Mitochondrial Complex 1 Deficiency

[Hutan]

A member with the symptoms of severe ME/CFS along with some swallowing issues had their genome sequenced by Sequencing.com.

This is the report on one of the variants found:

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High Evidence
Mitochondrial Complex 1 Deficiency, Nuclear Type 1

Genetic variants detected for this condition
Variant ID rs 754873418, RCV005419177
Evidence: High
Risk Status: Likely carrier

Gene NDUFV2
Gene information: NDUFV2, also known as NADH: ubiquinone oxidoreductase core subunit V2, is a gene that provides instructions for making a protein that is a crucial component of Complex 1, the first major enzyme complex in the mitochondria that powers our cells. This protein helps convert nutrients into usable energy through a process called cellular respiration. Mutations in the NDUF2 gene can lead to mitochondrial disorders, which are rare genetic conditions characterised by muscle weakness, neurological problems, and other complications because cells cannot produce enough energy to function properly. these disorders typically appear in infancy or early childhood and can affect multiple organ systems especially those with high energy demand such as the brain, muscles, heart and liver.

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We note the 'Likely carrier' status, but, given the person's symptoms, it seems sensible to consider if this finding could account for them. The member hasn't had their mitochondrial genome sequenced.

We are interested in your thoughts about this.

 

[Jonathan Edwards]

Gene NDUFV2

It would probably be legitimate to check whether any signal has come up for this gene in the genetic studies of ME/CFS to date, including DecodeME or the Snyder study?

A nuclear (as opposed to mitochondrial) DNA segment would be expected to produce disease in early childhood if acting alone. But it is conceivable that having a gene mutation might make the course of ME/CFS worse or make the difference between having it or not, I guess.

 

[Hutan]

Link to the Genecard entry for NDUFV2

And here's the Malacard - link

A form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non- specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN7 transmission pattern is consistent with autosomal recessive inheritance.

Disease Ontology
A nuclear type mitochondrial complex I deficiency that has material basis in homozygous or compound heterozygous mutation in the NDUFV2 gene on chromosome 18p11.22.

 

[forestglip]

It would probably be legitimate to check whether any signal has come up for this gene in the genetic studies of ME/CFS to date, including DecodeME

Nothing much in DecodeME. Maybe a single variant downstream of the gene with a p-value of 1e-4: https://my.locuszoom.org/gwas/894183/region/?chrom=18&start=8963196&end=9250245

 

[forestglip]

Genetic variants detected for this condition
Variant ID rs 754873418, RCV005419177
Evidence: High
Risk Status: Likely carrier

ClinVar page for this variant: https://www.ncbi.nlm.nih.gov/clinvar/variation/1194462/

 

[forestglip]

the Snyder study?

It's not ranked highly at all in the Zhang preprint. It's ranked 14287. The lower the number, the more relevant the gene was considered.

 

[mariovitali]

I wonder how this patient feels if given Flavin Mononucleotide (FMN)

 

[Violeta]

I wonder how this patient feels if given Flavin Mononucleotide (FMN)

Thank you! I was trying to figure out what would help Complex I but just kept thinking it would be thiamine. But nothing would come up in searches for thiamine.

 

[Violeta]

Can you ask the person if he/she has had a blood test showing a problem with iron?

 

[Hutan]

Noting that it's recommended that someone with the Mitochondrial Complex 1 Deficiency should not take metformin (e.g. as someone with Type 2 diabetes might), because metformin lowers blood sugar by inhibiting Mitochondrial Complex 1 Deficiency.

Medsafe NZ - notes metformin causes lactic acidosis in people with MC1D. It mentions other drugs that affect MC1 including anti-psychotics and beta-blockers.

Spoiler: more papers on this

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1).

Also: Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences
and: Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycemic control, 2025

There's mention of berberine acting in the same way.

 

[mariovitali]

Noting that NDUFV2 is a flavoprotein and that requires FMN (acts as an essential electron carrier in Complex I of the mitochondrial electron transport chain, derived from Riboflavin and available as a supplement) :

NDUFV2 encodes the NADH:ubiquinone oxidoreductase flavoprotein 2, a mitochondrial Complex I subunit that initiates electron transfer from NADH to ubiquinone. It functions in the inner mitochondrial membrane as part of the respiratory chain and contributes to proton gradient generation for ATP synthesis. The protein is also detected in the cytosol and nucleoplasm, and expression is high in brain, endocrine system, and respiratory system.

Within Complex I, NDUFV2 acts in the peripheral arm and supports electron flow through FMN and iron-sulfur clusters. This placement links it to the first steps of mitochondrial respiration, where it helps drive the conversion of redox energy into the proton motive force. The protein is associated with the NuoE domain and has reported acetylation and phosphorylation sites. RNA expression is also observed in muscle tissue, the hepatobiliary system, and the cardiovascular system.

Source : https://www.genecards.org/card/NDUFV2 [1]


What are the key takeaways if this patient has confirmed ME/CFS? Could this condition be picked up by DecodeME?


The NDUF* part rang a bell and I found a network analysis I ran in 2017 . As you can see the analysis picked up flavoproteins and NDUFS7 (which is also a Complex I related gene and closesly associated with NDUFV2, per link [1] above)



Link : https://blogger.googleusercontent.c...zDt3D3jSPaTohfD3Y/s1600/2017-Oct-unmasked.png

 

[Hutan]

Could this condition be picked up by DecodeME?

@forestglip posted about that upthread. He attached the chart of the hits from DecodeME.

I've pasted it here:


See the genes listed along the bottom. There is nothing interesting going on for NDUFV2.

(I'd love to be able to interpret these charts in terms of the percentage of people in the DecodeME ME/CFS sample with a certain variant - is that possible? )

Anyway, there is a slightly interesting blip at around 9.15, but that looks to be associated with the neighbouring ANKRD12 gene, which has a completely different function.

However, I don't think DecodeME looked at all the variants, and particularly not rare variants, and the variant that is the topic of this thread will, I think, be a rare variant. So, it will be interesting to keep an eye out for it in the studies now underway looking at those.

I may have got things wrong, if so, I'm happy to be corrected.

 

[mariovitali]

See the genes listed along the bottom. There is nothing interesting going on for NDUFV2.

I should have explained what I am after instead of asking a question. In my understanding there may be cases such as this patient which are not frequent enough to be picked up by DecodeME. Please someone correct me if I am wrong.

Is it possible that via other multi-gene alterations , patients get a -say- 40% reduction in Complex I function ? What would the implications of this be in term of symptoms? Would it affect glutamate levels ? Is there a way to check this possibility (=multi gene alterations affecting certain mitochondrial functions) ?