Mitochondrial Mutations and Autism
August 18th, 2008
My piece on how “alternative” practitioners keep people from recognizing the futility of their treatments will have to wait a bit longer. Something has come up.
Since the Hannah Poling case was conceded late last year, the “autism community” has been abuzz with talk of mitochondrial disease. It is a measure of how “hip” mitochondrial diseases have become that they have acquired their own shorthand term: “mito” (as in, “My DAN! doctor wants to test my son for mito.”).
More recently, the same community has thrilled to what they have been told is a “bombshell” in the hypothetical link between autism and mitochondrial disease. I refer, of course, to the study published by Elliot et al in the 8 August 2008 edition of The American Journal of Human Genetics.
The Article:
In this study, the authors looked for ten of the most common pathological (i.e. associated with one of more diseases) mutations in the mitochondrial DNA (mtDNA) extracted from the cord blood samples from 3168 consecutive births in North Cumbria. They found 15 children with mutations in their mtDNA.
They then went back and tried to find blood samples from the mothers of these 15 children with mtDNA mutations. They found maternal samples for eight of the fifteen children (one was from the same mother, which suggests twins) and found that only three of the eight mutations were not found in the mother (i.e. five of the eight children - 63% - had the same mutations as their mothers).
Now, this worked out to about 0.47% of the children having mtDNA mutations that have been associated with mitochondrial diseases, or about 1 in 211. If you look only at the subjects where mtDNA sequencing was successful, it works out to 0.54%, or 1 in 185. This is much higher than the prevalence of mitochondrial disease – generally thought to be about 1 in 5000.
As a result, the authors felt that it was very important to let the scientific and medical communities know – via their article – that the prevalence of mitochondrial mutations is much higher than would be predicted by the prevalence of mitochondrial diseases. They made two comments in their conclusion that are relevant to this point:
The first, which has been taken up as a rallying cry by certain scientifically under-literate journalists, was:
“We have identified a massive reservoir of pathogenic mtDNA mutations in the general population, placing greater emphasis on developing techniques to prevent the transmission of pathogenic alleles that could segregate to high levels and thus cause mtDNA diseases in subsequent generations.”
[Note: the authors fail to explain why this is a problem that needs to be addressed, given that the "massive reservoir of pathogenic mtDNA mutations" has probably been present for most of recorded history, if not longer. They present no data or explanations to suggest that this "problem" is either new or increasing. While it is always better for prospective parents to have all possible information about potential genetic disease issues in their offspring, this "problem" is one that is essentially insoluble - the prospective mother-to-be who has a modest percentage of mutated mtDNA will have no options except to forgo having children.]
The second, which has largely been ignored, is perhaps even MORE relevant:
“Detecting heteroplasmic mtDNA mutations in >1 in 200 individuals of the background population has implications for studies reporting mtDNA mutations in specific disease groups. Our data show that putative disease associations, such as the reported high frequency of m.3243A/G in diabetes mellitus, could be a chance finding irrelevant to pathogenesis.” [emphasis added]
So, what Elliot et al have shown is that mtDNA mutations appear to be much more common than can be explained by the prevalence of mitochondrial diseases. This suggests that there is more to the story than we currently know.
It also suggests that people who have trumpeted that “1 in 200 people have mitochondrial disease” or even “1 in 200 people have mitochondrial mutations” as vindication of the “autism is a mitochondrial disease” need to read the paper. If having the mutation was enough to cause a mitochondrial disease, 1 in 200 people would have a mitochondrial disease, not just be able to transmit it to their children.
In fact, this study shows that mtDNA mutations found “in association” with certain diseases may be simply due to chance, not because the mutation causes the disease. This finding should cause people to be much more cautious about attributing a disease to the presence of a mutated gene and makes the “1 in 200″ number much more of a question mark.
If you were just interested in the study, you can stop reading here. For more information about mitochondria and their fascinating genetics, read on…
Mitochondrial Genetics 101:
Much of the confusion over the relationship between mitochondrial disease and autism lies in the rather confusing (to the average layperson) genetics of the mitchondria themselves.
Each human cell (except mature red blood cells) has between dozens and thousands of mitochondria. They carry out a variety of metabolic processes, the most famous being the production of ATP, the energy “currency” of the cell, through oxidative phosphorylation. Mitochondria look and act like bacteria – in fact, they are distantly related to alpha-proteobacteria. They each have their own circular chromosome (like bacteria) which encodes for bacteria-like ribosomal RNA (rRNA), among other things.
Over the course of evolution (it is thought that the mitochondrial association with eukaryotic cells is about 2 billion years old), the mitochondrial DNA (mtDNA) has lost a lot of genes (compared to their free-living alpha-proteobacterial “cousins”) and transferred nearly all of the rest (about 1400) to the nuclear DNA (nDNA) of their host cell.
There are three important points to remember about the mitochondrial genome:
[1] The mtDNA replicates separately from the nuclear DNA (which, in mature differentiated cells may happen essentially never) and behaves like a bacterial chromosome. However, unlike bacteria, the mtDNA has only 37 genes. This is smaller than many viral genomes and is inadequate for the functions that the mitochondria perform. Most of the mitochondrial genes (about 1400) are located on the nuclear DNA.
[2] Genes on the mtDNA are present in one copy per genome (each mitochondria can have between 5 and 20 copies of its genome, which doesn’t change the issue – all the copies are essentially identical). There are no “homozygous/heterozygous” or “recessive/dominant” genes in mtDNA – what see is what you’ve got. In other words, you can’t have a “silent carrier” state in mtDNA mutations in the same way that you can have “silent carriers” in nuclear genes.
[3] Each cell has multiple mitochondria. Depending on when in development a mutation occurred - and the random “luck of the draw” in the mitochondria the original oocyte (egg cell) got from mother - the mitochondria can all have the mutation or just some of them can have it. This is referred to as homoplasmy (all mitochondria have identical genomes) or heteroplasmy (the mitochondria do not all have identical genomes).
At the time the oocytes (egg cells) form (very early embryonic development), the mitochondria in the oogonia are divided randomly between the resulting primary oocytes and, later, between the resulting secondary oocytes and polar bodies. If the cells are heteroplasmic, there is a chance that the resulting secondary oocyte will end up with more (or less) of one type of mitochondria than the other cells in the embryo.
At least one study has estimated that as few as ten mitochondria are passed from the oogonia to the resulting secondary oocyte, which would mean that there is a significant probability that a heteroplasmic embryo could end up with oocytes (”egg cells”) that have a very different percentage of mitochondrial genotypes than the rest of the embryo. That, of course, translates to the heteroplasmic mother passing down to her children a different percentage of mitochondrial genotypes than she has. In fact, a heteroplasmic mother’s children will most likely have a different distribution of mitochondrial genotypes, just as a function of chance.
Now, this could be bad (as Elliot et al discuss) if the children end up with a higher percentage of “bad” mitochondrial genotypes (mutations). However, depending on the percentages, it may be that the percentage of “bad” genotypes would be lower in the children than in the mother. Let’s “run the numbers:
If mother’s mitochondria are 50% “good” and 50% “bad”, and only 10 are randomly selected to form the egg’s mitochondrial population, the chance that the reulting egg will have mitochondria that are:
more than 50% “bad” = 37.7%
exactly 50% “bad” = 24.6%
less than 50% ”bad = 37.7%
In this scenario, the probabilities are equal the the offspring will end up with more or fewer ”bad” mitochondria. What if “mom” has 80% “bad mitochondria?:
more than 80% “bad” = 37.6%
exactly 80% ”bad” = 30.2%
less than 80% “bad” = 32.2%
Here we see that if “mom” has a high percentage of “bad” mitochondria, the trend will be toward getting more “bad” mitochondria. On the flip side, if “mom” has only 20% “bad” mitochondria:
more than 20% “bad” = 32.2%
exactly 20% “bad” = 30.2%
less than 20% ”bad” = 37.6%
Then the numbers “flip over” and the trend is toward a lower percentage of ”bad” mitochondria than “mom”.
So, while there is a chance that the offspring will have a higher percentage of “bad” mitochondria, it depends a lot on the percentage of “bad” mitochondria.
In the Elliot et al study, most of the children with mutations were heteroplasmic – with between 89% and 0.5% of the mitochondria having the mutation in question. The median heteroplasmy was 12.9%. Three of the children were homoplasmic, with 100% of their mitochondria having the mutation. These three children came from two mothers (again, suggesting a twin birth or two births in fairly rapid succession) who were also homoplasmic for the same mutations.
The article is silent about whether the mothers of these three children had any signs of mitochondrial disease or had a history of mitochondrial disease in the family. Perhaps that will come out in a later article.
Homoplasmy/heteroplasmy in mitochondria plays much the same role as homozygosity/heterozygosity in the nuclear chromosomes, with a difference.
If a cell has a small percentage of its mitochondria that cannot function adequately, it will probably be able to function normally by relying on the rest. As the percentage of “dysfunctional” mitochondria increases, so does the likelihood that the cell will be unable to function normally. That’s the simplified version of mitochondrial genetics.
It gets more complicated when you look at the mitochondrial genes on the nuclear chromosomes. These genes code for (primarily) proteins which are then tagged and exported to the mitochondria. If the nuclear genes code for something that can substitute for the mutation on the mtDNA, then the mitochondria will work just fine. This is what causes the folks working on the genetics of mitochondrial disorders to have sleepless nights. It might take TWO mutations – one in the mtDNA and one in the nuclear DNA – to cause a mitochondrial disease.
Mitochondria and “Toxins”:
Much of the “alternative” press on mitochondrial diseases and autism has focused on the possibility that an “environmental factor” (care to guess which ones?) can cause mitochondrial damage, leading to a permanent disability. In the next few paragraphs, I’ll run through two ways that has been proposed to happen.
Mitochondrial damage:
Killing or damaging mitochondria is serious business. Some of the most lethal poisons (e.g. cyanide) work on the mitochondria. Damaged mitochondria can trigger apoptosis (programmed cell death). If this happens in the wrong place or at a developmentally sensitive time, the results can be catastrophic.
If the mitochondria are more “fragile” than normal – due to a mutation in either mtDNA or the nuclear genes encoding for mitochondrial components – they may be more sensitive ”stressors”. Heavy metals (e.g. mercury) have been shown to “stress” mitochondria, as have a number of other compounds. The fever caused by viral, bacterial or parasitic infections – as well as by vaccines – can potentially cause mitochondrial “stress” as well, although the vaccines typically cause less of a response than the disease they were developed to prevent. The idea of leaving a child with mitochondrial “dysfunction” unvaccinated begs the question: isn’t it better to prevent the “full blown” disease, even if you run the risk of “triggering” mitochondrial “stress”?
Another well-studied stressor for mitochondria is oxygen. Under “normal” oxygen concentrations, mitochondria produce a lot of reactive oxygen species (ROS), which cause a lot of damage to the mitochondrial proteins, membranes and mtDNA (which may be one reason that most of the mitochondrial genes “migrated” to the nucleus). Elevated oxygen concentrations (e.g. HBOT) increase the production of ROS, leading to more damage.
Damage to “fragile” mitochondria by “stress” (”toxins”, heat, oxygen, viral infection, etc.) at a developmentally critical point is perhaps the only plausible connection between autism and mitochondrial disease. Although it may have been fever caused by vaccination that caused the damage in Hannah Poling’s case, it could have just as easily been caused by any of thousands (if not millions) of viral and bacterial infections that children are susceptible to.
mtDNA mutations:
Mutating the mtDNA can also be a catastrophic event….for the individual mitochondrion. If it is severe enough to prevent the mitochondrion from functioning, it will die, leaving the other 99 to 1999 mitochondria to carry the load. Of course, the mitochondria periodically divide, so they will soon make good any losses. Even mitochondria in the brain cells divide about once a month, so any loss of mitochondria that is not acutely lethal will be made good in a short while.
Non-lethal mtDNA mutations are passed down to all of the “daughters” of the mutated mitochondrion. Again, since the other non-mutated mitochondria are also dividing, this affects only a small percentage of the mitochondria present in the cell. In fact, if the mutation makes the mitochondrion slower to grow and divide, it will eventually be “diluted out” by the daughter cells of the non-mutated mitochondria, which are dividing faster.
Mitochondrial mutations that occur after a point in early embryonic development cannot be passed on to offspring (of the larger, multicellular organism “hosting” the mitochondria, such as a human) unless the mutation occurs in the mitochondria of an egg cell (which are all formed during embryonic development). And since mammals get all of their mitochondria from their mothers, paternal mtDNA mutations - even in the sperm - don’t go anywhere (sometimes literally - sperm with dysfunctional mitochondria can’t swim).
So, the idea of a “toxin” or “virus” causing mtDNA mutations is not implausible. What is implausible is the idea of the same mutation occurring in a significant number of mitochondria. To give you an idea of the magnitude of the problem, let’s “run the numbers”.
The human mtDNA has 16,571 base pairs (bp). Each of these can be mutated to one of three bases (apart from the one “correct” base). Even if we assume that mutating the base to any one of the other three will cause a “dysfunctional” mutation, the odds of the same mutation happening by chance in one other mitochondrion is 1 in 16,571.
If we also assume that there are only 100 mitochondria in the cell and that mutating as little as 50% of them will cause “dysfunction” (both are low numbers – there are usually more mitochondria and it usually takes more than 50% to manifest disease), then the odds of that happening are:
1 in 1.2 X 10^182
Rounding down, that’s a 1 followed by 182 zeroes. Pretty long odds, even for a lottery. And that’s only for a single cell. If you want to imagine the same “toxic” exposure causing the same level of mutation in more than one cell, the numbers go up pretty fast.
Conclusion:
So, the Elliot et al study didn’t “prove” that mitochondrial disease is more prevalent than previously thought - they didn’t even look at the presence of disease at all. The study did show that mtDNA mutations are more common than the prevalence of mitochondrial disease would indicate. This suggests that there is more to “mitochondrial dysfunction” than simply genetics.
Does this mean that autism can’t be a “mitochondrial dysfunction”, at least in some cases? No. But is also no data to support that it can. When a study is done comparing the prevalence of mitochondrial disease or “dysfunction” in autistic and non-autistic matched controls, that question will begin to be answered. Currently, there is only speculation.
Postscript:
As I predicted earlier, practitioners have rushed to promote their own unique treatments for “mitochondrial autism”, including the usual suspects: supplements, vitamins, minerals and chelation. Some have even touted HBOT as a “treatment” (rather than a cause) of “mitochondrial dysfunction”. No doubt they all have carefully reasoned explanations of how their particular “treatment” will reverse whatever mitochondrial “dysfunction” is present.
Testing has lagged behind, although some local practitioners say that the “routine biomedical testing” will pick up “mitochondrial autism”. They fail to mention why this “routine biomedical testing” failed to detect mitochondrial “dysfunction” previously.
Clearly, there is money to be made in “mitochondrial autism” and the advertisements and postings on the Internet indicate that there is no shortage of people trying to cash in. If you are concerned that your child has a mitochondrial disorder, please see a real doctor and get real testing done. Mitochondrial testing is far from routine and requires a lab that is both meticulous and experienced. Mail-order labs are not going to be able to do it right. The sample preparation and analysis are too complex for most hospital labs - let alone direct-to-consumer mail-order labs.
Caveat emptor
Prometheus
Filed under: Autism Science, Autism Treatments, Critical Thinking
August 18th, 2008 at 11:30 pm
I think I speak for many interested parties - who lack the scientific background to easily understand the available information - when I thank you for taking the time to break this topic down into digestible pieces.
August 19th, 2008 at 4:46 pm
Another great post.
You didn’t address one question which really seems at odds with “mitrochrondrial autism”. The ASD diagnoses ratio male to female is roughly 4 to 1, indicating strongly that there is a relationship between ASD and gender (and a genetic basis related to the X & Y chromosomes). However, 100% of the mtDNA comes from the mother. So, if mtDNA is causally related to ASD, the diagnosis ratio should be close to 1 to 1. Even if mtDNA is related to ASD, there would have to be other genetic factors involved for the “mitrochrondrial autism” to manifest itself.
Also, as I recall, Poling suffered a high fever and from encephalitis of some type. Under DSM-IV-RT standards, an ASD diagnosis for her appears very questionable. Again, this undercuts the idea of “mitochondrial autism.”
August 19th, 2008 at 6:40 pm
WFJAG,
The sex ratio is another puzzle in mtDNA mutations. For example, in the Elliot et al study, the mtDNA mutations that were homoplasmic (100% of their mitochondria had the mutation) in three children were two of the three associated with LHON (Leber’s Hereditary Optic Neuropathy). People with these mutations do not always develop the disease; about 85% of the women and 50% of men with the mutation do not show signs of the disease.
This means - assuming that males and females have similar incidence of the mutations, which is expected - that the ratio of symptomatic LHON patients would be about 3:1 male:female. There is no clear understanding of how this ratio occurs.
Now, before someone gets excited about how this “proves” that autism is a mitochondrial disorder, it’s important to note that most mitochondrial disorders are degenerative, typically starting between mid-childhood and early-adulthood and showing progressive - if somewhat erratic - reduction in functional ability throughout life.
Before anyone unilaterally decides that their autistic child is suffering from a mitochondrial disorder, I suggest that they read this article:
http://www.mitosoc.org/blogs/diagnosis/genetics
This gives a very detailed, if rather technical, description of the major mitochondrial disorders. You will note that none of these disorders follows a pattern similar to that seen in autism.
Prometheus
August 19th, 2008 at 10:11 pm
Good description of a few of the factors involved in mitochondria.
I have a fairly extensive blog on how immune system activation turns off mitochondria. I see it as part of the normal “life-cycle” of mitochondria. Mitochondria are born, generate ATP for their useful life, crap-out, and are recycled. In neurons, at least a few percent go through this process every day. Mitochondria do some very difficult things. There is no way for them to avoid oxidative damage. The way physiology has evolved to deal with that oxidative damage is to replace mitochondria before the damage gets too bad, or too many mitochondria get damaged. The problem isn’t that some mitochondria get damaged; the problem is that they are not replaced fast enough.
Mitochondria in cells have a finite lifetime and are turned over quite regularly. This has been measured in rats where the longest lived mitochondria are in the CNS, where they have a lifetime of about a month. The measurement hasn’t been done in humans, but presumably it is only a few times longer.
When mitochondria are damaged, which occurs all the time, they get worn out, “tired”, and are reprocessed by autophagy. The redox active metals are recycled and new mitochondria are generated to take the place of the old ones. In nerve cells, this replacement has to occur in the cell body, because that is where the nuclear DNA is that codes for 99%+ of the proteins. The cell body is also where the cellular machinery is to reprocess the old mitochondria via autophagy, and to synthesize new proteins from RNA.
When mitochondria are damaged, their turn-over accelerates.
Precisely where the mitochondria are that divide to replace the old ones isn’t not known. It may be that there are some fairly pristine mitochondria that hang out in the cell body waiting to replicate their DNA to make new DNA for the new mitochondria that are being made every day.
It is quite clear to me that “toxins” in vaccines cannot be involved in mitochondria damage. The most complex mitochondria are in the liver where in addition to making ATP they also make other things, oxidize lipids, make lipids, and make urea. The simplest mitochondria are in the brain, where all they do is make ATP and other house-keeping things. They have very limited synthetic capacity, they don’t oxidize lipids. If we think about the sensitivity of mitochondria to “toxins”, which mitochondria are going to be the most sensitive? Pretty obviously the most complex ones in the liver will be more sensitive than the simple ones in the brain. Most toxins actually affect the liver and cause liver necrosis, not brain damage. The liver is the target organ for most types of chemical toxicity, alcohol, acetaminophen, chlorinated hydrocarbons, etc.
When a vaccine is injected SC, IP or IM (never intravenously), the concentration of any “toxins” at the local site of injection is many orders of magnitude higher than it can possibly be in a remote site such as the brain. If there were mitochondrial “toxins” in vaccines, we would expect to see acute necrosis at the sites of injection long before we would see any signs of toxicity in peripheral sites such as the brain. If someone didn’t develop a necrotic spot where a vaccine was injected, it is extremely (verging on impossible) unlikely that vaccine “toxins” caused any significant mitochondria damage in a remote site.
If the mitochondrial DNA is damaged too much, there is no treatment that will restore it. If a cell has mitochondria with damaged DNA, those damaged mitochondria can be cleared. If there are enough mitochondria with good DNA, then the cell can replace the cleared mitochondria and survive. If not, then the cell will die and be cleared. If the tissue compartment has enough good cells with enough good mitochondria, then the organ can survive. If not, then the organ dies and the organism dies. If an organism is alive with different mtDNA that what is “standard” or “wild type”, at some level that mtDNA is functioning OK.
When oocytes go through the bottle neck of only having a few mitochondria that is a “feature”. If the oocyte ends up with only or with too many “bad” mitochondria, it won’t survive. It won’t have the metabolic capacity to implant or to divide further. That ends up being a cycle that didn’t “take”.
August 20th, 2008 at 10:09 am
Right now there’s also no evidence that autistics have these mtDNA mutations at a greater frequency. In Oliveira et al. (2007) they found no evidence of mtDNA alterations in any autistic child. Granted, they only tested 69 children. Given this, however, it’s hard to imagine the frequency of mtDNA mutations is much greater in autistics than in the general population.
August 20th, 2008 at 10:36 am
Clearly, there is money to be made in “mitochondrial autism” and the advertisements and postings on the Internet indicate that there is no shortage of people trying to cash in
That says A LOT!
August 20th, 2008 at 11:08 pm
August 21st, 2008 at 12:26 pm
The male:female ratio in autism has shown an interesting trend. Early on, the ratio was about 3:1, but as the diagnosis became more well-known and it began to be “diagnosed” by people with less training and experience, the ratio increased to 5:1.
One of the simplest explanations of this trend is that autism is perceived to affect primarily males. As a result, females showing the same ensemble of behaviors would have an additional “hurdle” to overcome before being diagnosed with (or even evaluated for) autism.
This same sort of “bias” is/was seen in females presenting with chest pain - a male with the same symptoms would immediately be evaluated for a heart attack, whereas a female - since women are supposed to be at lower risk for heart attack - might first be evaluated for other problems. This led to poorer outcomes in women presenting with heart attacks, primarily due to a delay in making the correct diagnosis. But I digress.
Because autism (and for that matter, ADD/ADHD) is seen primarily as a disorder/disability of males, females may well be under-diagnosed, which could explain both the sex ratio AND the general observation that females with autism tend to be “more severely affected”. Both could be partly or even largely due to the assumption that females are much less likely to have autism.
With the diagnostic criteria widening, I would have expected that more females would have “made the cut” for an autism diagnosis, but the opposite effect has been seen. This may serve to highlight the many problems with the way autism is diagnosed in the community as well as the flaws in the data sources used to monitor its prevalence.
Prometheus
August 22nd, 2008 at 12:03 pm
What would happen if you got a mutation in your mitochondria that impaired their ability to contribute to some important cellular function, but actually enhanced their ability to replicate?
Or what if there was a function-neutral mutation that increased replication, but all those extra mitochondrial choked up the autophagy pathway and prevented neurons (or other cells, I suppose) from normal autophagy-dependent maintainence?
I am highly skeptical of any mitochondria-autism connection, but I am incredibly interested in what *is* going on with regulation of mitochondrial division and autophagy.
As far as autism is concerned, I think people might not be so inclined to latch onto this kind of explaination when we have a better one (that goes beyond different diagnosis standards ‘creating’ an epidemic).
August 22nd, 2008 at 12:33 pm
Really great post, Prometheus. Wish I’d written it.
I guess, given the ways things work in Woo-world, (including autism quackery), we can expect to see one lot of crazies pushing mega-dose antioxidant vitamin supplements “To avoid the oxidant radical damage”, while another sub-crew tout hyperbaric oxygen therapy (HBOT) “to give your mitochondria extra helping oxygen”.
*sigh*
As ever, mutually exclusive varieties of Alt.Reality bullshit can happily co-exist, since the common theme is Alternative Reality (and bullshit).
August 22nd, 2008 at 2:23 pm
Becca,
Part of the “fun” of dealing with mitochondrial diseases is that the mitochondrial genome is in two places - a small part is in the mitochondria themselves, with the majority of the mitochondrial genome being in the nuclear chromosomes.
Let me try to answer your “what if” questions:
Since all of the genes pertaining to mitochondrial replication (in humans) are on the nuclear genome, what happened to one mitochondrion would happen to all. In this case, the cell’s ability to perform that particular “important cellular function” would be impaired and all of the mitochondria would be better able to replicate.
Depending on the degree of impaired function and the degree of increased replication, the results might be fatal for the cell.
Again, since the change would be at the nuclear genome level, it is quite possible that all of the mitochonrdria would replicate out of control. Oddly enough, I’m not aware of this ever being reported.
I suspect that there are multiple “checks” on mitochondrial replication, because uncontrolled replication would probably lead to cell death, just as uncontrolled viral replication can cause cell death, even if the virus doesn’t lyse the cell. This may be the reason that we don’t see this mutation - it self-eliminates.
I think that mitochondria have attracted so much popular attention in the autism community because they are so “mysterious”.
This is similar to the attraction that “alternative” medicine has for quantum physics: it’s “mysterious” and counter-intuitive and, as such, it acts as a socially acceptable substitute for “magic”. If you take the “alternative” medicine (and “New Age”) explanations that use “quantum physics” and substitute the word “magic”, they make just as much (or little) sense.
Prometheus
August 22nd, 2008 at 4:18 pm
To elaborate on P’s answer to Becca, mitochondria in each tissue compartment are different. Neural mitochondria are quite different than liver mitochondria. However the mtDNA in all mitochondria in the body is the same (except for heteroplasmy). The differences in mitochondria in different tissue compartments are due to nuclear genome stuff. No doubt it is some sort of epigenetic programming of the nuclear DNA during differentiation of the different tissues.
99%+ of the proteins in mitochondria come from the nucleus. The protein manufacturing enzymes in mitochondria come from the nucleus, not the mitochondria. There are many absolutely essential proteins in mitochondria that come from the nucleus, including a few that would very rapidly completely shut down essentially all functions of mitochondria if they were missing, including MnSOD, and cytochrome c. Some of the synthetic steps for heme synthesis are done in the cytoplasm and some are done in mitochondria. Many enzymes in mitochondria have heme, heme is used a lot for O2 and electron transfer.
It needs to be remembered that the association of mitochondria goes way back to very deep evolutionary time. All animals have the same 13 proteins coded for by their mtDNA, except for nematodes, a bivalve, and cnidarians (as I remember). That means all insects, all vertebrates, virtually all animals have mitochondria that are “the same” as far as mtDNA goes. That means that all the movement of DNA from mitochondria to the nucleus happened before the ancestors of those different organisms diverged a long time ago. Plants and fungi also have these same 13 proteins in their mitochondria, plants have a few more.
All the regulation of mitochondria comes from the nucleus. There is very limited regulatory DNA in mitochondria. The only proteins coded for are for the active sites of the respiratory complex and ATP synthesis.
There are some rare types of tumors that are characterized by too many mitochondria but those mitochondria appear to be not functioning normally. Many of the neurodegenerative diseases end up with the accumulation of damaged and dysfunctional mitochondria, I see that as the normal putting off of autophagy under conditions of not enough ATP which is a state of oxidative stress and a state of low NO. That state can become self-perpetuating because not enough mitochondria make more ATP by increasing their potential, which increases production of superoxide which lowers NO levels. NO is what triggers mitochondria biogenesis, and oxidative stress inhibits autophagy. I think that inhibition of autophagy is to conserve ATP during an ATP crisis.
August 22nd, 2008 at 7:19 pm
Fascinating stuff, thanks, I learned something new today
Can’t really contribute on this topic, I’m afraid, but I figured I could at least say “thank you”.
August 23rd, 2008 at 4:38 am
I also would like to add a big “thank you.” You really are an asset to the autism community, Prometheus.
August 23rd, 2008 at 1:13 pm
Genetic variants associated with mitochondrial disease have been associated with ‘autism’ long before the Polling case. A recently published study replicated te previous findings. Interestingly though,the association is with a mental retardation phenotype. Autism researchers have yet to explain the confounding variable of mental retardation in ‘autism’ studies. In families with high functioning autism (Asperger Syndrome) the association was not found.
http://www3.interscience.wiley.com/journal/120835851/abstract?CRETRY=1&SRETRY=0
Autism is a complex multifactorial condition and simplistic single cause theories make no sense whether it is vaccines cause autism or extreme maleness causes autism or gene-gene interactions cause autism.
Behavioral Genetics is a part of the total picture but it is not the entire picture since no gene specific to autism has ever been identified.
August 23rd, 2008 at 4:45 pm
I still don’t understand how Mitochondrial Mutations could lead to autism (or even where that idea came from).
If the worst case scenario is that you have a decrease in ATP synthesis, how does that lead to autism.
August 23rd, 2008 at 10:51 pm
Orodriguez, the path from mitochondrial mutation to autism is neither straight nor obvious. It is, in fact, a gigantic “what if…” story.
Mitochondrial disorders can cause developmental delay by interfering with apoptosis (programmed cell death). Much of neurodevelopment in human children involves destroying specific neurons at the right time. And the mitochondria are the driving force behind apoptosis.
How this can lead to something like autism is still an open question, since we still don’t know the neurological difference that makes autism. Presumably, certain types and degrees of developmental delay - which is seen in some types of mitochondrial dysfunction - can appear similar enough to the current overly broad definition of “autism”.
However, since most people with autism do not have significant involvement of other organ systems, it seems unlikely that mitochondrial dysfunction will be found in more than a small fraction of autistic people.
Research into this question is getting underway, which should lead to an answer. Of course, the people who are most vocal in asserting that autism is a mitochondrial dysfunction have also been the most reluctant to accept the results of other scientific research.
Prometheus
August 24th, 2008 at 4:25 am
The biological systems is very complex in the world. I just understand the basic systems of DNA.
August 24th, 2008 at 9:05 am
The classic case that they whip out, however is Hannah Poling, who has an Oxidative Phosphorylation disorder. Of the symptoms it can cause, like Optic Neuropathy, Myopathy, Lactic Acidosis, Myoclonic Epilepsy, etc, none of them are even remotely similar to Autism.
Not only that, but the people pushing the Mitochondria Hypothesis are not using your apoptosis mechanism but tend to argue that Vaccination + Pre-existing Mitochondrial disorder = autism. Which is even more difficult to reconcile with the evidence.
It seems like a dead end no matter how you cut it.
August 24th, 2008 at 12:16 pm
Orodriguez, if I might expand on what Prometheus said. We know that in most instances of autism no mitochondrial defects have been detected. Autism-like symptoms can be produced by exposure to certain drugs at very specific times in utero (which isn’t due to mitochondria stuff). We know there are a lot of genetic mutations that do cause autism-like symptoms, such as MeCP2 deletion (Rett Syndrome). For diverse mutations (and also non-mutations) to cause similar symptoms, it is likely that there is a final common pathway that these conditions trigger which in turn triggers autism-like symptoms. I think that one of the final common pathways is the generic “stress” pathway, of oxidative stress which is equivalent to low NO.
ATP is one of the most important molecules in physiology. It must also be one of the best regulated molecules in physiology. Most of that regulation is not understood, largely because there are no experimental techniques to measure ATP on the length, time and concentration scale that physiology regulates it at.
ATP directly couples to virtually every pathway in physiology. Those pathways it doesn’t directly couple to, it couples to indirectly.
There is a quote which is considered a truism in mitochondria research (which I am paraphrasing), that “a mitochondrial disorder can produce any symptom in any tissue compartment at any age and by any mode of inheritance.”
ATP levels are coupled to the oxidative stress level. When ATP drops, cells induce oxidative stress to produce ischemic preconditioning, a state which temporarily reduces ATP requirements. When ATP drops, mitochondria turn on and attempt to generate more ATP. They do this by increasing their membrane potential, which increases their production of superoxide which decreases the local NO level, which disinhibits cytochrome c oxidase, which allows O2 to be consumed at the mitochondria at a high rate and a low O2 partial pressure so a larger concentration gradient in O2 develops between the blood vessel and the mitochondria so a high flux of O2 can diffuse down that concentration gradient.
During that state of oxidative stress, superoxide remains confined to mitochondria. Superoxide is an anion, and can’t pass through lipid membranes (and there are 2 between the mitochondria inner matrix where superoxide is generated and the cytosol). However nitric oxide (the subject of my research) freely passes through lipid membranes and reacts with superoxide under near diffusion limited kinetics (near how fast MnSOD dismutates superoxide in the mitochondria matrix). Superoxide in the mitochondrial matrix will pull down the NO level in the cytosol (and beyond). It is NO diffusing beyond the cell that signals to adjacent cells the oxidation state of the mitochondria within that cell. This is an extremely important signaling pathway which is absolutely necessary for whole organs to be regulated “in sync”.
NO and ATP levels are coupled through their common action on sGC, soluble guanylyl cyclase. When NO binds to its heme, it produces cGMP. ATP modulates the sensitivity of sGC to NO, such that ATP and NO levels are coupled. As ATP goes up, sGC becomes less sensitive to NO, and so NO levels go up too. As ATP levels fall, sGC becomes more sensitive to NO.
There is pretty good evidence that autism is a state of oxidative stress; but which is cause and which is effect remains obscure. My own thought is that essentially all states of oxidative stress are a “setpoint” issue, and that physiology is regulating its own state of oxidative stress for its own purposes (such as to trigger ischemic preconditioning) and that state of oxidative stress is not regulated at all by dietary levels of antioxidants (all the large double blind placebo controlled studies of antioxidants supplements show no positive effects and support this idea). In other words, even if autism is a state of oxidative stress, all the antioxidants in the world are not going to fix that if it is a setpoint issue. Antioxidants will actually make it worse because physiology would just make more superoxide to destroy the antioxidants. Mitochondria have unlimited capacity to make superoxide.
To use an analogy, if your furnace (mitochondria) is staying on too much (operating at a high potential) and making your house too hot (create a state of oxidative stress), you could try and fix it by bring in ice (antioxidants) to cool things down (reduce the oxidative stress). But if the thermostat is still calling for 90 degrees (high oxidative stress setpoint), enough ice (antioxidants) may let you cool the living room (tissue compartment A) where the thermostat is, but the boiler room (tissue compartment B) stays too hot or gets even hotter because the furnace (the mitochondria) is now running maxxed out. You have now substituted open loop control (bringing ice to room X when it feels too hot) for closed loop control (thermostat). If the furnace gets too hot (too high a mitochondrial potential) the furnace safety systems activate, fusible plugs open, safety relief valves open, emergency fire control sprinklers activate, fire stop doors close (uncoupling protein gets expressed, respiration chain gets inhibited) extinguishing the furnace (mitochondria irreversibly turn off) and the house loses the capacity to make heat (ATP), the rooms get cold (multiple organ failure) and the house becomes uninhabitable (the organism dies).
In the analogy I used, the “problem” is the normal temperature (ATP) regulatory processes of the house (organism). The only way to fix it is by fixing the thermostat that is set too high (high oxidative stress setpoint) and not by chasing the symptoms of high temperature (high oxidative stress) by adding cooling. How to adjust the thermostat (ATP and oxidative stress setpoint) is critical. My research indicates that it is the coupled interactions of NO and ATP on sGC that are involved in the critically important ATP and oxidative stress setpoint. To extend the analogy (perhaps one step farther than is exactly appropriate) some thermostats works by a fluid being expanded by increased temperature. If the thermometer leaks fluid, it takes a higher temperature to expand the remaining fluid and reach the point where the furnace is turned off. Fluid leaking out has the effect of increasing the thermostat setpoint. I see not enough NO as doing exactly the same thing. Just as fluid expansion and temperature are coupled, so are NO and ATP coupled through sGC. Not enough NO shows up as a increased setpoint for ATP demand which mitochondria turn on to try and provide. In the short term that is ok, it is only in the long term that bad things happen through how physiology adjusts itself to the chronic condition.
My own thought is that low basal nitric oxide is one of the final common pathways in the mix of things that cause autism-like symptoms (and I write about this at length on my blog). Mitochondria could be involved in that because mitochondria are major sinks for NO, and they become larger sinks for NO when they are “stressed” or called on to make more superoxide. The generic stress response for mitochondria is to increase superoxide formation. That accelerates ATP production, but it can also accelerate mitochondria damage where they then require more frequent replacement. NO is what triggers mitochondria replacement, so if a perpetual state of low NO is induced, insufficient mitochondria could perpetuate it.
I want to emphasize that the scenario I have outlined can occur with 100% completely normal mitochondria in 100% completely normal individuals. There is nothing “abnormal” about this regulation of mitochondria. No defect is required for mitochondria to exhibit this type of behavior. Mitochondria with defects will likely exhibit this type of behavior with a lower threshold (depending on what the defect is). To go back to the analogy, mitochondria with defect XYZ might exhibit this behavior at 87 degrees, completely normal mitochondria might exhibit it at 90 degrees. Many other things will influence it too, nutritional state, age, gender, physical condition, etc. etc. etc.
August 25th, 2008 at 10:27 am
[...] the opportunity to understand why—and why not—to connect it with Autism. Learn about Mitochondrial Mutations and Autism. Sphere: Related Content « Input [...]
August 25th, 2008 at 10:52 am
One of the contributing factors to the increased rate of autism (and ADD/ADHD) in boys compared to girls is that boys have less glutathione. Glutathione is a potent antioxidant that neutralizes the reactive oxygen species (ROS) that can damage the mitochondria. These are widely known as free radicals. Glutathione is essential in both phase I and Phase II detoxification. Therefore, any toxic exposure, including thimerosal in vaccines, will be more likely to induce damage in children with lower glutathione stores. Autistic children are often genetically predisposed to lower glutathione levels.
Hope this helps. (I explain this in greater detail in Chapter 19 of [title redacted])
Teresa Holler
[Ed: The author of this comment is a PA who offers advice about "toxicity" on her website. This 'blog is not an advertising site, so references to her website and book were redacted.]
August 25th, 2008 at 3:54 pm
Erythrocyte glutathione levels are indeed lower in adult males than in adult females. Strangely enough, this doesn’t lead to increased lipid peroxidation, so the lower glutathione levels are apparently balanced by some other anti-oxidation pathway.
It also isn’t clear that immature males (”boys”) have lower glutathione levels - insufficient data are available to make the comparison.
Studies looking at glutathione levels in autistic children have looked - as far as I can tell - solely at plasma or serum glutathione, which is much lower and does not necessarily reflect intracellular glutathione levels. It is not clear if these lower serum glutathione levels are genetic, due to unspecified “toxins” or are simply an artifact.
One thing about Ms. Holler’s explanation that doesn’t hold together is that males have had lower glutathione - at least after puberty - for tens of thousands of years, yet the “autism epidemic” (and, presumably, the “ADD/ADHD epidemic”) have been fairly recent.
Oh, and before thimerosal gets dragged out, remember that the removal of thimerosal from childhood vaccines has not led to a decline in the prevalence of autism or ADD/ADHD.
Prometheus
September 1st, 2008 at 10:21 pm
Hey, the Mercury Militia is circling the following study:
http://iospress.metapress.com/content/133622276585h1t0/?p=fa206c6a376d481989c5868d1cd8c409&pi=2
Just a heads up, in case any one has access to the study or at least the conclusion.
September 2nd, 2008 at 5:29 pm
Orodriguez,
Thanks for the “heads up”!
I’ve asked the library to get me a copy of the article, since we don’t carry the journal it is in. Reading the abstract, I can already see three major errors, since the author (David Austin) asserts the following:
Actually, autism is nothing like the symptoms of mercury poisoning and only one article - in Medical Hypotheses - written by a group of authors who had never seen mercury poisoning, has ever made that assertion.
Again, there are no animal models of autism and mercury has never been shown to cause autism in animals - whatever that might look like.
And once again, this has never been demonstrated.
Given the author’s assertions as outlined in his abstract, it seems fair to assume that his conclusions are equally flawed.
Prometheus
September 4th, 2008 at 11:12 pm
[...] http://photoninthedarkness.com/?p=149 [...]
September 10th, 2008 at 1:19 pm
Well all this proves that there is new sucker born every minute.
Mito or whatever might be the new black for the moment, but when this ceases to bring home the bacon for the DAN brigade something else will turn up which is equally “significant” and the acolytes will fall for it.
Any way to prove my point that there are fringe, wierd and wacky theries and profiteers out there just waiting for there 15 minutes what do you think of this
http://tinyurl.com/699l5f
September 10th, 2008 at 3:10 pm
The website that Laurentius Rex is pointing us to contains the following statement:
I think that the person promoting this nonsense really believes in it. That doesn’t make them a bad person, just one of the millions who are unable to distinguish fairy tales from science.
Prometheus
September 25th, 2008 at 9:44 am
“The idea of leaving a child with mitochondrial “dysfunction” unvaccinated begs the question: isn’t it better to prevent the “full blown” disease, even if you run the risk of “triggering” mitochondrial “stress”?”
One thing to keep in mind here is that currently vaccinations a given at a very early age and there are many of them. A natural full blown disease will be comparatively rare and will typically come at a later age, when children have past some critical phases of development.
Which approach is better for the child’s development when it comes to mitochondrial stress: vaccinate, not vaccinate or vaccinate at a later age? Speculation can go either way. We have no data.
October 16th, 2008 at 9:05 am
Bisser, please take my comment just as a pointer, as I cannot remember where I read it, but during the high time of the poling case, a mother of a child with “mito” stressed that vaccinating is especially important for these kids, as they are very vulnerable towards these preventable illnesses. Sorry that I do not have the source, but the d ata is there and it says vaccinate.
November 2nd, 2008 at 7:59 pm
[...] This first appeared on Photon In The Darkness. [...]
February 11th, 2009 at 8:44 pm
[...] findings. And we have the, by now, familiar references to Hannah Poling (and here) and Dr Bernardine Healy. The whole sundae is then topped off as Phillips echoes Wakefield’s [...]