The SARS-CoV-2 main protease causes mitochondrial dysfunction in a yeast model

TL;DR

This study shows that the SARS-CoV-2 main protease harms mitochondria in yeast, suggesting similar effects might occur in more complex organisms.

Contribution

The study reveals that SARS-CoV-2 Mpro causes mitochondrial dysfunction in a yeast model, highlighting its potential impact in eukaryotic systems.

Findings

Mpro expression was highly toxic and significantly impaired yeast growth.

Mpro caused pronounced changes in mitochondrial morphology and function.

Mitochondrial pathways were found to be exceptionally sensitive to Mpro activity.

Abstract

Saccharomyces cerevisiae has proven to be an invaluable model organism for studying mitochondrial function owing to its genetic tractability and the high conservation of mitochondrial processes among eukaryotes, including humans. Yeasts are easy to culture and manipulate genetically, which allows rapid generation of mutant strains and detailed dissection of mitochondrial pathways. In addition, the ability of yeasts to survive without functional mitochondria allows the study of mutations that are lethal to organisms that are dependent on aerobic metabolism. Taking advantage of these benefits, we investigated the toxicity of SARS-CoV-2 main protease (Mpro) expression in yeast under conditions that enforce mitochondria-dependent aerobic metabolism. Our results showed that Mpro expression was highly toxic and significantly impaired yeast growth. Pronounced changes in the morphology and mitochondrial function were observed, indicating that mitochondrial pathways are exceptionally sensitive to Mpro activity. These results provide insights that may be relevant for understanding the effects of Mpro in more complex eukaryotic systems.

The online version contains supplementary material available at 10.1038/s41598-025-11993-w.

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