What does autism with mitochondrial dysfunction mean?

I don't mind admitting that I'm a little bit baffled by mitochondrial function. Yes, I know all about the 'powerhouse' label which they have been given. But still, it's a topic which confuses me quite a bit.

Masquerade - Beardsley @ Wikipedia 

With autism in mind, I've skirted around the edges of the growing literature suggestive of some mitochondrial dysfunction being present in cases (see here and here) but to be honest it's always seemed a little bit too big of an area for me to tackle. That and the fact that some authors have already written some pretty good (peer-reviewed) review papers on the topic as per the example of Rossignol & Frye* (open-access) and Frye & Rossignol** (open-access) (yes, the same authors).

Indeed it is with the name Dr Richard Frye that I'm talking today about a new paper of his*** (open-access) published in what seems to be a favourite journal, Translational Psychiatry (that and its sister journal, Molecular Psychiatry). The latest offering with possibly the longest abstract I've seen in a while looked at a group of children diagnosed with an autism spectrum disorder (ASD) "who met criteria for probable or definite MD" [MD = mitochondrial disease] to see whether there was any tie-in with another interesting area of autism research looking at abnormal redox metabolism and all that oxidative stress work.

This is quite a big paper in terms of the wealth of data which has been included. Quite a lot of it goes well above what I would consider myself comfortable with explaining so you'll have to excuse me if I use quite a few quotes and perhaps skip over certain reported findings. The paper is open-access so please do read it.

Data are presented from 18 children who fitted both the autism and MD bill compared with 18 kids with autism but no MD. Immediately I'm struck by the focus on a specific subgroup of the autisms which is definitely the way ahead for autism research. Bearing in mind the small participant numbers and although there were some differences on things like the VABS, the groups were fairly consistent when it comes to the presentation of autistic behaviours and language abilities. Most of the differences (significant differences) were noted in the biochemistry looked at, and not exactly the way most people would have figured.

So for example, when it came to that elephant in the room that is glutathione and autism, there were indications of a "more favourable glutathione redox status in the ASD/MD group" as a function of the balance between reduced and oxidised levels (see here). Bearing in mind though that when compared with an asymptomatic control group - typically developing controls - both the MD and non-MD autism groups were quite a bit below what the glutathione balance should have been which accords with other work.

I was interested also to see that 3-chlorotyrosine (3CT), a marker of chronic inflammation was also looked at in the latest study. 3-CT was discussed in another Frye paper on another pet topic of mine, tetrahydrobiopterin or BH4 talked about recently with autism in mind (see here). A long quote: "Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD". Irrespective of the MD side of things, this finding in particular is of potentially real interest to autism research.

Levels of another compound "3-nitrotyrosine (3NT), a biomarker of oxidative damage to proteins" were also tied into a few interesting findings between and across the groups examined. Again perhaps slightly counter to what would be expected was the suggestion that higher levels of 3NT "were associated with more favourable adaptive behaviour, language and ASD-related behavior". Again I was drawn back to another study from this authorship group suggesting 3NT was a feature of post-mortem brain specimens linked to autism (see here).

So as not to get you and I even more confused I'm moving to some of the paper conclusions. That for example, there is more uniting the autism-MD and autism non-MD groups than which divides them is perhaps not so surprising. Another quote: "both ASD groups manifested abnormal redox and immune metabolism, but in slightly different ways".

The issue of inflammation as a consequence of those 3CT levels being elevated in autism cases is really interesting. The authors cover this point well by speculating that the chronological age factor in this relationship (younger children presented with higher levels) is potentially reflective of early life inflammation triggering a cascade of events which "initiated the mitochondrial dysfunction and damage". The speculation continues that even though the inflammatory issues become 'resolved' as children get older, the mitochondrial damage remains. I'm intrigued at this notion of how specific biological events might appear during a window of infancy and development but not necessarily persisting yet leaving a lasting impression. That and the very preliminary evidence talking about markers of inflammation in mums of children with autism (see here) asks some interesting questions about the value of functional here-and-now testing if the 'damage has already been done'.

I've not done justice to the Frye paper in this post simply because I freely admit that I don't understand all of it. To the question which forms the title of this post about what MD might mean to autism, I'm minded to say quite a bit but not necessarily as centrally as we might have first thought. Perhaps also encompassing quite a bit of other research as per some other recent results on tryptophan metabolism in relation to autism**** (open-access) and quote: "Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs". That and endorsing their idea that 'compensation' is an attribute of our wonderfully engineered bodies that we would do well not to forget about.

To close, I've talked about the Richard Linklater film 'Dazed and Confused' before on this blog. I'm going to leave you with another classic featured in the film.... Rock and Roll All Nite by a group with a very famous tongue.

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* Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012 March; 17(3): 290–314.

** Frye RE. & Rossignol D. Mitochondrial physiology and autism spectrum disorder. OA Autism. 2013; 1: 5.

*** Frye RE. et al. Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Translational Psychiatry 2013; 3: e273. doi:10.1038/tp.2013.51

**** Boccuto L. et al. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013 Jun 3;4(1):16. doi: 10.1186/2040-2392-4-16.

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Frye, R., DeLaTorre, R., Taylor, H., Slattery, J., Melnyk, S., Chowdhury, N., & James, S. (2013). Redox metabolism abnormalities in autistic children associated with mitochondrial disease Translational Psychiatry, 3 (6) DOI: 10.1038/tp.2013.51