Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Naibedya Dutta, Joe A Gerke, Sofia F Odron, Joseph D Morris, Adam Hruby, Juri Kim, Toni Castro Torres, Sarah J Shemtov, Jacqueline G Clarke, Michelle C Chang, Hooriya Shaghasi, Marissa N Ray, Maxim Averbukh, Sally Hoang, Maria Oorloff, Athena Alcala, Matthew Vega, Hemal H Mehta, Max A Thorwald, Phillip Crews, Marc Vermulst, Gilberto Garcia, Tyler A Johnson, Ryo Higuchi-Sanabria

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA. · pubmed

Paper

Abstract

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function. Similar to rotenone (Rote), MTZ, a newly employed ETC complex I inhibitor, exhibited higher cytotoxicity against cancer cell lines compared to certain non-cancer cell lines. Interestingly, 8-OAc demonstrated greater selectivity for cancer cells when compared to both MTZ and Rote, which has promising potential for anticancer therapeutic development. Furthermore, in vivo experiments with these small molecules utilizing a C. elegans model demonstrate their unexplored potential to investigate aging studies. We observed that both molecules have the ability to induce a mitochondria-specific unfolded protein response (UPR

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper investigates the effects of mycothiazole and its analog on mitochondrial function, which is directly related to aging mechanisms. The focus on mitochondrial electron transport chain inhibitors and their potential role in aging studies suggests a contribution to understanding the biological processes underlying aging. However, while the findings are solid, they do not present groundbreaking insights that would significantly advance the field, hence the moderate impact score.

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