Dataset Information

Proteomic analysis of whole brains from Ndufs4-/- mice treated with doxycycline

ABSTRACT: Mice with mitochondrial complex I deficiency (Ndufs4-/-) suffer from severe energy impairment primarily affecting the brain and die at P55. A small molecule screen developed by our lab using cells harboring human mitochondrial disease mutations identified antibiotics targeting mitochondrial translation as potent inhibitors of cell death under nutrient stress conditions. Doxycycline, which was identified amongst these antibiotics, was administered in the diet of Ndufs4-/- mice after weaning at P21. Mice fed with doxycycline showed improved motor function and significantly increased lifespan relative to untreated Ndufs4-/- mice. In order to investigate the molecular changes promoted by doxycycline in the brains of these mice, Ndufs4-/- doxycycline treated (DOX), Ndufs4-/- untreated (KO), and Ndufs4+/+ (WT) control mice were sacrificed at P55 and their brains harvested. Proteomic analysis revealed doxycycline treatment largely prevented the neuroimmune and inflammatory profile identified in the Ndufs4-/- mice. These findings implicate a potentially causality of these proteins in the neuronal cell death ultimately leading to the observed brain pathology.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: mark Jedrychowski

LAB HEAD: Pere Puigserver

PROVIDER: PXD022860 | Pride | 2021-09-09

REPOSITORIES: pride

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			Action	DRS
	393287_JM1615PP_LIZ_5_14_19.mzIdentML	Mzid
	393288_JM1614PP_LIZ_5_14_19.mzIdentML	Mzid
	393289_JM1613PP_LIZ_5_14_19.mzIdentML	Mzid
	393290_JM1612PP_LIZ_5_14_19.mzIdentML	Mzid
	393291_JM1611PP_LIZ_5_14_19.mzIdentML	Mzid

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Publications

Tetracyclines promote survival and fitness in mitochondrial disease models.

Perry Elizabeth A EA Bennett Christopher F CF Luo Chi C Balsa Eduardo E Jedrychowski Mark M O'Malley Katherine E KE Latorre-Muro Pedro P Ladley Richard Porter RP Reda Kamar K Wright Peter M PM Gygi Steven P SP Myers Andrew G AG Puigserver Pere P

Nature metabolism 20210118 1

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from mutations in nuclear or mitochondrial DNA genes encoding mitochondrial proteins1,2. MDs cause pathologies with severe tissue damage and ultimately death3,4. There are no cures for MDs and current treatments are only palliative5-7. Here we show that tetracyclines improve fitness of cultured MD cells and ameliorate disease in a mouse model of Leigh syndrome. To identify small molecul ...[more]

PMID: 33462515

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