Possible Therapeutic Intervention Strategies for COVID-19 by Manipulating the Cellular Proteostasis Network.

INTRODUCTION: The recent outbreak of coronavirus infection by SARS-CoV-2 that started from the Wuhan Province of China in 2019 has spread to most parts of the world infecting millions of people. Although the case fatality rate of SARS-CoV-2 infection is less than the previous epidemics by other closely related coronaviruses, due to its high infectivity, the total number of SARS-CoV-2 infection-associated disease, called Covid-19, is a matter of global concern. Despite drastic preventive measures, the number of Covid-19 cases are steadily increasing, and the future course of this pandemic is highly unpredictable. The most concerning fact about Covid-19 is the absence of specific and effective preventive or therapeutic agents against the disease. Finding an immediate intervention against Covid-19 is the need of the hour. In this chapter, we have discussed the role of different branches of the cellular proteostasis network, represented by Hsp70-Hsp40 chaperone system, Ubiquitin-Proteasome System (UPS), autophagy, and endoplasmic reticulum-Unfolded Protein Response (ER-UPR) pathway in the pathogenesis of coronavirus infections and in the host antiviral defense mechanisms. RESULTS: Based on scientific literature, we present that pharmacological manipulation of proteostasis network can alter the fate of coronavirus infections and may help to prevent the resulting pathologies like Covid-19.

Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress.

Mitochondria and endoplasmic reticulum (ER) remain closely tethered by contact sites to maintain unhindered biosynthetic, metabolic, and signalling functions. Apart from its constituent proteins, contact sites localize ER-unfolded protein response (UPR) sensors like Ire1 and PERK, indicating the importance of ER-mitochondria communication during stress. In the mitochondrial sub-compartment-specific proteotoxic model of yeast, Saccharomyces cerevisiae, we show that an intact ER-UPR pathway is important in stress tolerance of mitochondrial intermembrane space (IMS) proteotoxic stress, while disrupting the pathway is beneficial during matrix stress. Deletion of IRE1 and HAC1 leads to accumulation of misfolding-prone proteins in mitochondrial IMS indicating the importance of intact ER-UPR pathway in enduring mitochondrial IMS proteotoxic stresses. Although localized proteotoxic stress within mitochondrial IMS does not induce ER-UPR, its artificial activation helps cells to better withstand the IMS proteotoxicity. Furthermore, overexpression of individual components of ER-mitochondria contact sites is found to be beneficial for general mitochondrial proteotoxic stress, in an Ire1-Hac1-independent manner.

Stress Responses Elicited by Misfolded Proteins Targeted to Mitochondria.

The double-membrane-bound architecture of mitochondria, essential for ATP production, sub-divides the organelle into inter-membrane space (IMS) and matrix. IMS and matrix possess contrasting oxido-reductive environments and discrete protein quality control (PQC) machineries resulting inherent differences in their protein folding environments. To understand the nature of stress response elicited by equivalent proteotoxic stress to these sub-mitochondrial compartments, we took misfolding and aggregation-prone stressor proteins and fused it to well described signal sequences to specifically target and impart stress to yeast mitochondrial IMS or matrix. We show, mitochondrial proteotoxicity leads to growth arrest of yeast cells of varying degrees depending on nature of stressor proteins and the intra-mitochondrial location of stress. Next, by employing transcriptomics and proteomics, we report a comprehensive stress response elicited by stressor proteins specifically targeted to mitochondrial matrix or IMS. A general response to proteotoxic stress by mitochondria-targeted misfolded proteins is mitochondrial fragmentation, and an adaptive abrogation of mitochondrial respiration with concomitant upregulation of glycolysis. Beyond shared stress responses, specific signatures due to stress within mitochondrial sub-compartments are also revealed. We report that stress-imparted by bipartite signal sequence-fused stressor proteins to IMS, leads to specific upregulation of IMS-chaperones and TOM complex components. In contrast, matrix-targeted stressors lead to specific upregulation of matrix-chaperones and cytosolic PQC components. Finally, by systematic genetic interaction using deletion strains of differentially upregulated genes, we found prominent modulatory role of TOM complex components during IMS-stress response. In contrast, VMS1 markedly modulates the stress response originated from matrix.

Alterations in inter-organelle crosstalk and Ca2+ signaling through mitochondria during proteotoxic stresses.

BACKGROUND: Biogenesis and function of mitochondria is profoundly dependent on cytosolic translation of mitochondrial pre-proteins and its subsequent translocation and folding inside the organelle. Continuous exposure of non-native precursor proteins, exposure to damaging by-products of oxidative phosphorylation, load of mis-targeted or misfolded proteins from neighbouring compartments and unremitting demand of communication between mitochondrial and nuclear genomes, continuously pose proteotoxic threats to the organelle. Our knowledge of cellular mechanisms to cope up with such impending threat of proteotoxicity to mitochondria, is currently evolving. In recent years, several unique response and survival pathways have been discovered shedding light on cellular strategies to cope with stressed and dysfunctional mitochondria. As mitochondria compulsorily communicate with nucleus, cytosol and endoplasmic reticulum (ER) for its own biogenesis and function and in turn maintain critical cellular processes for survival, any impairment in communication by stressed or dysfunctional mitochondria may end up with fatal consequences. DISCUSSION AND IMPLICATION: In this review, we have discussed about possible sources of mitochondrial proteotoxicity and the recent developments regarding cellular strategies to counter such stress to overcome dysfunctions of the organelle. Mitochondrial communication with neighbouring subcellular compartments like ER and cytosol during proteotoxic stress have been explored. In the context of mitochondrial proteotoxicity, alterations of crucial inter-organelle connections like ER-mitochondria contact sites and its implication on mitochondrial signaling activity like Ca2+ signaling have been dissected. Furthermore, an overview of pathological conditions, mainly neurodegenerative disorders that are known to be associated with mitochondrial proteotoxicity and Ca2+ dysregulation has been presented.