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Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models./
作者:	Perry, Elizabeth Aguilar.
面頁冊數:	1 online resource (136 pages)
附註:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
標題:	Biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28965465click for full text (PQDT)
ISBN:	9798819380116

Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models.
Perry, Elizabeth Aguilar.

Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models. - 1 online resource (136 pages)

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

Mitochondrial diseases (MD) are a heterogeneous group of disorders resulting from genetic mutations in nuclear or mitochondrial DNA (mtDNA) genes encoding for mitochondrial proteins (Area-Gomez and Schon, 2014; Wallace and Chalkia, 2013). MD cause pathologies with severe tissue damage and ultimately death (El-Hattab et al., 2015; Gorman et al., 2016). There are no cures for MD and current treatments are only palliative (El-Hattab et al., 2017; Pfeffer et al., 2012; Russell et al., 2020). To search for new drug-targeted therapies, we designed a chemical high-throughput screen using cells carrying human MD mutations to identify small molecules that prevent cellular damage and death under nutrient stress conditions. Top hits in the screen were a series of antibiotics that maintain survival of different human MD mutant cells. A sub-library of tetracycline analogs, including doxycycline, rescued cell death and inflammatory signatures in mutant cells through partial and selective mitochondrial translation inhibition, causing a mitohormetic response that was ATF4 independent. Remarkably, doxycycline treatment strongly promoted fitness and survival of Ndufs4-/- mice, a pre-clinical Leigh syndrome mouse model (Kruse et al., 2008). Brain proteomic analysis showed that doxycycline treatment largely prevented neuronal death and the increases of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causality of these proteins in this brain pathology. These findings strongly implicate tetracyclines as a potential therapeutic treatment for MD.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798819380116Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

DoxycyclineIndex Terms--Genre/Form:

542853
Electronic books.

Tetracyclines Promote Survival and Fitness in Mitochondrial Disease Models.
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520 $a Mitochondrial diseases (MD) are a heterogeneous group of disorders resulting from genetic mutations in nuclear or mitochondrial DNA (mtDNA) genes encoding for mitochondrial proteins (Area-Gomez and Schon, 2014; Wallace and Chalkia, 2013). MD cause pathologies with severe tissue damage and ultimately death (El-Hattab et al., 2015; Gorman et al., 2016). There are no cures for MD and current treatments are only palliative (El-Hattab et al., 2017; Pfeffer et al., 2012; Russell et al., 2020). To search for new drug-targeted therapies, we designed a chemical high-throughput screen using cells carrying human MD mutations to identify small molecules that prevent cellular damage and death under nutrient stress conditions. Top hits in the screen were a series of antibiotics that maintain survival of different human MD mutant cells. A sub-library of tetracycline analogs, including doxycycline, rescued cell death and inflammatory signatures in mutant cells through partial and selective mitochondrial translation inhibition, causing a mitohormetic response that was ATF4 independent. Remarkably, doxycycline treatment strongly promoted fitness and survival of Ndufs4-/- mice, a pre-clinical Leigh syndrome mouse model (Kruse et al., 2008). Brain proteomic analysis showed that doxycycline treatment largely prevented neuronal death and the increases of neuroimmune and inflammatory proteins in Ndufs4-/- mice, indicating a potential causality of these proteins in this brain pathology. These findings strongly implicate tetracyclines as a potential therapeutic treatment for MD.
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538 $a Mode of access: World Wide Web
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