There is concern that the global burden of coronavirus disease of 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might yield an increased occurrence of Guillain-Barré syndrome (GBS). It is currently unknown whether concomitant SARS-CoV-2 infection and GBS are pathophysiologically related, what biomarkers are useful for diagnosis, and what is the optimal treatment given the medical comorbidities, complications, and simultaneous infection. We report a patient who developed severe GBS following SARS-CoV-2 infection at the peak of the initial COVID-19 surge (April 2020) in New York City and discuss diagnostic and management issues and complications that may warrant special consideration in similar patients.
Mitochondrial complex I (CI) deficiency is the most frequent cause of oxidative phosphorylation (OXPHOS) disorders in humans. In order to benchmark the effects of CI deficiency on mitochondrial bioenergetics and dynamics, respiratory chain (RC) and endoplasmic reticulum (ER)-mitochondria communication, and superoxide production, fibroblasts from patients with mutations in the ND6, NDUFV1 or ACAD9 genes were analyzed. Fatty acid metabolism, basal and maximal respiration, mitochondrial membrane potential, and ATP levels were decreased. Changes in proteins involved in mitochondrial dynamics were detected in various combinations in each cell line, while variable changes in RC components were observed. ACAD9 deficient cells exhibited an increase in RC complex subunits and DDIT3, an ER stress marker. The level of proteins involved in ER-mitochondria communication was decreased in ND6 and ACAD9 deficient cells. |ΔΨ| and cell viability were further decreased in all cell lines. These findings suggest that disruption of mitochondrial bioenergetics and dynamics, ER-mitochondria crosstalk, and increased superoxide contribute to the pathophysiology in patients with ACAD9 deficiency. Furthermore, treatment of ACAD9 deficient cells with JP4-039, a novel mitochondria-targeted reactive oxygen species, electron and radical scavenger, decreased superoxide level and increased basal and maximal respiratory rate, identifying a potential therapeutic intervention opportunity in CI deficiency.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global pandemic. Beyond the well-described respiratory manifestations, SARS-CoV-2 may cause a variety of neurologic complications, including headaches, alteration in taste and smell, encephalopathy, cerebrovascular disease, myopathy, psychiatric diseases, and ocular disorders. Herein we describe SARS-CoV-2’s mechanism of neuroinvasion and the epidemiology, outcomes, and treatments for neurologic manifestations of COVID-19.
Endogenous mitochondrial genes encode critical oxidative phosphorylation components and their mutation results in a set of disorders known collectively as mitochondrial encephalomyopathies. There is intensive interest in modulating mitochondrial function as organelle dysfunction has been associated with numerous disease states. Proteins encoded by the mitochondrial genome cannot be genetically manipulated by current techniques. Here we report the development of a mitochondrial-targeted RNA expression system (mtTRES) utilizing distinct non-coding leader sequences (NCLs) and enabling in vivo expression of small mitochondrial-targeted RNAs. mtTRES expressing small chimeric antisense RNAs were used as translational inhibitors (TLIs) to target endogenous mitochondrial protein expression in vivo. By utilizing chimeric antisense RNA we successfully modulate expression of two mitochondrially-encoded proteins, ATP6 and COXII, and demonstrate the utility of this system in vivo and in human cells. This technique has important and obvious research and clinical implications.
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