Tag: mitochondrial DNA

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19

Abstract:

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production.

The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Source: Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19. Pharmacol Res. 2024 Apr 11:107170. doi: 10.1016/j.phrs.2024.107170. Epub ahead of print. PMID: 38614374. https://www.sciencedirect.com/science/article/pii/S1043661824001142 (Full text)

A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes

Abstract:

A substantial fraction of the 15% with double-jointedness or hypermobility have the traditionally ascertained joint-skeletal, cutaneous, and cardiovascular symptoms of connective tissue dysplasia and its particular manifestation as Ehlers-Danlos syndrome (EDS). The holistic ascertainment of 120 findings in 1261 EDS patients added neuro-autonomic symptoms like headaches, muscle weakness, brain fog, chronic fatigue, dyspnea, and bowel irregularity to those of arthralgia and skin laxity, 15 of these symptoms shared with those of post-infectious SARS-CoV-2 (long COVID-19).

Underlying articulo-autonomic mechanisms guided a clinical qualification protocol that qualified DNA variants in 317 genes as having diagnostic utility for EDS, six of them identical (F2-LIFR-NLRP3-STAT1-T1CAM1-TNFRSF13B) and eighteen similar to those modifying COVID-19 severity/EDS, including ADAMTS13/ADAMTS2-C3/C1R-IKBKG/IKBKAP-PIK3C3/PIK3R1-POLD4/POLG-TMPRSS2/TMPRSS6-WNT3/WNT10A.

Also, contributing to EDS and COVID-19 severity were forty and three genes, respectively, impacting mitochondrial functions as well as parts of an overlapping gene network, or entome, that are hypothesized to mediate the cognitive-behavioral, neuro-autonomic, and immune-inflammatory alterations of connective tissue in these conditions. The further characterization of long COVID-19 natural history and genetic predisposition will be necessary before these parallels to EDS can be carefully delineated and translated into therapies.

Source: Wilson GN. A Clinical Qualification Protocol Highlights Overlapping Genomic Influences and Neuro-Autonomic Mechanisms in Ehlers-Danlos and Long COVID-19 Syndromes. Curr Issues Mol Biol. 2023 Jul 17;45(7):6003-6023. doi: 10.3390/cimb45070379. PMID: 37504295; PMCID: PMC10378515. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378515/ (Full text)

Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome

Abstract:

Symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are common in rheumatic diseases, but no studies report the frequency of these in early systemic sclerosis. There are no known biomarkers that can distinguish between patients with ME/CFS, although mitochondrial abnormalities are often demonstrated.

We sought to assess the prevalence of ME/CFS in limited cutaneous SSc (lcSSc) patients early in their disease (<5 years from the onset of non-Raynaud’s symptoms) and to determine if alterations in mitochondrial electron transport chain (ETC) transcripts and mitochondrial DNA (mtDNA) integrity could be used to distinguish between fatigued and non-fatigued patients.

All SSc patients met ACR/EULAR classification criteria. ME/CFS-related symptoms were assessed through validated questionnaires, and the expression of ETC transcripts and mtDNA integrity were quantified via qPCR.

SSc patients with ME/CFS could be distinguished from non-fatigued patients through ETC gene analysis; specifically, reduced expression of ND4 and CyB and increased expression of Cox7C. ND4 and CyB expression correlated with indicators of disease severity.

Further prospective and functional studies are needed to determine if this altered signature can be further utilized to better identify ME/CFS in SSc patients, and whether ME/CFS in early SSc disease could predict more severe disease outcomes.

Source: van Eeden C, Redmond D, Mohazab N, Larché MJ, Mason AL, Cohen Tervaert JW, Osman MS. Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(15):12057. https://doi.org/10.3390/ijms241512057 https://www.mdpi.com/1422-0067/24/15/12057 (Full text)

Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Cultured Microglia to Release IL-1β

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems. The pathogenesis of ME/CFS is presently unknown and serum levels of potential biomarkers have been inconsistent. Here we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise. Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia. These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.

Source: Tsilioni I, Natelson B, Theoharides TC. Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Cultured Microglia to Release IL-1β. Eur J Neurosci. 2022 Sep 24. doi: 10.1111/ejn.15828. Epub ahead of print. PMID: 36153118. https://pubmed.ncbi.nlm.nih.gov/36153118/

MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants

Abstract:

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease.

We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS.

Source: Venter M, Tomas C, Pienaar IS, Strassheim V, Erasmus E, Ng WF, Howell N, Newton JL, Van der Westhuizen FH, Elson JL. MtDNA population variation in Myalgic encephalomyelitis/Chronic fatigue syndrome in two populations: a study of mildly deleterious variants. Sci Rep. 2019 Feb 27;9(1):2914. doi: 10.1038/s41598-019-39060-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393470/ (Full article)

Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms

Abstract:

Earlier this year, we described an analysis of mitochondrial DNA (mtDNA) variants in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients and healthy controls. We reported that there was no significant association of haplogroups or singe nucleotide polymorphisms (SNPs) with disease status. Nevertheless, a commentary about our paper appeared (Finsterer and Zarrouk-Mahjoub. J Transl Med14:182, 2016) that criticized the association of mtDNA haplogroups with ME/CFS, a conclusion that was absent from our paper.

The aforementioned commentary also demanded experiments that were outside of the scope of our study, ones that we had suggested as follow-up studies. Because they failed to consult a published and cited report describing the cohorts we studied, the authors also cast aspersions on the method of selection of cases for inclusion. We reiterate that we observed statistically significant association of mtDNA variants with particular symptoms and their severity, though we observed no association with disease status.

You can read the rest of this rebuttal here:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175376/

 

Source: Hanson MR, Gu Z, Keinan A, Ye K, Germain A, Billing-Ross P. Association of mitochondrial DNA variants with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms. J Transl Med. 2016 Dec 20;14(1):342. doi: 10.1186/s12967-016-1104-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175376/ (Full article)

 

Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Letter to the Editor:

With interest we read the article by Billing-Ross et al. [1] about 193 patients with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda or Canadian Consensus criteria and undergoing sequencing of the mtDNA, the DePaul Symptom questionnaire and the Medical Outcome Survey Short Form-36. The study showed that CFS is associated with mtDNA haplogroups J, U and H, that 8 mtDNA single nucleotide polymorphisms (SNPs) were associated with 16 symptom categories, and that three haplogroups were associated with six symptom categories [1]. We have the following comments and concerns.

The main limitation of this study is that only the mtDNA was investigated for sequence variants. Since it is well-known that mitochondrial disorders (MIDs) may be also caused by mutations in nDNA-located genes, particularly in children [2], disease-causing mutations or SNPs facilitating the development of CFS may have been missed. Furthermore, MIDs may not only be due to respiratory chain dysfunction but also due to disruption of other mitochondrial pathways, such as the beta-oxidation, the hem synthesis, the calcium handling, the coenzyme-Q metabolism, or the urea cycle. There is also consensus that investigations of mtDNA mutations or SNPs in mtDNA from lymphocytes may not be constructive since some mutations may not be present or heteroplasmy rates may be lower than in more severely affected tissues [3].

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/

 

Source: Finsterer J, Zarrouk-Mahjoub S. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? J Transl Med. 2016 Jun 18;14(1):182. doi: 10.1186/s12967-016-0939-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/ (Full article)