD of ORF6 can further augment its antagonistic function, probably by increasing interaction with KPNA1 and KPNB1, which has been described to be independent of Nup93 binding via the conserved methionine at amino acid position 58.

    This is unfortunately bad news, since it is suspected that the interferon sensibility of Sars2 may move towards that of Sars through mutation.

    But regarding the JNK dependency – which was the reason why I was looking at ORF6 – it seems this is not so direct. In particular I have found the articles
    SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria and
    c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD + cleavage activity to inhibit mitochondrial respiration . In the second article it is described:

    In this study, we showed that Ser-548 of SARM1 is phosphorylated by a stress-responsive kinase, JNK, and that the phosphorylation enhances NAD+ cleavage activity of SARM1 and inhibition of mitochondrial respiration. The function of each domain of SARM1 has been uncovered in recent studies. It has been shown that the SAM domain promotes dimer formation of SARM1 and that the TIR domain dimerized via the SAM domain evokes NAD+ loss, eventually leading to axonal degeneration and neuronal cell death (17, 18).

    Where I haven’t yet understood whether JNK phosphorylation of SARM1 may inhibit ATF6 binding.

  14. Edgar von Hohentreffen Says:

    Interesting Corona thread here. However I think you should observe that people may get irritated by too elaborated discussions and then finally nothing gets done. In that vein I think the halt of Astra-Zeneca vaccinations in Germany displays already an oversensitivity which is probably due to too much talking. I mean there were 7 cases of thrombosis out of 1.6 MILLION vaccinations.

  15. Lucinda Says:

    @Edgar von Hohentreffen
    I think this is less a result of too much talking but rather a question of who obeys whom, i.e. a political question. I cite from the New York Times:

    Germany’s decision set off a domino effect of defections from the vaccine. A cascade of countries — Italy, France and Spain — soon joined the decision to suspend AstraZeneca, dealing a significant blow to Europe’s already shaky inoculation drive despite a lack of clear evidence that the vaccine had caused any harm.

    and

    “It was a political choice,” Nicola Magrini, the director, told La Repubblica newspaper on Monday, saying that Italy suspended the administration of the AstraZeneca vaccine because other European countries had decided to do so.

    and

    Some cases of immune thrombocytopenia, the disorder characterized by a lack of platelets, have also been reported in the United States in people who have received the Pfizer or Moderna vaccines.

    There was a case of thrombosis detected in Spain last weekend, and some regions had stopped distributing a batch of AstraZeneca vaccines, amid safety concerns.

    But the chief motivation was political.

    and

    France, too, appeared to bow to pressure to act in unison with its powerful neighbors

  16. nad Says:

    Lucinda wrote:

    France, too, appeared to bow to pressure to act in unison with its powerful neighbors

    According to the ministry of health here had been -following a vaccination with Astra-Zeneca within roughly the last 5 weeks- alone in Germany 13 out of 1.6. million occurrences of the very rare Cerebral venous sinus thrombosis, three of them fatal. The cases were in conjunction with Thrombocytopenia and hemorrhage. This is about 5-10 times more than to be expected. There had been similar cases in other european countries and the first countries to suspend vaccination were according to the news network nrd Denmark, Norway, Island, Bulgaria etc and not Germany.

    I can’t of course tell how much France felt “pressured to bow to its powerful neighbours” because of that decision, but I could imagine that since in France – just like in Germany and other european countries- there is a third Corona wave on the rise, France may have felt rather pressured about the sudden halt of “US vaccine” Pfizer:

    The US pharmaceutical firm has had to cut deliveries temporarily while cases in many European countries surge.

    espcially given the current vaccination statistics.

  17. gebunkabunkafeier Says:

    You wrote here:

    Where I haven’t yet understood whether JNK phosphorylation of SARM1 may inhibit ATF6 binding.

    The interesting question here seems to me not whether PINK1 is “stabilized” on the outside of mitohypochondrial membranes but why it accumulates there at all.

    The article: “Human telomerase reverse transcriptase positively regulates mitophagy by inhibiting the processing and cytoplasmic release of mitochondrial PINK1” explains this:

    PINK1 synthesized de novo in the cytosol is then rapidly and constitutively imported into the mitochondria by translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM) complexes4. Once in the mitochondria, PINK1 is cleaved by mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like protease (PARL)5,6, and the processed form of PINK1 is transported back to the cytosol and degraded rapidly by the proteasome7,8.

    Treatment with carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a mitochondrial uncoupler that induces mitochondrial depolarization, leads to the accumulation of PINK1 on the outer mitochondrial membrane and the phosphorylation of the Ser65 residue of ubiquitin (Ub) and parkin, an Ub E3 ligase9,10. Phosphorylated parkin is subsequently recruited to the mitochondria, where it attaches to the Ub chains of the substrate protein present on the mitochondrial surface. Autophagy adapters then bind to phospho-Ub at Ser65 and the autophagic machinery facilitates lysosomal degradation of the damaged mitochondria through mitophagy11. Importantly, the precise regulation of PINK1 processing is critical to mitophagy, and the accumulation of PINK1 in the mitochondrial outer membrane in response to various internal and exterior stimuli that cause the mitochondrial damage, including oxidative stress or the loss of mitochondrial membrane potential, is specifically required.

    The authors show that the catalytic protein subunit human telomerase reverse transcriptase (hTERT) of ribonucleoprotein telomerase plays an important role here:

    Our results demonstrated that hTERT increases mitophagy by decreasing the processing of PINK1, resulting in the accumulation of full-length PINK1 on the outer mitochondrial membrane. We also determined that hTERT binds to the β subunit of MPP (MPPβ) and inhibits the cleavage of PINK1 through MPP, which might be the mechanism underlying the hTERT-induced suppression of PINK1 processing within the mitochondria and its subsequent release into the cytosol.

  18. nad Says:

    Antwort:
    @gebunkabunkafeier
    thanks for pointing out the article “Human telomerase reverse transcriptase positively regulates mitophagy by inhibiting the processing and cytoplasmic release of mitochondrial PINK1”. We are here still trying to find a bit more help with our patients alleged long covid and so any hint might be useful. I am though not fully sure how much I should delve into realms I barely understand. Anyways for the time being, let me tell you why I found this article especially interesting.

    In this article one finds a strong indication on possible major interferences of Sars-2 with PINK1 functioning and in particular their functioning as a mitochondrial “quality control”.

    That is the article describes that:

    Because PINK1 functions in a pro-survival pathway, its activity is presumably tightly regulated upstream. However, only a few studies have focused on the mechanism underlying the modulation of steady-state PINK1 levels and the identification of the factor(s) involved. For example, it is known that the UPS regulates PINK1 stability. Specifically, the TRAF6-mediated Lys63-linked ubiquitination of PINK1 is required for PINK1 stabilization on damaged mitochondria41. Moreover, the cleaved form of PINK1 is a target of the N-end rule pathway, a component of the UPS that mediates its rapid turnover42. Recently, we demonstrated that CHIP acts as a novel E3 ligase of PINK1, promoting its ubiquitination and subsequent proteasome degradation, and ultimately resulting in cytotoxicity by reducing the cytoprotective effect of PINK1 43. In addition to UPS, BAG2, BAG5, and Hsp90, a component of the Hsp90/Cdc37 molecular chaperone complex, reportedly regulate PINK1 stability via protein–protein interactions, allowing for the proper mitochondrial translocation of PINK1 and execution of the mitochondrial quality control pathway16,44,45.

    and

    Considering the relationship between hTERT and heat shock proteins, the chaperone complex including Hsp70, Hsp90, and p23, is also critical to the correct assembly of telomerase and its proper function15,46,47.

    I read this as that in particular for the correct processing of PINK1 in connection to mitophagy the chaperone Hsp90 plays a significant role, as it may interact directly with PINK1 via “protein–protein interactions” which are e.g. explained in reference [16] in such a way:

    Here we report that PINK1 forms a complex with the molecular chaperones Hsp90 and Cdc37/p50 within cells, which appears to enhance its stability. When cells were treated with an Hsp90 inhibitor (geldanamycin or novobiocin), levels of PINK1 were greatly diminished, reflecting its rapid degradation via ubiquitin-proteasome pathway.

    – or via the correct assembly of telomerase, which in the turn regulates the “processing” of PINK1.

    As a matter of fact Hsp90 is not only a chaperone but seems to play also a role in membrane deformation. In the article Hsp90 Mediates Membrane Deformation and Exosome Release it is written:

    Hsp90 is a master regulator of protein homeostasis. Lauwers et al. now find that Hsp90 directly binds and deforms membranes in addition to operating as chaperone.

    and

    We now find that Hsp90 also has the ability to directly interact with and deform membranes via an evolutionarily conserved amphipathic helix.

    I haven’t though found sofar anything on whether HSP90 operates in a similar deforming way for other membrane-like structures besides the cell membrane. This quest might sound far-fetched but according to Wikipedia the “membranes of the ER are continuous with the outer nuclear membrane” and then according to the article Mechanism of membrane-curvature generation by ER-tubule shaping proteins the tubules of the ER are “generated by the reticulons and REEP” (in particular as it seems REEP5), which “have two pairs of trans-membrane (TM) segments, followed by an amphipathic helix (APH). The “TMs and APH cooperate to generate high membrane curvature.” The concrete way HSP90 deforms membranes looks to me on the first sight to be similar, at least it includes dimerization, but then I couldn’t find anything on the TM’s. Could it hook to TM’s?

    Why would this be interesting? Because Hsp90 plays also a significant role in the socalled Unfolded protein response (UPR) which is a sign of “ER stress”. In fact Hsp90 modulates the UPR, which is detailed in the article Heat Shock Protein 90 Modulates the Unfolded Protein Response by Stabilizing IRE1α” . And the connection to membrane deformation may eventually unveil other roles of Hsp90 in the UPR.

    So for example an additional hint could be that the Hsp90 interacts with the CF-transmembrane conductance regulator (CFTR) according to the article The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma, in particular:

    Here, a specific mutation(DF508) results in defective folding and trafficking of CFTR from the endoplasmic reticulum (ER) to the plasma membrane, which is considered to be the molecular cause of cystic fibrosis(CF) (Goetz and Ren, 2019;Kerem et al., 1989).

    and

    The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication. However, it has remained unclear whether transmembrane protein-specific QC hubs exist. Here we identify cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determineschaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90.

    But there are also other direct interactions with the Endoplasmic reticulum -see e.g. the article Evidence for interaction between Hsp90 and the ER membrane complex.

    Anyways it was already mentioned in some of the above articles that HPS90-like chaperones are at least in the lumen of the ER they are called GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum, they operate and react (like to the drug Geldnamycin) quite similar to the Hsp90 but not fully. It maybe important to keep that in mind.

    But why at all so much fuss about the PINK1-Hsp90 connection? Because in the article: Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy Hsp90 had been identified as a drug target for Sars-2:

    Detailed investigations of cellular gene expression programs suggest an involvement of the protein folding chaperone and autophagy regulator HSP90 in the viral infection cycle. Inhibition of HSP90 by multiple inhibitors resulted in reduced viral replication and cytokine mRNA levels. Overall, our study provides a detailed picture of the gene expression changes in cell line models for CoVs and particularly SARS-CoV-2, highlights the cell-type specificity of the transcriptional response to infection and identifies HSP90 as a potential target for therapeutic interventions.

    Hence it is important to better understand the role of Hsp90, especially in its regulatory function in mitophagy, but eventually also with repect to membrane deformations, at least
    REEP5 seems to be strongly interacting with Sars-2 (see the “interaction table” on page 21 in the article
    Mapping the SARS-CoV-2–Host Protein–Protein Interactome byAffinity Purification Mass Spectrometry and Proximity-DependentBiotin Labeling: A Rational and Straightforward Route to Discover Host-Directed Anti-SARS-CoV-2 Therapeutics
    ). Where I don’t want to suggest that the realistic situation is as simple as the idea that “if REEP5 stops functioning due to sars-2 and Hsp90 tries to take over membrane folding, then sars-2 reactions get worse”.

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