title: Age-Related Phasic Patterns of Mitochondrial Maintenance in Adult Caenorhabditis elegans Neurons.
abstract: Aging is associated with cognitive decline and increasing risk of neurodegeneration. Perturbation of mitochondrial function, dynamics, and trafficking are implicated in the pathogenesis of several age-associated neurodegenerative diseases. Despite this fundamental importance, the critical understanding of how organismal aging affects lifetime neuronal mitochondrial maintenance remains unknown, particularly in a physiologically relevant context. To address this issue, we performed a comprehensive in vivo analysis of age-associated changes in mitochondrial morphology, density, trafficking, and stress resistance in individual Caenorhabditis elegans neurons throughout adult life. Adult neurons display three distinct stages of increase, maintenance, and decrease in mitochondrial size and density during adulthood. Mitochondrial trafficking in the distal neuronal processes declines progressively with age starting from early adulthood. In contrast, long-lived daf-2 mutants exhibit delayed age-associated changes in mitochondrial morphology, constant mitochondrial density, and maintained trafficking rates during adulthood. Reduced mitochondrial load at late adulthood correlates with decreased mitochondrial resistance to oxidative stress. Revealing aging-associated changes in neuronal mitochondria in vivo is an essential precedent that will allow future elucidation of the mechanistic causes of mitochondrial aging. Thus, our study establishes the critical foundation for the future analysis of cellular pathways and genetic and pharmacological factors regulating mitochondrial maintenance in aging- and disease-relevant conditions.
  
  
  CONCLUSIONS
  Using Caenorhabditis elegans as a model, we address long-standing questions: How does aging affect neuronal mitochondrial morphology, density, trafficking, and oxidative stress resistance? Are these age-related changes amenable to genetic manipulations that slow down the aging process? Our study illustrates that mitochondrial trafficking declines progressively from the first day of adulthood, whereas mitochondrial size, density, and resistance to oxidative stress undergo three distinct stages: increase in early adulthood, maintenance at high levels during mid-adulthood, and decline during late adulthood. Thus, our study characterizes mitochondrial aging profile at the level of a single neuron in its native environment and establishes the critical foundation for the future genetic and pharmacological dissection of factors that influence long-term mitochondrial maintenance in neurons.
authors.affiliation: Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Morsci
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and.
authors.forename: David H
authors.initials: DH
authors.lastname: Hall
authors.affiliation: Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey 08855 shengz@ninds.nih.gov driscoll@dls.rutgers.edu.
authors.forename: Monica
authors.initials: M
authors.lastname: Driscoll
authors.affiliation: Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, shengz@ninds.nih.gov driscoll@dls.rutgers.edu.
authors.forename: Zu-Hang
authors.initials: ZH
authors.lastname: Sheng
mesh_terms: D000054:Acceleration; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure*; D018384:Oxidative Stress / Q000502:physiology; D034622:RNA Interference / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D024101:Mitochondrial Proteins; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide
keywords: Caenorhabditis elegans; age-related changes; in vivo microscopy; mitochondrial trafficking; neuronal mitochondria
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