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2 results on '"Dynamins/genetics"'

1. Synaptic dysfunction, memory deficits and hippocampal atrophy due to ablation of mitochondrial fission in adult forebrain neurons

Author

Josef Bischofberger, Maria Licci, Markus Tolnay, Amandine Grimm, Lorenzo Morè, Stephan Frank, Katsuyoshi Mihara, Luca Scorrano, Naotada Ishihara, Patrizia D'Adamo, Lisa Michelle Restelli, Karen Schmitt, Claudia Savoia, Björn Oettinghaus, Paul Franken, Jan M. Schulz, Anne Eckert, Alexander Schmidt, and Jürgen Hench

Subjects
Dynamins, 0301 basic medicine, Nervous system, endocrine system, Pathology, medicine.medical_specialty, B140, Hippocampus, Mitochondrion, Neurotransmission, Biology, Mitochondrial Dynamics, Nervous System, Antioxidants, Mice, 03 medical and health sciences, Prosencephalon, Atrophy, medicine, Animals, Molecular Biology, Neurons, Original Paper, Memory Disorders, Neurodegeneration, Antioxidants/administration & dosage, Atrophy/genetics, Atrophy/metabolism, Dynamins/biosynthesis, Dynamins/genetics, Hippocampus/growth & development, Hippocampus/metabolism, Memory Disorders/genetics, Memory Disorders/pathology, Mitochondria/metabolism, Mitochondria/pathology, Mitochondrial Dynamics/genetics, Nerve Degeneration/genetics, Nerve Degeneration/metabolism, Nervous System/growth & development, Nervous System/pathology, Neurons/metabolism, Neurons/pathology, Prosencephalon/growth & development, Prosencephalon/metabolism, Cell Biology, medicine.disease, Mitochondria, 030104 developmental biology, medicine.anatomical_structure, nervous system, Nerve Degeneration, Forebrain, Mitochondrial fission, Neuroscience
Abstract

Well-balanced mitochondrial fission and fusion processes are essential for nervous system development. Loss of function of the main mitochondrial fission mediator, dynamin-related protein 1 (Drp1), is lethal early during embryonic development or around birth, but the role of mitochondrial fission in adult neurons remains unclear. Here we show that inducible Drp1 ablation in neurons of the adult mouse forebrain results in progressive, neuronal subtype-specific alterations of mitochondrial morphology in the hippocampus that are marginally responsive to antioxidant treatment. Furthermore, DRP1 loss affects synaptic transmission and memory function. Although these changes culminate in hippocampal atrophy, they are not sufficient to cause neuronal cell death within 10 weeks of genetic Drp1 ablation. Collectively, our in vivo observations clarify the role of mitochondrial fission in neurons, demonstrating that Drp1 ablation in adult forebrain neurons compromises critical neuronal functions without causing overt neurodegeneration.

Published
2016

2. Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death

Author

Marc Segarra-Mondejar, Manuel Palacín, Alejandro Martorell-Riera, Jordi Olloquequi, Juan Pablo Muñoz, Jeús Pérez-Clausell, Manuel Reina, Antonio Zorzano, Vanessa Ginet, Julien Puyal, Francesc X. Soriano, and Universitat de Barcelona

Subjects
Male, Excitotoxicity, MFN2, Mitochondrion, medicine.disease_cause, Mitochondrial Dynamics, Mitocondris, GTP Phosphohydrolases, Rats, Sprague-Dawley, Homeostasis, Cells, Cultured, bcl-2-Associated X Protein, Neurons, biology, Cell Death, MEF2 Transcription Factors, General Neuroscience, Malalties neurodegeneratives, Animals, Calcium/metabolism, Cell Line, Down-Regulation, Dynamins/genetics, Dynamins/metabolism, Gene Expression Regulation, Humans, MEF2 Transcription Factors/genetics, MEF2 Transcription Factors/metabolism, Membrane Proteins/genetics, Membrane Proteins/metabolism, Mitochondria/physiology, Mitochondrial Dynamics/physiology, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Models, Animal, Mutation, Neurons/physiology, Rats, bcl-2-Associated X Protein/genetics, bcl-2-Associated X Protein/metabolism, Neurodegenerative Diseases, Articles, Cell biology, Mitochondria, mitochondrial fusion, Mef2, Dynamins, Programmed cell death, General Biochemistry, Genetics and Molecular Biology, Mitochondrial Proteins, Bcl-2-associated X protein, Downregulation and upregulation, medicine, Molecular Biology, General Immunology and Microbiology, Membrane Proteins, biology.protein, Calcium
Abstract

Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke.

Published
2014

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