title: Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice.
abstract: Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wild-type and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.
authors.affiliation: Department of Pathology.
authors.forename: XiuJie
authors.initials: X
authors.lastname: Li-Harms
authors.affiliation: Department of Immunology.
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: John
authors.initials: J
authors.lastname: Lynch
authors.affiliation: Department of Pathology.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Pathology.
authors.forename: Aashish
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Pathology.
authors.forename: Rekha
authors.initials: R
authors.lastname: Iyengar
authors.affiliation: Hartwell Center for Bioinformatics & Biotechnology.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Cell and Molecular Biology, and.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Department of Genetics, University of Wisconsin-Madison, Madison, WI; and.
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: James E
authors.initials: JE
authors.lastname: Thompson
authors.affiliation: Department of Cell and Molecular Biology, and.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.affiliation: Department of Immunology.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: John
authors.initials: J
authors.lastname: Schuetz
authors.affiliation: Department of Pathology.
authors.forename: Mondira
authors.initials: M
authors.lastname: Kundu
mesh_terms: D000375:Aging; D000740:Anemia / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002469:Cell Separation; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology*; D041905:Erythroid Cells / Q000378:metabolism; D005434:Flow Cytometry; D006579:Heterozygote; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D010101:Oxygen Consumption; D010641:Phenotype; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D046988:Proteasome Endopeptidase Complex