Issue 36, 2024

Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology

Abstract

Dysfunction of mitochondria is implicated in various diseases, including cancer and neurodegenerative disorders, but drug discovery targeting mitochondria and mitochondrial proteins has so far made limited progress. Targeted protein degradation (TPD) technologies represented by proteolysis targeting chimeras (PROTACs) are potentially applicable for this purpose, but most existing TPD approaches leverage the ubiquitin-proteasome system or lysosomes, which are absent in mitochondria, and TPD in mitochondria (mitoTPD) remains little explored. Herein, we describe the design and synthesis of a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. This compound successfully induced the degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix. Furthermore, in cells overexpressing mSA fused to short transmembrane protein 1 (mSA-STMP1), which enhances mitochondrial fission, our mitochondrial mSA degrader restored the mitochondrial morphology by reducing the level of mSA-STMP1. A preliminary structure–activity relationship study indicated that a longer linker length enhances the degradation activity towards mSA. These findings highlight the potential of mitoTPD as a tool for drug discovery targeting mitochondria and for research in mitochondrial biology, as well as the utility of mSA as a degradation tag for mitochondrial protein.

Graphical abstract: Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology

Supplementary files

Article information

Article type
Edge Article
Submitted
14 5 2024
Accepted
01 8 2024
First published
28 8 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 14625-14634

Targeted protein degradation in the mitochondrial matrix and its application to chemical control of mitochondrial morphology

W. Yamada, S. Tomoshige, S. Nakamura, S. Sato and M. Ishikawa, Chem. Sci., 2024, 15, 14625 DOI: 10.1039/D4SC03145H

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