title: Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging.
abstract: Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process. Here, using a model carrying a proofreading-defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging, including anemia, lymphopenia, and myeloid lineage skewing. However, in contrast to physiological stem cell aging, rapidly accumulating mitochondrial DNA mutations had little functional effect on the hematopoietic stem cell pool, and instead caused distinct differentiation blocks and/or disappearance of downstream progenitors. These results show that intact mitochondrial function is required for appropriate multilineage stem cell differentiation, but argue against mitochondrial DNA mutations per se being a primary driver of somatic stem cell aging.
authors.affiliation: Immunology Section, Institution for Experimental Medical Science, BMC D14, Lund University, Tornavägen 10, 221 84 Lund, Sweden.
authors.forename: Gudmundur L
authors.initials: GL
authors.lastname: Norddahl
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Pronk
authors.forename: Martin
authors.initials: M
authors.lastname: Wahlestedt
authors.forename: Gerd
authors.initials: G
authors.lastname: Sten
authors.forename: Jens M
authors.initials: JM
authors.lastname: Nygren
authors.forename: Amol
authors.initials: A
authors.lastname: Ugale
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: David
authors.initials: D
authors.lastname: Bryder
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology; D019588:Aging, Premature / Q000235:genetics* / Q000503:physiopathology; D000740:Anemia; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D002678:Chimera; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008231:Lymphopenia; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D012038:Regeneration
chemical_list: D004272:DNA, Mitochondrial; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase