Abstract
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.
Highlights
Alzheimer’s disease (AD) is characterized by the deposition of extracellular amyloid (Aβ ) plaques, intraneuronal neurofibrillary tangles comprised of hyperphosphorylated tau protein, synaptic loss, and neuronal cell death[1]
Using transmission electron microscopy (TEM), we examined mitochondria in the CA1 hippocampal region from 5 transgenic mouse models carrying human familial AD (FAD) mutations for presenilin 1 (PS1), amyloid precursor protein (APP), and mutant Tau protein (Table 1)
We found that compared to uniformly elongated mitochondria in the hippocampi of NTG mice (Fig. 1a), FAD mice exhibited a broader variety of mitochondrial shapes ranging from ovoid (0.3 by 0.5 μ m in diameter, Fig. 1b) to teardrop profiles with tubular membrane extension(s) at one or both ends (Fig. 1c), and to teardrop shaped mitochondria (0.5 μ m in diameter) connected by thin double membrane extending up to 5 μ m long that we termed “mitochondria-on-a-string” (MOAS) (Fig. 1e,f)
Summary
Alzheimer’s disease (AD) is characterized by the deposition of extracellular amyloid (Aβ ) plaques, intraneuronal neurofibrillary tangles comprised of hyperphosphorylated tau protein (pTau), synaptic loss, and neuronal cell death[1]. Fission and fusion machinery depends on the fidelity of dynamin related protein 1 (Drp1), mitochondrial fission factor (Mff), mitochondrial fission protein 1 (Fis1), mitofusin-1 and mitofusin-2 (Mfn[1], Mfn2), and optical atrophy 1 (Opa1) protein[3,6,7,8,9,10] These proteins regulate the assembly and stability of the respiratory chain supercomplexes inducing the remodeling of mitochondrial cristae and shaping mitochondrial morphology in response to the energetic demand of the cell[11,12], which directly affects the development and maintenance of synapses[13]. ATP, altered dynamics and hypometabolism detected before the onset of amyloid plaques. ATP levels, altered dynamics and hypometabolism are detected before the onset of amyloid plaques.
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