Altered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.

TitleAltered brain energetics induces mitochondrial fission arrest in Alzheimer's Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhang L, Trushin S, Christensen TA, Bachmeier BV, Gateno B, Schroeder A, Yao J, Itoh K, Sesaki H, Poon WW, Gylys KH, Patterson ER, Parisi JE, Brinton RDiaz, Salisbury JL, Trushina E
JournalSci Rep
Date Published2016 Jan 05
KeywordsAlzheimer Disease, Amyloid beta-Protein Precursor, Animals, Brain, CA1 Region, Hippocampal, Disease Models, Animal, Dynamins, Energy Metabolism, Hypoxia, Mice, Knockout, Mice, Transgenic, Mitochondria, Mitochondrial Dynamics, Phenotype, Phosphorylation

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.

Alternate JournalSci Rep
PubMed ID26729583
PubMed Central IDPMC4700525
Grant ListR01 ES020715 / ES / NIEHS NIH HHS / United States
P01 AG000538 / AG / NIA NIH HHS / United States
GM089853 / GM / NIGMS NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R01ES020715 / ES / NIEHS NIH HHS / United States
R01 GM089853 / GM / NIGMS NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D