Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches

GeroScience, Год журнала: 2024, Номер 46(5), С. 5267 - 5286

Опубликована: Апрель 26, 2024

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced medical community to phenomenon of long COVID, a condition characterized persistent symptoms following resolution acute phase infection. Among myriad reported COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond initial viral pathology. Emerging evidence pointed mitochondrial dysfunction as potential underpinning mechanism contributing persistence diversity symptoms. This review aims synthesize current findings related in exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic endothelial dysfunction. Through comprehensive analysis literature, we highlight significance health pathophysiology drawing parallels with similar clinical syndromes linked post-infectious states other diseases where impairment been implicated. We discuss therapeutic strategies targeting function, including pharmacological interventions, lifestyle modifications, exercise, dietary approaches, emphasize need further research collaborative efforts advance our understanding management COVID. underscores critical role calls multidisciplinary approach address gaps knowledge treatment options those affected this condition.

Язык: Английский

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Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study

PLoS Medicine, Год журнала: 2025, Номер 22(1), С. e1004511 - e1004511

Опубликована: Янв. 23, 2025

Background Self-reported health problems following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are common and often include relatively non-specific complaints such as fatigue, exertional dyspnoea, concentration or memory disturbance sleep problems. The long-term prognosis of post-acute sequelae COVID-19/post-COVID-19 (PCS) is unknown, data finding correlating organ dysfunction pathology with self-reported symptoms in patients non-recovery from PCS scarce. We wanted to describe clinical characteristics diagnostic findings among persisting for >1 year assessed risk factors persistence versus improvement. Methods This nested population-based case-control study included subjects aged 18–65 years ( n = 982) age- sex-matched control without 576) according an earlier questionnaire (6–12 months after infection, phase 1) consenting provide follow-up information undergo comprehensive outpatient assessment, including neurocognitive, cardiopulmonary exercise, laboratory testing four university centres southwestern Germany (phase 2, another 8.5 [median, range 3–14 months] 1). mean age the participants was 48 years, 65% were female. At 67.6% at 1 developed persistent PCS, whereas 78.5% recovered remained free related PCS. Improvement associated mild index previous full-time employment, educational status, no specialist consultation not attending a rehabilitation programme. development new initially intercurrent secondary SARS-CoV-2 status. Patients less frequently never smokers (61.2% 75.7%), more obese (30.2% 12.4%) higher values body mass (BMI) fat, had lower status (university entrance qualification 38.7% 61.5%) than continued recovery. Fatigue/exhaustion, neurocognitive disturbance, chest symptoms/breathlessness anxiety/depression/sleep predominant symptom clusters. Exercise intolerance post-exertional malaise (PEM) >14 h compatible myalgic encephalomyelitis/chronic fatigue reported by 35.6% 11.6% patients, respectively. In analyses adjusted sex-age class combinations, centre qualification, significant differences between those recovery observed performance three different tests, scores perceived stress, subjective cognitive disturbances, dysautonomia, depression anxiety, quality, quality life. handgrip strength (40.2 [95% confidence interval (CI) [39.4, 41.1]] 42.5 CI [41.5, 43.6]] kg), maximal oxygen consumption (27.9 [27.3, 28.4]] 31.0 [30.3, 31.6]] ml/min/kg weight) ventilatory efficiency (minute ventilation/carbon dioxide production slope, 28.8 [28.3, 29.2]] 27.1 [26.6, 27.7]]) significantly reduced relative group adjustment centre, education, BMI, smoking use beta blocking agents. There measures systolic diastolic cardiac function rest, level N-terminal brain natriuretic peptide blood levels other measurements (including complement activity, markers Epstein–Barr virus [EBV] reactivation, inflammatory coagulation markers, serum cortisol, adrenocorticotropic hormone dehydroepiandrosterone sulfate). Screening viral (PCR stool samples spike antigen plasma) subgroup negative. Sensitivity (pre-existing illness/comorbidity, obesity, medical care infection) revealed similar findings. PEM pain worse results almost all tests. A limitation that we objective on exercise capacity cognition before infection. addition, did unable attend clinic whatever reason illness, immobility social deprivation exclusion. Conclusions this study, majority working recover second their illness. Patterns essentially similar, dominated complaints. Despite signs deficits capacity, there major investigations, our do support persistence, EBV adrenal insufficiency increased turnover pathophysiologically relevant history disease might help stratify cases severity.

Язык: Английский

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Towards an understanding of physical activity-induced post-exertional malaise: Insights into microvascular alterations and immunometabolic interactions in post-COVID condition and myalgic encephalomyelitis/chronic fatigue syndrome

Infection, Год журнала: 2024, Номер unknown

Опубликована: Сен. 6, 2024

Язык: Английский

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Skeletal muscle adaptations and post-exertional malaise in long COVID

Trends in Endocrinology and Metabolism, Год журнала: 2024, Номер unknown

Опубликована: Дек. 1, 2024

When acute SARS-CoV-2 infections cause symptoms that persist longer than 3 months, this condition is termed long COVID. Symptoms experienced by patients often include myalgia, fatigue, brain fog, cognitive impairments, and post-exertional malaise (PEM), which the worsening of following mental or physical exertion. There little consensus on pathophysiology exercise-induced PEM skeletal-muscle-related symptoms. In opinion article we highlight intrinsic mitochondrial dysfunction, endothelial abnormalities, a muscle fiber type shift towards more glycolytic phenotype as main contributors to reduced exercise capacity in The mechanistic trigger for induce unknown, but rapid skeletal tissue damage intramuscular infiltration immune cells contribute PEM-related

Язык: Английский

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Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: population-based, nested case-control study

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 22, 2024

Abstract Objective To assess risk factors for persistence vs improvement and to describe clinical characteristics diagnostic evaluation of subjects with post-acute sequelae COVID-19/post-COVID-19 syndrome (PCS) persisting more than one year. Design Nested population-based case-control study. Setting Comprehensive outpatient assessment, including neurocognitive, cardiopulmonary exercise, laboratory testing in four university health centres southwestern Germany (2022). Participants PCS cases aged 18 65 years (n=982) age sex-matched controls without (n=576) according an earlier questionnaire study (six 12 months after acute infection, phase 1) consenting provide follow-up information undergo assessment (phase 2, another 8.5 [median] 1). Main outcome measures Relative frequencies symptoms problems distribution symptom scores test results between persistent controls. Additional analysis included predictors changing case or control status over time adjustments potentially confounding variables. Results At the examination 2), 67.6% initial remained cases, whereas 78.5% continued report no related PCS. In adjusted analyses, among were mild index previous full-time employment, educational status, specialist consultation not attending a rehabilitation programme. Among controls, new worsening development intercurrent secondary SARS-CoV-2 infection status. less frequently never smokers, had higher values BMI body fat, lower Fatigue/exhaustion, neurocognitive disturbance, chest symptoms/breathlessness anxiety/depression/sleep predominant clusters, exercise intolerance post-exertional malaise >14 h (PEM) compatible ME/CFS (according Canadian consensus criteria) reported by 35.6% 11.6% respectively. significant differences stable (at 2) observed performances, perceived stress subjective cognitive disturbances, indicating dysautonomia, depression anxiety, sleep quality, fatigue, quality life. handgrip strength, maximal oxygen consumption, ventilator efficiency significantly reduced. However, there systolic diastolic cardiac function, level pro-BNP blood levels other measurements (including complement activity, serological markers EBV reactivation, inflammatory coagulation markers, cortisol, ACTH DHEA-S serum levels). Screening viral (based on PCR stool samples spike antigen plasma subgroup cases) was negative. Sensitivity analyses (pre-existing illness/comorbidity, obesity, PEM, medical care infection) revealed similar findings showed that PEM pain worse almost all tests. Conclusions This nested demonstrates majority do recover second year their illness, patterns remaining essentially similar, nonspecific dominated complaints. We found objective signs deficits reduced capacity likely be unrelated primary pulmonary dysfunction some but major pathology investigations. A history which associated severe as well disease may pragmatic means stratify severity. What is already known this topic Self-reported following have commonly been described persist months. They typically include relatively non-specific complaints such exertional dyspnoea, concentration memory disturbance problems. The incidence post-COVID-19 varying sociodemographic variables, pre-existing comorbidities, severity factors. long-term prognosis unknown differ different clusters. Evidence measurable single multiple organ correlation self-reported patients non-recovery from described. adds describes (need for) programme (the latter probably due reverse causation) PCS, changes clusters After comprehensive correlated symptoms, detected often longer lasting malaise, both physical (diminished consumption ventilatory efficiency), performances while investigations adjustment possible confounders.

Язык: Английский

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Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence

Journal of Cachexia Sarcopenia and Muscle, Год журнала: 2024, Номер 16(1)

Опубликована: Дек. 27, 2024

ABSTRACT Background Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In 2021 review article on the ME/CFS, we postulated that hypoperfusion and ischemia can result excessive sodium calcium overload muscles ME/CFS patients to cause mitochondrial damage. Since then, experimental has been provided supports this concept. Methods We collect, summarize discuss current state knowledge pathophysiology. try explain which risk factors mechanisms are responsible subgroup with post COVID (PCS) develop (PC‐ME/CFS). Results Mitochondrial dysfunction is long‐held assumption cardinal symptoms ME/CFS. However, could not be convincingly shown leukocytes. By contrast, recent tissue An electron microscopy study directly show damage mitochondria preferential subsarcolemmal localization but PCS. Another shows signs regeneration biopsies taken one day after exercise PC‐ME/CFS. The simultaneous presence necroses concept repeated Other correlated diminished hand grip strength (HGS) symptom severity prognosis. A MRI showed intracellular elevated levels correlate inversely HGS. This finding corroborates our consecutive as muscular caused by enhanced proton‐sodium exchange due anaerobic metabolism activity sodium‐potassium‐ATPase. histological investigations exclude microvascular obstruction, viral or immune myositis. only known exercise‐induced mechanism left induced overload. If ionic disturbance severe enough patient may captured vicious circle. energy deficit most likely exertional intolerance malaise further aggravated exertion. Conclusion Based pathomechanism, future treatment approaches should focus normalizing disbalance. Current strategies targeting have potential improve ion transporters.

Язык: Английский

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Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(7), С. 2153 - 2153

Опубликована: Апрель 8, 2024

Background: Post-COVID syndrome (PCS) encompasses a diverse array of symptoms persisting beyond 3 months after acute SARS-CoV-2 infection, with mental as well physical fatigue being the most frequent manifestations. Methods: In 144 female patients PCS, hand grip strength (HGS) parameters were assessed an objective measure muscle fatigue, 78 meeting Canadian Consensus Criteria for postinfectious myalgic encephalomyelitis/chronic (ME/CFS). The severity disability and key was evaluated using self-reported questionnaires. Results: Patients ME/CFS exhibited heightened overall symptom severity, including lower function (p < 0.001), greater degree more severe postexertional malaise autonomic dysfunction = 0.004) compared to other PCS. While HGS impaired similarly in all PCS significant correlation across entire patient group, uniquely demonstrated associations symptoms. Conclusions: Thus, serves marker Only criteria is also associated hallmark This suggests common mechanism subtype, distinct from that types

Язык: Английский

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Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Июль 5, 2024

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with broad overlap of symptomatology Post-COVID (PCS). Despite the severity symptoms and various neurological, cardiovascular, microvascular, skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter neuropeptide release, mechanoregulation, vasorelaxation, immune defense, shows altered function ME/CFS. Dysfunction TRPM3 natural killer (NK) cells, characterized by reduced calcium flux, has observed ME/CFS PCS patients, suggesting role ineffective pathogen clearance virus persistence autoimmunity development. dysfunction NK cells can be improved naltrexone vitro ex vivo, which may explain moderate clinical efficacy low-dose (LDN) treatment. We propose that broader involvement pathophysiology, affecting other organs. This paper discusses TRPM3's expression organs its impact on symptoms, focus small nerve fibers brain, where presynaptic GABA release.

Язык: Английский

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Novel biomarkers of mitochondrial dysfunction in Long COVID patients

GeroScience, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 4, 2024

Abstract Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30–40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 or post-acute sequelae of syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, difficulties, body pain, short-term memory loss, concentration issues, sleep disturbances, persist for months. According recent studies, SARS-CoV-2 causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy reveal distinct structural abnormalities COVID patients, notably significant swelling, disrupted cristae, an overall irregular morphology, which indicates distress. We noted increased levels superoxide dismutase 1 signals oxidative stress elevated autophagy-related 4B cysteine peptidase levels, indicating mitophagy. Importantly, our analysis also identified reduced circulating cell-free DNA (ccf-mtDNA) these serving a novel biomarker the condition. findings underscore crucial role dysfunction pathogenesis COVID. Further exploration molecular mechanisms underlying post-viral is critical, particularly understand roles autoimmune reactions reactivation latent viruses perpetuating conditions. This comprehensive understanding could pave way targeted therapeutic interventions designed alleviate chronic impacts By utilizing ccf-mtDNA other biomarkers, we enhance diagnostic capabilities improve management this complex syndrome.

Язык: Английский

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How can mitochondrial damage explain post-COVID-19 symptoms? A synthesis of current evidences

Clinical Infection in Practice, Год журнала: 2024, Номер 22, С. 100355 - 100355

Опубликована: Март 29, 2024

Язык: Английский

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