Decoding Chronic Fatigue: The Crucial Role of WASF3 in Mitochondrial Dysfunction in ME/CFS
News Release, World Mitochondria Society, Berlin - Germany – August 15, 2023
A significant study was reported in the Proceedings of the National Academy of Sciences yesterday, shedding new light on the molecular mechanisms underlying chronic fatigue and strategic role of mitochondria. Here are the main takeaways from the study:
Main Finding
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a protein called WASF3, induced by endoplasmic reticulum (ER) stress, detrimentally affects mitochondrial functions, resulting in exercise intolerance.
Patient Case
In a detailed examination of a 38-year-old woman suffering from chronic fatigue, an overexpression of WASF3 was identified. This overexpression is linked to a disruption in the formation of mitochondrial respiratory supercomplexes.
Mouse Model Insights
- Mice with heightened WASF3 levels exhibited reduced exercise capabilities.
- A clear association was observed between elevated WASF3 levels and compromised mitochondrial functionality in skeletal muscles.
Mitigation Strategy
The study suggests a potential intervention. By diminishing ER stress, WASF3 levels were reduced, leading to a noticeable improvement in mitochondrial function.
Extended Research
Further corroborating the primary findings, muscle biopsies from a wider group of ME/CFS patients also presented elevated WASF3 levels, coupled with signs of aberrant ER stress activation.
Broader Implications
Beyond the primary focus on ME/CFS, the findings from this research provide valuable insights that could inform understanding of other fatigue-related disorders. This includes conditions like rheumatic diseases and the emerging concerns surrounding long COVID.
This study marks a pivotal step forward in understanding the intricacies of chronic fatigue at the molecular level, offering hope for improved diagnostic and therapeutic approaches in the future.
Don't miss Trageting Mitochondria 2023 this November in Berlin to stay updated with the latest findings on mitochondria and fatigue. Learn more about the topics that will be covered during Targeting Mitochondria 2023.
Targeting Mitochondria 2023 Congress
October 11-13, 2023 - Berlin, Germany
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Winners of the 2023 Lurie Prize in Biomedical Sciences: Unveiling Distinct Discoveries in Mitochondrial Science
With great admiration, the WMS would like to extend its most sincere and heartfelt congratulations to Navdeep S. Chandel, Ph.D., and Vamsi Mootha, MD. Their relentless dedication and pioneering research in the field of mitochondrial science have not only advanced our understanding of this vital area but have also garnered them the honor of being named the recipients of the highly prestigious 2023 Lurie Prize in Biomedical Sciences.
Each of Dr. Chandel and Dr. Mootha has made important and distinct discoveries in the field of mitochondrial science by exploring the characteristics and functions of mitochondria in human physiology and disease.
Dr. Navdeep Chandel is the David W. Cugell Professor of Medicine, Biochemistry, and Molecular Genetics at Northwestern University Feinberg School of Medicine. The Chandel research team has shown that mitochondria do much more than supply energy to cells. His research team has revealed how mitochondria function as signaling organelles that control the body’s normal functions and impact diseases, including cancer and inflammation.
Dr. Vamsi Mootha is an investigator of the Howard Hughes Medical Institute, investigator in the Department of Molecular Biology at Massachusetts General Hospital, a member of the Broad Institute of MIT and Harvard, and a professor of Systems Biology and Medicine at Harvard Medical School. His laboratory team combines genomics and computation with classic biochemistry and physiology to gain a holistic view of the genes and proteins relevant to mitochondrial function. Although mitochondria contain their own DNA that encodes just 13 proteins, the Mootha research team has identified the other 99% of mitochondrial proteins encoded by nuclear DNA and compiled their findings in a widely used reference tool used to discover new protein functions and disease genes.
The impact of their work will undoubtedly resonate throughout the scientific community and beyond for years to come.
Source: FNIH Press Release
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Targeting Mitochondria 2023 Congress
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Maternal and Fetal Mitochondrial Gene Dysregulation in Hypertensive Disorders of Pregnancy
Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive.
In their new study, Nicole R. Phillips (University of North Texas Health Science Center), Styliani Goulopoulou (Loma Linda University) and their colleagues investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH.
Further, they measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia.
Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load.
The reported findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.
In summary, this study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.
Image credits: Ricci et al. Physiological Genomics (2023)
Targeting Mitochondria 2023, this October, will shed light on the latest discoveries related to mitochondria. Submit a related abstract.
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New Outstanding Study Linking Post-Covid to Mitochondrial Damage
The World Mitochondria Society (WMS) congratulates Professor Douglas Wallace, and his team on the outstanding publication in yesterday's issue of Science, focusing on Post Covid and Mitochondria. It is truly impressive and represents a significant leap forward in understanding the strategic role of mitochondria and mitochondrial energetics in both health and diseases.
The WMS strongly believes that the implications of this study extend beyond Covid, encompassing all diseases linked to mitochondria.
This excellent study delved into the impact of SARS-CoV-2 on host mitochondria and gene expression. The research revealed that SARS-CoV-2 viral proteins have the potential to hinder oxidative phosphorylation (OXPHOS) and encourage glycolysis by binding to host mitochondrial proteins. In nasopharyngeal samples, decreasing viral titers were associated with the suppression of nuclear DNA (nDNA) – encoded mitochondrial OXPHOS genes. Additionally, the virus led to the activation of microRNA 2392, HIF-1α (which prompts glycolysis), and host immune responses, including the integrated stress response.
In autopsy tissues of COVID-19 patients, the virus was absent, yet mitochondrial gene expression had recovered in the lungs. However, suppressed nDNA mitochondrial gene expression persisted in the heart, kidney, and liver autopsy tissues, while mitochondrial DNA transcription was activated, and immune defense pathways were engaged. In early SARS-CoV-2 infection in hamsters, the lung's mitochondrial gene expression remained largely unaffected, but perturbations were observed in the cerebellum and striatum. During the mid-phase of infection in mice, lung mitochondrial gene expression started to recover. This data suggests that during the initial viral peak, a systemic host response takes place, followed by the virus hindering mitochondrial gene transcription and prompting glycolysis, leading to antiviral immune responses. Despite lung recovery, mitochondrial dysfunction persists in the heart, kidney, liver, and lymph nodes, potentially contributing to severe COVID-19 symptoms.
We will discuss during the World Mitochondria Society Annual Meeting this October in Berlin how to enhance mitochondrial function and strategies to target mitochondrial energetics in health and disease.
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Targeting Mitochondria 2023 Congress
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Freiburg research team casts light on signal-dependent formation of mitochondria
Scientists reveal the transport of positively charged signal sequences through negatively charged groove
Known as the power plant of the cell, mitochondria are essential to human metabolism. Human mitochondria consist of 1,300 different proteins and two fatty biomembranes. The vast majority of mitochondrial proteins are produced with a cleavable transport signal and have to be actively transported into the mitochondria. Using biochemical and cell-biology experiments, a team of researchers have now shown for the first time precisely how mitochondrial proteins with signal sequences are imported into the mitochondria via a negatively charged, unique groove. Headed by Prof. Dr. Nils Wiedemann and Prof. Dr. Carola Hunte from the Medical Faculty at the University of Freiburg, and Prof. Dr. Martin van der Laan from the University of Saarland the work was carried out at the University of Freiburg’s Cluster of Excellence CIBSS – Centre for Integrative Biological Signalling Studies. Their results have been published in the science journal Nature.
Model of the import of mitochondrial proteins with a signal sequence across the mitochondrial inner membrane at the Tim17 groove. Illustration: Laura Fielden
Transport mechanism is an important building block
“Forty years after the discovery of mitochondrial signal sequences, our experiments have now revealed the precise mechanism by which proteins are transported and the power stations of our cells are gradually built up,” says Wiedemann. “Information about the transport mechanism for mitochondrial proteins is an important component in basic cellular research.” Malfunctions of over 500 mitochondrial proteins cause a variety of diseases, so research into the mitochondria is hugely important to medicine.
It was already known that mitochondrial proteins were imported using the signal sequence translocase of the inner membrane (TIM) into the mitochondrial matrix. The two vital core subunits of this translocase are Tim17 and Tim23. Until now, it was assumed that mitochondrial proteins with signal sequences were transported across the inner membrane via a water-filled Tim23 channel. However, recent artificial intelligence-based structural predictions indicate that Tim23 does not form a channel. The research team has now been able to prove that mitochondrial proteins with signal sequences are actually imported into the mitochondria via a groove in the Tim17 protein.
Negatively charged groove in Tim17-protein
Most proteins that are transported into the mitochondria contain a complex molecular signal sequence which is positively charged and water-soluble on one side, and on the opposite side has fat-soluble molecular residues. In contrast to the positively charged side of the transport signal, the groove of Tim17 contains a strongly negatively charged region which is present in all Tim17 proteins, from yeast to humans.
The lead authors of the study, Dr. Laura Fielden and Dr. Jakob Busch from the Institute of Biochemistry and Molecular Biology at the University of Freiburg, employed functional in vitro transport experiments using chemically-marked proteins with isolated mitochondria to show that the negative charges in the groove of Tim17 interact with the positively charged signal sequences and are therefore essential to the transportation of mitochondrial proteins. Meanwhile the fat-soluble side of the mitochondrial signal sequences is aligned with the lipid membrane, enabling the transport of signal sequences at the interface between Tim17 and the mitochondrial inner membrane.
Basis for further research
“Now we have clarified this fundamental mechanism of mitochondrial proteins with a signal sequence at the interface to the biomembrane, we can understand why mitochondrial signal sequences have one positively charged side and one fat-soluble side and need this for their transportation,” Fielden explains, emphasising the importance of the results which can now serve as a basis for further research into mitochondria.
Source: Universität Freiburg
Targeting Mitochondria 2023, this October, will shed light on the latest discoveries related to mitochondria. Submit a related abstract.
Media contact:
World Mitochondria Society
This email address is being protected from spambots. You need JavaScript enabled to view it.
+33-1-5504-7755
Targeting Mitochondria 2023 Congress
October 11-13, 2023 - Berlin, Germany
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