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Case Reports
. 2024 May 9:2024:6475425.
doi: 10.1155/2024/6475425. eCollection 2024.

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 , Alan R Light  3
Affiliations
Case Reports

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 et al. Case Rep Genet. .

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.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Chromosomes of mitochondria (ChrMT). Mitochondria in the cytoplasm of cells contain their own circular dsDNA (ChrMT). (a) ChrMT located outside of the nucleus. Offspring inherit ChrMT from their mothers. (b) Map of human ChrMT, derived from Shokolenko et al. [11]. ND1-ND6 and ND4L encode subunits of CI; Cox1-Cox3 encode subunits of CIV; ATP6 and ATP8 encode subunits of CV; and cyt b encodes CIlI. The ChrMT encodes 13 proteins, composed of complexes of CI, CIV, CV, and CIII.
Figure 2
Figure 2
Mitochondrial chromosome DNA (ChrMT DNA) purification from the long-term ME/CFS female patient. 1. Extracellular ChrMT DNA isolated from the plasma; 2. cellular ChrMT DNA isolated from WBCs and platelets.
Figure 3
Figure 3
Methylamine tungstate, negatively stained, whole-mount TEM analysis of mitochondria (mt) isolated from the patient's plasma. Mitochondria with different shapes and sizes, ranging from ∼400 nm (Panel (a)) to over 1 µm (Panel (f)), were identified. Some mitochondria are attached to “vesicle-like” structures protruding from the membrane (∼100 nm in diameter), pointed by white arrows in Panels (a–c). Scale bar: 100 nm.
Figure 4
Figure 4
Structural localization of identified ChrMT DNA mutations in proteins and analyses of physiochemical features of mutated amino acids. (a) Complex V subunit A and ChrMT: 8981A > G (ATP6: Q152R, pointed by purple arrows). The mutation is located in one transmembrane helical structure (138–158, highlighted in green). The mutation from Gln to Arg changes certain physiochemical features. (b) Complex IV subunit 1 and ChrMT: 6268C > T (Cox1: A122V, pointed by green arrows). The mutation from Ala to Val is located in a topological domain (118–140, highlighted in green) and appears to cause less consequence on the protein structure and/or function. Structure predictions were prepared using AlphaFold [34].
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