title: AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons.
abstract: Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20-22kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau -but not the physiological full-length protein- interacts with Aβ at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles.
authors.affiliation: Institute of Translational Pharmacology (IFT), CNR, Via Fosso del Cavaliere 100-00133, Rome, Italy; European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy. Electronic address: g.amadoro@inmm.cnr.it.
authors.forename: G
authors.initials: G
authors.lastname: Amadoro
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Corsetti
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy; Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Florenzano
authors.affiliation: Insitute of Biomembrane and Bioenergetic (IBBE), CNR, Via Amendola 165/A-70126, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Atlante
authors.affiliation: Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Ciotti
authors.affiliation: Institute of Cellular Biology and Neurobiology (IBCN), CNR, IRCSS Fondazione Santa Lucia, Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Mongiardi
authors.affiliation: UCO Anatomy and Pathological Histology, Hospital of Cattinara, Strada di Fiume 447-34149, Trieste Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bussani
authors.affiliation: University of Trieste, Clinical Department of Medical, Surgical and Health Science-section of Human Morphology, Via Manzoni 16-34138, Trieste, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Nicolin
authors.affiliation: University of Salerno, Department of Pharmaceutical and Biomedical Sciences (FARMABIOMED), NANOMATES, Via Ponte don Melillo 1-85084, Fisciano (SA), Italy.
authors.forename: S L
authors.initials: SL
authors.lastname: Nori
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy; Department of Comparative Biomedical Sciences, The Royal Veterinary College, and Consortium for Mitochondrial Research, University College London, Royal College Street, NW1 0TU, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Campanella
authors.affiliation: European Brain Research Institute (EBRI), Via del Fosso di Fiorano 64-65-00143, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Calissano
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D016875:tau Proteins
keywords: (carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone); AD; ANT-1; APP; Adenine Nucleotide Translocator-1; Alzheimer's Disease; Alzheimer's Disease (AD); Autophagy; Aβ; BAF-A1; COX; CQ; CS; FAD; FCCP; Familiar Alzheimer's Disease; MOI; MT; Mitochondrial dynamics; NH(2)-human tau fragment of 20–22kDa; NH(2)-tau fragment; NH(2)htau; Neurodegeneration; PD; Parkinson's disease; Synapse(s); amyloid beta; amyloid precursor protein; bafilomycin A1; chloroquine; citrate synthase; cytochrome c oxidase; microtubules; mitochondrial DNA; mtDNA; multiplicity of infection; α-syn; α-synuclein