Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells |
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Authors: | Dr Batakrishna Jana Sangpil Kim Jae-Byoung Chae Prof Hyewon Chung Dr Chaekyu Kim Prof Ja-Hyoung Ryu |
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Affiliation: | 1. Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919 South Korea;2. Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919 South Korea
These authors contributed equally to this work.;3. Department of Ophthalmology, Konkuk University School of Medicine, Seoul, Korea |
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Abstract: | Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging. |
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Keywords: | alkyl-quaternary ammonium-TPP Senescentretina mouse model membrane disruption mitochondria senescence |
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