# Evidence of mitochondria origin of SARS-CoV-2 double-membrane vesicles: a review

## TL;DR

This review explores how mitochondria may be the source of SARS-CoV-2's replication structures, suggesting new therapeutic strategies for treating COVID-19.

## Contribution

The paper proposes that mitochondria-derived vesicles are the origin of SARS-CoV-2 double-membrane vesicles, offering a novel framework for therapeutic development.

## Key findings

- Mitochondria may serve as the origin of SARS-CoV-2 replication niches, similar to other viruses.
- Mitochondria-derived vesicles (MDV) share characteristics with SARS-CoV-2-induced double-membrane vesicles (DMV).
- MDV formation under stress and their dynamic nature may explain why they are hard to detect in imaging studies.

## Abstract

The coronavirus disease-19 (COVID-19) pandemic is caused by the coronavirus, SARS-CoV-2, which has infected in a year more than 200 million people and has killed almost 4.5 million people worldwide. This infection affects mainly certain groups of people that have high susceptibility to present severe COVID-19 due to comorbidities. Moreover, long-COVID-19 comprises a series of symptoms that may remain in some patients for months after infection that further compromises health of individuals. Therefore, this pandemic poses a serious emergency worldwide. Thus, since this pandemic is profoundly affecting economic and social life of societies, a deeper understanding of SARS-CoV-2 infection cycle could help to envisage novel therapeutic alternatives that limit or stop COVID-19.

Several recent findings have unexpectedly found that mitochondria play a critical role in SARS-CoV-2 cell infection. Indeed, it has been suggested that this organelle could be the origin of its replication niches, the double membrane vesicles (DMV), as it has been observed with other virus. In this regard, mitochondria derived vesicles (MDV), involved in mitochondria quality control, were discovered more than 10 years ago and, interestingly, there is a population characterized by a double membrane. MDV shedding is induced by mitochondrial stress and it has a fast assembly dynamic, reason that perhaps has precluded their identification in electron microscopy or tomography studies. These and other features of MDV together with recent SARS-CoV-2 protein interactome with the host and other findings linking SARS-CoV-2 to mitochondria, support that these vesicles are the precursors of SARS-CoV-2 induced DMV. In this work, the celular, molecular phenotypical and biochemical evidence that supports this hypothesis is reviewed and integrated into the current model of SARS-CoV-2 cell infection. In this scheme, some relevant questions are raised as pending topics for research that would help in the near future to test this hypothesis. The intention of this work is to provide a novel framework that could open new possibilities to tackle SARS-CoV-2 pandemic through mitochondria targeted therapies.