title: Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.
abstract: mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: J-P
authors.initials: JP
authors.lastname: Louboutin
authors.forename: P
authors.initials: P
authors.lastname: Datta
authors.forename: C P
authors.initials: CP
authors.lastname: Landel
authors.forename: D
authors.initials: D
authors.lastname: Martinez
authors.forename: A S
authors.initials: AS
authors.lastname: Zervos
authors.forename: D S
authors.initials: DS
authors.lastname: Strayer
authors.forename: T
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.forename: E S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D001343:Autophagy; D009202:Cardiomyopathies / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse