Altered brain energetics induces mitochondrial fission arrest in Alzheimer’s Disease

• Published in: Scientific reports Vol. 6; no. 1; p. 18725
• Main Authors: Zhang, Liang, Trushin, Sergey, Christensen, Trace A., Bachmeier, Benjamin V., Gateno, Benjamin, Schroeder, Andreas, Yao, Jia, Itoh, Kie, Sesaki, Hiromi, Poon, Wayne W., Gylys, Karen H., Patterson, Emily R., Parisi, Joseph E., Diaz Brinton, Roberta, Salisbury, Jeffrey L., Trushina, Eugenia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.01.2016; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 13/51; 14/19; 14/28; 631/378/87; 64/110; 692/617/375/132/1283; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Animal models; Animals; Bioenergetics; Brain; Brain - metabolism; Brain - pathology; Brain - ultrastructure; Brain architecture; CA1 Region, Hippocampal - metabolism; CA1 Region, Hippocampal - ultrastructure; Disease Models, Animal; Dynamin; Dynamins - metabolism; Electron microscopy; Energy Metabolism; Guanosine triphosphatases; Humanities and Social Sciences; Hypoxia; Hypoxia - metabolism; Mice, Knockout; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial Dynamics; multidisciplinary; Neurodegenerative diseases; Organelles; Phenotype; Phosphorylation; Science; Translocation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep18725

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.