Mitochondrial DNA Missense Mutations ... Identified in a Caucasian Female with (ME/CFS) Triggered by the [EBV],2024,Tang-Siegel

Dolphin · May 11, 2024

https://www.hindawi.com/journals/crig/2024/6475425/

Full title: Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein–Barr Virus

Gaoyan G. Tang-Siegel,1
David W. Maughan,1
Milah B. Frownfelter,2
and Alan R. Light3

1Department of Molecular Physiology and Biophysics, College of Medicine, University of Vermont, Burlington, VT, USA
2Seattle Medical Associates, 1124 Columbia St. Suite 620, Seattle, WA, USA
3Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA

Academic Editor: Sofia Priyadarsani Das

Received19 Jan 2024
Revised23 Apr 2024
Accepted25 Apr 2024
Published09 May 2024
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Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disabling disease with unclear etiology and pathophysiology, whose typical symptoms include prolonged debilitating recovery from fatigue or postexertional malaise (PEM).

Disrupted production of adenosine triphosphate (ATP), the intracellular energy that fuels cellular activity, is a cause for fatigue.

Here, we present a long-term case of ME/CFS: a 75-year-old Caucasian female patient, whose symptoms of ME/CFS were clearly triggered by an acute infection of the Epstein–Barr virus 24 years ago (mononucleosis).

Before then, the patient was a healthy professional woman.

A recent DNA sequence analysis identified missense variants of mitochondrial respiratory chain enzymes, including ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V).

Protein subunits ATP6 and Cox1 are encoded by mitochondrial DNA outside of the nucleus: the Cox1 gene encodes subunit 1 of complex IV (CIV: cytochrome c oxidase) and the ATP6 gene encodes subunit A of complex V (CV: ATP synthase).

CIV and CV are the last two of five essential enzymes that perform the mitochondrial electron transport respiratory chain reaction to generate ATP.

Further analysis of the blood sample using transmission electron microscopy demonstrated abnormal, circulating, extracellular mitochondria.

These results indicate that the patient had dysfunctional mitochondria, which may contribute directly to her major symptoms, including PEM and neurological and cognitive changes.

Furthermore, the identified variants of ATP6 (ChrMT: 8981A > G; Q152R) and Cox1 (ChrMT: 6268C > T; A122V), functioning at a later stage of mitochondrial ATP production, may play a role in the abnormality of the patient’s mitochondria and the development of her ME/CFS symptoms.

https://twitter.com/user/status/1789274903062987120

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Creekside · May 11, 2024

Lots of assumptions there, such as ME's fatigue-like state being regular physical fatigue, and that the patient's mitochondrial abnormalities are due to ME or part of ME's mechanism. I expect there are plenty of people who would report "fatigue" on a questionnaire who don't have these genetic defects.

Hutan · May 11, 2024

It's a clear read, so far.

It's certainly not the first time that it has been proposed that problems with complex IV and complex V of the electron transport chain.

Prior to her bout of EBV infection in 1999, the patient was a healthy, professional woman. After acquiring the infection, the patient has suffered from ME/CFS with severe dysautonomia, cognitive impairment, and widespread pain. The patient also maintained relatively high titers of EBV antibodies, including anticapsid antigen (anti-VCA) IgM/IgG and anti-early antigen (EA) IgG, despite the fact that she has been taking antiviral drugs, including valacyclovir and valganciclovir for long periods. The elevated anti-VCA and anti-EA antibodies indicated an acute phase of EBV infections, suggesting repeated re-infections (or lytic infections) of EBV, during multiple episodes of her “crash” times. A very recent blood test was performed in June 2023, which demonstrated anti-VCA IgG > 600.0 (standard range 0.0–17.9) and anti-EA IgG > 103.0 U/mL (standard range 0.0–8.9 U/mL).

The elevated anti-EBV antibodies of the patient, however, did not meet the diagnostic criteria for chronic active Epstein–Barr virus (CAEBV) disease, which requires extremely high antibody detection, including anti-EA IgG ≥ 160 U/mL [16]. In addition to antibody titers, simultaneous quantitative PCR analyses of her blood samples at the same time indicated relatively low viral DNA loads and her most current laboratory tests (June 2023) showed 248 IU/mL, significantly lower than 10,000 IU/mL, the diagnostic criteria for CAEBV [16]. Furthermore, the patient did not present any common symptoms of CAEBV, which are normally indicators of uncontrolled viral infiltrations of multiple organs, such as lymphadenopathy, splenomegaly, hepatitis, and pancytopenia [16, 17], except for a fever at the time when she was initially diagnosed with infectious mononucleosis in 1999.
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The onset following a triggering EBV infection seems quite clear. That association of elevated EBV antibodies with ME/CFS crashes seems to be supposition though.

Strikingly, EBV DNA replication has been found to be significantly more active in ME/CFS patients than in healthy individuals [3], including the current patient. This female patient showed significantly high anti-EA IgG antibody production (the titer was 6–10 times higher than the normal detection range, including the latest two tests in the past year), concomitant with her typical ME/CFS symptoms.
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I'm not sure that the evidence that there is more EBV DNA replication in ME/CFS has been particularly convincing.

Ref 3 is E. Shikova, V. Reshkova, А. Kumanova et al., “Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome,” Journal of Medical Virology, vol. 92, no. 12, pp. 3682–3688, 2020. Publisher Site
Here's the link to the forum thread for that paper:
Cytomegalovirus, Epstein‐Barr Virus and Human Herpesvirus 6 Infections in Patients with [ME/CFS], 2020, Shikova et al
@Ravn made the point that, while there may be evidence of more EBV reactivation in ME/CFS than in healthy controls, it is not clear if that is causal or simply a result of a reduced inability to suppress viral reactivations.

Hutan · May 11, 2024

To our knowledge, the ChrMT: 6268C > T; Cox1: A122V variant, which we identified here, is the first reported mutation of the cox1 gene.
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We proposed that the mutations we have identified and characterized here may have potentially predisposed this patient to develop abnormal mitochondria, as observed, which could have contributed to her major symptoms of ME/CFS: debilitating PEM and neurological and cognitive alterations.
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Interestingly, an extensive study performed by Billing-Ross et al. investigated the correlation between ChrMT DNA variants and ME/CFS based on 193 cases versus 196 control individuals and indicated that ME/CFS patients with certain mitochondrial haplogroups or point mutations at certain positions (ChrMT:150, ChrMT:930, ChrMT:1719, ChrMT:3010, ChrMT:5147, ChrMT:16093, ChrMT:16223, and ChrMT:16519) are more likely to develop certain symptoms [39]. However, the ChrMT:8981 and ChrMT:6268 mutations, which we identified in this patient, were not on their list. Furthermore, the study performed by Billing-Ross et al. did not identify any ChrMT variants, which would potentially increase the susceptibility of an individual to develop ME/CFS [39]. Given these findings, we hypothesize that the point mutations of ChrMT identified in this patient might occur later in her life randomly, due to accumulated mitochondrial stress, including viral exposure and infection. Consistently, there are studies convincing a strong correlation between ME/CFS and mitochondrial dysfunction [40, 41].
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Hutan · May 12, 2024

The timing and severity of her symptoms were not limited to her immune cells, if the mutations did occur later in her life, which suggests that ChrMT DNA sequencing analyses of family members of the patient would be an important further step to understand the individual and combined role of viral infections, mitochondrial ChrMT DNA mutations, and mitochondrial malfunction in the development of postinfection syndromes with profound disabling fatigue featured in the typical case of ME/CFS reported here.
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That's a confusing long sentence, but there is a good point in there - that DNA sequencing of family members of the patient would be interesting.

I have the feeling that mitochondrial DNA has been looked at, and nothing of significance has been found. But, perhaps it is worth looking again.

In this case of ME/CFS, we observed that free, extracellular mitochondria appeared to “protrude” or “secrete” vesicle-like structures (Figure 3), like those secreted from Gram-negative bacteria in stressful conditions.
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Recently, the essential roles that mitochondria may play during the viral invasion of the host have been recognized [25]. It is likely that the abnormal appearance of the free mitochondria we observed in this patient is a consequence of malfunctional mitochondria responding to viral exposures. The causes and sequelae of large numbers of extracellular, abnormal mitochondria in the blood circulation of this ME/CFS patient, and of other patients with ME/CFS-like, postinfection syndromes, require further investigations.
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Given this is an n=1 case study, it's hard to know whether this phenomenon of protrusions from extracellular mitochondria also occurs in healthy controls. Extra-cellular mitochondria are interesting. This paper has more information:
Forms of extracellular mitochondria and their impact in health
That paper mentions the link between mitochondria and extracellular vesicles which came up on another thread recently e.g.

Larger EVs such as MVs can contain entire mitochondria, and smaller EVs like exosomes can transport mtDNA and other nucleic acids to target cells
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Kitty · May 12, 2024

Hutan said: ↑

it's hard to know whether this phenomenon of protrusions from extracellular mitochondria also occurs in healthy controls
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Same thing struck me about the EBV reactivation. If people have reactivation but there are no symptoms clear enough to alert them, it's very hard to know whether pwME have greater, lower, or roughly the same levels of viral activity.

Mij · May 12, 2024

I mean, who's going to their doctors office every time they feel 'viral'? In this case I'd be there every few months and my doctor would say 'no' that they don't test.

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