Mitochondrial Dysfunction: A Prelude to Neuropathogenesis of SARS-CoV‐2, 2022, Pliss et al

[SNT Gatchaman]

Mitochondrial Dysfunction: A Prelude to Neuropathogenesis of SARS-CoV‐2
Artem Pliss, Andrey N. Kuzmin, Paras N. Prasad, Supriya D. Mahajan

The SARS-CoV-2 virus is notorious for its neuroinvasive capability, causing multiple neurological conditions. The neuropathology of SARS-CoV-2 is increasingly attributed to
mitochondrial dysfunction of brain microglia cells. However, the changes in biochemical content of mitochondria that drive the progression of neuro-COVID remain poorly understood.

Here we introduce a Raman microspectrometry approach that enables the molecular profiling of single cellular organelles to characterize the mitochondrial molecular makeup in the infected microglia cells. We found that microglia treated with either spike protein or heat-inactivated SARS-CoV-2 trigger a dramatic reduction in mtDNA content and an increase in phospholipid saturation levels. At the same time, no significant changes were detected in Golgi apparatus
and in lipid droplets, the organelles that accommodate biogenesis and storage of lipids.

We hypothesize that transformations in mitochondria are caused by increased synthesis of reactive oxygen species in these organelles. Our findings call for the development of mitochondria-targeted therapeutic approaches to limit neuropathology associated with SARS-CoV-2.

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[SNT Gatchaman]

Remarkably, the capabilities of biochemical analysis have been recently expanded with optical biosensing tools. Raman spectrometry, one of the most valuable biosensing technologies, relies on analysis of molecular vibrational spectra and enables the identification of diverse molecular groups in biological samples.

[...] enables selective detection and concentration measurements of the major categories of biomolecules, including lipids, proteins, nucleic acids, and saccharides

In this study, we employed Raman spectrometry together with the [biomolecular component analysis] algorithm to characterize the changes in the molecular composition of mitochondria in response to treatment with heat-inactivated SARS-CoV-2 or the SARS- CoV-2 spike protein. In addition, we studied key organelles involved in lipid metabolism: Golgi apparatus (GA) and lipid droplets (LD). The roles lipids play in viral infection include viral endocytosis and exocytosis, viral entry into the host cell via membrane fusion, and viral replication,

Our data indicate that infection with SARS-CoV-2 causes mitochondrial dysfunction in microglia cells, which triggers metabolic alterations that result in a substantial increase in glycolysis. These findings suggest that a metabolic switch to glycolysis compensates for mitochondrial dysfunction and an energy deficit in microglia and that a consequence of this metabolic change is an enhanced inflammatory response that contributes to neuropathology associated with COVID-19.

Overall, our findings support a view that viral infection of host cells results in higher metabolic alterations to cope with the increased anabolic demand of the cell for viral replication. Furthermore, SARS-CoV-2-induced manipulation of the host- cell metabolic machineries alters transcriptional regulation of key metabolic pathways.

 

[SNT Gatchaman]

We found that treatment with [...] spike protein or [heat-inactivated]-SARS induced significant alterations in the concentrations of diverse types of biomolecules in the mitochondria. First, the concentration of mitochondrial DNA was reduced almost 2-fold in the infected cells

At the same time, the concentration of mtRNA was increased from ∼2.25 mg/mL in the control to 2.8 mg/mL in HI-SARS-treated cells and ∼4.0 mg/mL in cells treated with the spike protein; the latter difference was statistically significant. This increase in RNA is consistent with previous reports on mitochondrial genome upregulation in cells infected by SARS-CoV-2.

We also found a significant reduction in mitochondrial saccharides from ∼1.5 mg/mL in the control to ∼0.9 mg/mL in the HI-SARS-treated cells and ∼0.7 mg/mL in the cells treated with the spike protein. The mitochondrial saccharide fraction includes glucose and pyruvate, and its reduction suggests a decrease of the respiratory function of mitochondria.

Furthermore, we detected a significant perturbation in the saturation of phospholipids populating the mitochondrial lipidome. The average number of unsaturated C=C bonds per phospholipid was significantly reduced from ∼4.3 in the control to ∼3.8 in the cells treated with the HI-SARS viral construct and ∼3.7 in the cells treated with the spike protein.