title: Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.
abstract: Altered brain metabolism is associated with progression of Alzheimer's Disease (AD). Mitochondria respond to bioenergetic changes by continuous fission and fusion. To account for three dimensional architecture of the brain tissue and organelles, we applied 3-dimensional electron microscopy (3D EM) reconstruction to visualize mitochondrial structure in the brain tissue from patients and mouse models of AD. We identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles, "mitochondria-on-a-string" (MOAS). Our data suggest that MOAS formation may occur at the final stages of fission process and was not associated with altered translocation of activated dynamin related protein 1 (Drp1) to mitochondria but with reduced GTPase activity. Since MOAS formation was also observed in the brain tissue of wild-type mice in response to hypoxia or during chronological aging, fission arrest may represent fundamental compensatory adaptation to bioenergetic stress providing protection against mitophagy that may preserve residual mitochondrial function. The discovery of novel mitochondrial phenotype that occurs in the brain tissue in response to energetic stress accurately detected only using 3D EM reconstruction argues for a major role of mitochondrial dynamics in regulating neuronal survival.
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Sergey
authors.initials: S
authors.lastname: Trushin
authors.affiliation: Electron Microscopy Core Facility, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Trace A
authors.initials: TA
authors.lastname: Christensen
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Benjamin V
authors.initials: BV
authors.lastname: Bachmeier
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gateno
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD, USA.
authors.forename: Kie
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Institute for Memory Impairments and Neurological Disorders. University of California Irvine, CA, USA.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: UCLA School of Nursing, CA, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Gylys
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Patterson
authors.affiliation: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.|Neuroscience Program, University of Southern California, Los Angeles, CA, USA.|Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Diaz Brinton
authors.affiliation: Electron Microscopy Core Facility, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.|Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
authors.affiliation: Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.|Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Trushina
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D034281:Dynamins / Q000378:metabolism; D004734:Energy Metabolism; D000860:Hypoxia / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics; D010641:Phenotype; D010766:Phosphorylation
chemical_list: D016564:Amyloid beta-Protein Precursor; C486391:Dnm1l protein, mouse; D034281:Dynamins