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Ablation of Mitochondria Fusion Protein Mfn2 causes an Oxidative Stress Response and Eventual Neuronal Death in the Hippocampus and Cortex
Author(s) -
Jiang Sirui,
Wang Xinglong,
Nandy Priya,
Wang Chunyu,
Torres Sandy,
Siedlak Sandra L,
Zhu Xiongwei
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.659.7
Subject(s) - mfn2 , neurodegeneration , mitochondrial fusion , mitochondrion , mitochondrial fission , microbiology and biotechnology , biology , oxidative stress , neuroscience , mfn1 , mitochondrial dna , medicine , endocrinology , pathology , biochemistry , disease , gene
Mitochondria are the organelles responsible for energy metabolism and have a direct impact on neuronal function and survival. Mitochondrial abnormalities have been well characterized in Alzheimer disease, and significant advances have recently been made in the understanding of the changes in morphology and distribution of neuronal mitochondria in this devastating disease. It is believed that mitochondrial fragmentation, due to impaired fission and fusion balance, likely causes mitochondrial dysfunction that underlies many aspects of neurodegenerative changes in AD. It is clear that the mitochondrial fission and fusion proteins play a major role in maintaining the health and function of these important organelle. Mitofusion 2 (Mfn2) is one such protein that regulates mitochondrial fusion in which mutations lead to the development of neurodegeneration. To examine whether and how impaired mitochondrial fission/fusion balance causes neurodegeneration in AD, we developed a transgenic mouse model using the CAMKII promoter to knockout Mfn2 in the hippocampus and cortex. Electron micrographs of neurons from these mice show swollen mitochondria with cristae damage and mitochondria membrane abnormalities. Over time the mfn2 KO model demonstrates a progression of neurodegeneration via mitochondrial morphological changes, oxidative stress response, inflammatory changes, cell cycle induction, and loss of MAP2 in dendrites, leading to severe and selective neuronal death. In this model, hippocampal CA1 neurons were affected earlier and resulted in nearly total loss, while cortical neuronal death was associated with fewer neurons and decreased cortical size, but no changes in neuronal density. Overall, our findings indicate that impaired mitochondrial fission and fusion balance can cause many neurodegenerative changes and eventual neurodegeneration that characterize AD in the hippocampus and cortex which makes it a potential target for treatment strategies for AD. Support or Funding Information Thanks to the support of T32 NS077888, IIRG‐13‐284849, AARG‐16‐443584, R01 NS083385 and Dr. Robert M. Kohrman Memorial Fund.