Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome

[Dolphin]

http://www.sciencedirect.com/science/article/pii/S1567724916302215

Mitochondrion
Available online 28 October 2016

In Press, Accepted Manuscript — Note to users



Mitochondrial dysfunction in a family with psychosis and chronic fatigue syndrome

• Helena Torrella, 1,
• Yolanda Alonsob,
• Glòria Garrabouc,
• David Muletb,
• Marc Catalánc,
• Alba Valiente-Pallejàb,
• Lidia Carreño-Gagod,
• Elena García-Arumíd,
• Elena Montañaa,
• Elisabet Vilellaa,
• Lourdes Martorellb, , 1,

http://dx.doi.org/10.1016/j.mito.2016.10.007


Highlights


•
Mitochondrial dysfunction is associated with chronic fatigue symptoms (72 characters)

•
Lactate stress test as an assay to identify mitochondrial impairment in CFS (78 characters)

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Further studies are needed to know if C16179A and T16519A alter mtDNA function (81 characters)



Abstract
Mitochondrial impairment is hypothesized to be involved in chronic fatigue syndrome (CFS) and schizophrenia. We performed a clinical, genetic and functional mitochondrial study in a family consisting of a female presenting schizophrenia in addition to CFS symptoms and her mother and older sister, both presenting with CFS. The three family members showed higher blood lactate levels, higher mitochondrial mass, lower mtDNA content and overall lower mitochondrial enzymatic activities and lower oxygen consumption capacities than healthy women. This family presented mtDNA depletion; however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied.

Abbreviations

• ATP, adenosine triphosphate;
• C10orf2, chromosome 10 open reading frame 2;
• CI, mitochondrial complex one;
• CII, mitochondrial complex two;
• CIII, mitochondrial complex three;
• CIV, mitochondrial complex four;
• cDNA, complementary deoxyribonucleic acid;
• Cellox, global endogenous substrate consumption;
• CFS, chronic fatigue syndrome;
• CPK, creatine phosphokinase;
• CS, citrate synthase;
• DGUOK, deoxyguanosine kinase;
• DNA, deoxyribonucleic acid;
• DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition;
• EDTA, ethylenediaminetetraacetic acid;
• G3Pox, glyceraldehyde 3-phosphate oxidation;
• GMox, glutamate malate oxidation;
• GUSB, glucuronidase beta;
• HPRT1, hypoxanthine phosphoribosyltransferase 1;
• IPAQ, International Physical Activity Questionnaire;
• MPV17, MpV17 mitochondrial inner membrane protein;
• MRC, mitochondrial respiratory chain;
• MRI, magnetic resonance imaging;
• mtDNA, mitochondrial DNA;
• MT-ND1, mitochondrially encoded NADH dehydrogenase 1;
• MT-ND4, mitochondrially encoded NADH dehydrogenase 4;
• nDNA, nuclear DNA;
• PBMCs, peripheral blood mononuclear cells;
• PGM, personal genome machine;
• PMox, pyruvate malate oxidation;
• POLG, polymerase (DNA directed), gamma;
• qPCR, quantitative polymerase chain reaction;
• RNA, ribonucleic acid;
• RNAse P, ribonuclease P;
• RPPH1, ribonuclease P RNA component H1;
• RRM2B, ribonucleotide reductase M2 B;
• SCAN, Schedules for Clinical Assessment in Neuropsychiatry;
• SD, standard deviation;
• SEM, standard error of the mean;
• Sox, succinate oxidation;
• SPECT, single-photon emission computed tomography;
• TK2, thymidine kinase 2, mitochondrial;
• YWHAZ, tyrosine 3-monooxygenase

Keywords

• Chronic fatigue syndrome;
• Schizophrenia;
• Mitochondrial DNA;
• mtDNA;
• Mitochondrial respiratory chain complexes;
• mtDNA depletion

http://www.sciencedirect.com/science/article/pii/S1567724916302215

 

[A.B.]

It's on sci-hub. Conclusions:

We found that the three family members presenting CFS accompanied in one subject with psychotic symptoms, showed similar features: blood lactate levels that dramatically increased after five minutes of exercise, mitochondrial mass increased by 325%±100, mt DNA depleted by 74%±2, RNA expression reduced by 63%±1, and MRC oxygen consumption capacities and enzymatic activities that were 66%±1 and 62%±13 lower, respectively, than expected. However, no nucleotide substitution, insertion, or deletion was identified in the mitochondrial genomes of these women neither in the nuclear genes POLG , C10orf2 , DGUOK , RRM2B , MPV17 and TK2, which may have explained the decreased mtDNA content and consequent mitochondrial dysfunction , even though C16179A and T16519A variants sh ould be further studied . Therefore, other genes must be responsible for the mitochondrial DNA depletion and consequent mitochondrial dysfunction observed in this family. The observed mitochondrial dysfunction that may be associated with both illnesses or, at least, with the fatigue symptoms they all presented. Finally, we propose the suitability of the lactate stress test as a non - invasive, easy, and affordable procedure to identify mitochondrial impairment in patients presenting symptoms of chronic fatigue.

 

[A.B.]

Three people in my family. I need to find some researcher who wants to test us.

 

[Hutan]

Three people in my family. I need to find some researcher who wants to test us.

Have you, or others, considered getting a lactate monitor and checking for yourself? A monitor seems to cost around $300.

There was the thread on lactate monitoring
http://forums.phoenixrising.me/inde...-study-to-measure-blood-lactate-levels.40152/

(I was thinking about getting a monitor at the time, then forgot about it.)

 

[taniaaust1]

Three people in my family. I need to find some researcher who wants to test us.

Four people in my family with ME/CFS (my sister and two of my first cousins have too) and my father is on disability as he has had a schizophrenia diagnoses. We also have a lot of severe celiac disease (3-4 members) and also have Autism on that side of family too (3 with Aspergers) and also systemic mastocytosis (severe mast cell disorder).

I think its great they are doing family studies. I'd like to see more of these done to try to figure out the genes involved.

 

[Hip]

The Myhill, Booth and McLaren-Howard explanation for the dramatic lactate build up soon after exercise that is found in ME/CFS is the following:

Because of mitochondrial dysfunction in ME/CFS, there is not enough ATP supplied by the mitochondria. The cells try to make up for this lack of ATP by manufacturing ATP via the alternative route of glycolysis (glycolysis takes place in the cell cytosol, not in the mitochondria, so is not impacted by the mitochondrial dysfunction).

However, glycolysis without the participation of the mitochondria results in the production of lactic acid (in glycolysis, the pyruvate produced is either sent to the mitochondria to be burnt, or is otherwise converted to lactic acid).

So by making ATP in this way, you get a dramatic build up of lactic acid.

 

[alex3619]

The lower mitochondrial DNA is interesting, as is the lower RNA. If RNA is lower then the proteins made using it may also be deficient. So its possible, but not proven, that the mitochondria might have a problem with many of its proteins, which would also include transporters. I would need to know details of the oxygen testing and enzymatic testing before I could comment. Its possible these are from other causes than intrinsic mitochondrial dysfunction. Indeed this is possibly not incompatible with the recent ideas that mitochondrial dysfunction is induced by non-mitochondrial factors.

 

[anciendaze]

If there is no difference in mtDNA or nuclear DNA used by mitochondria there is a real possibility of autoantibodies interfering with mitochondrial activity and replication. Possible autoimmunity makes me wonder about onset in case histories. Detailed information might identify the type of defect.

The increase in mitochondrial mass and decrease in mtDNA and mtRNA sounds like a problem eliminating abnormal proteins, which slows mitochondrial replication. This fits the hypothesis of an autoimmune problem.

The bright spot in this is that it should be possible to treat this without replacing genes.

 

[ash0787]

So would this be the first study to assess these particular aspects of the mitochrondria ? im sure you can appreciate the issue with such a small sample size and them all being related to each other

 

[anciendaze]

This is a case history ash, not a statistical study. These are very different ways of gaining understanding about a problem.

As I learned repeatedly in my previous career, R.W. Hamming was right when he said "The purpose of computing is insight, not numbers."

Sheer numerical evidence can give a spurious impression of objectivity and understanding, as happened when PACE applied their preferred therapies to cohorts apparently defined as "patients who say they are tired when we don't think they should."

 

[pattismith]

My opinion is that every single CFS/ME should be checked for his mitochondrial function (at least monitored for the blood lactates), and that every time an impaired mitochondrial function would be noticed, a genetic cause should be looked for.
it would allow
-to identify a subgroup of CFS/ME patients with mitoD
-to improve the mitoD genetic science

Then if no genetic cause could be identifyed, auto-antibodies should be looked for

http://www.sciencedirect.com/science/article/pii/S1567724916302215
however, no mutation was identified neither in the mtDNA nor in the nuclear genes related with mtDNA depletion, even though C16179A and T16519A variants should be further studied.

I would like to know the genes concerned by these variants...:thumbdown: