Mitochondrial dynamics and transport in Alzheimer's disease

Abstract

Mitochondrial dysfunction is now recognized as a contributing factor to the early pathology of multiple human conditions including neurodegenerative diseases. Mitochondria are signaling organelles with a multitude of functions ranging from energy production to a regulation of cellular metabolism, energy homeostasis, stress response, and cell fate. The success of these complex processes critically depends on the fidelity of mitochondrial dynamics that include the ability of mitochondria to change shape and location in the cell, which is essential for the maintenance of proper function and quality control, particularly in polarized cells such as neurons. This review highlights several aspects of alterations in mitochondrial dynamics in Alzheimer's disease, which may contribute to the etiology of this debilitating condition. We also discuss therapeutic strategies to improve mitochondrial dynamics and function that may provide an alternative approach to failed amyloid-directed interventions.

Keywords: Alzheimer's disease; Axonal trafficking; Fission; Fusion; Mitochondria; Mitochondria-targeted therapeutics; Mitophagy.

Figure 1:. Generation of adenosine triphosphate (ATP) via glycolysis or oxidative phosphorylation (OXPHOS) pathways in neurons.

(A) Glucose uptake via Glut 3 receptors provides the substrate for a series of glycolytic reactions to generate two molecules of ATP in the cytoplasm. Conversion of glucose to pyruvate is necessary for production of ATP via OXPHOS in mitochondria that results in ~30–36 ATP molecules per one molecule of glucose. (B) The OXPHOS machinery is located at the mitochondrial inner membrane and consists of five complexes where complexes I – IV are involved in electron transfer and proton export to maintain protein gradient that is utilized by complex V to generate ATP to support neuronal function and synaptic activity.

Figure 2:. Mitochondrial fission/fusion dynamics in neurons.

(A) Mitochondria in neurons vary in shape and size constantly undergoing fission and fusion in response to metabolic demands. Intermediate morphological phenotype, mitochondria-on-a-string (MOAS), may represent a response to energetic stress that promotes mitochondrial stability and function. In AD, increased levels of MOAS and mitochondrial fragmentation were observed supporting high level of energetic stress. (B) Example of MOAS in a neuropil in brain tissue of a 3xTgAD female mouse 12 months of age. Micrograph was generated as part of the study described in (31). Scale bar, 0.5 μM.

Figure 3:. Mitochondrial transport in neurons.

Neurons have distinct cellular compartments comprised of the cell body, axons, dendrites, dendritic spines, axonal growth cones and synaptic boutons. Mitochondria are transported from the cell body to distal parts of neurons or to the sites of high energy demand along microtubule tracks using kinesin (anterograde direction) or dynein (retrograde direction) motor protein complexes. In AD, increased accumulation of Aβ and hyperphosphorylated Tau leads to abnormal trafficking in both directions compromising energy support for synaptic function.

Figure 4:. Mechanisms of mitochondrial quality control are interconnected with mechanisms of mitochondrial dynamics.

Dysfunctional mitochondria are transported in the retrograde direction from distal sites to the cell body for degradation and recycling by lysosomes via mechanism called mitophagy. The PINK1/ PARKIN proteins are involved in targeting mitochondria for mitophagy. Autophagosomes that are converted to amphisomes are transported by dynein-snapin motor complexes along microtubules to the cell body for lysosomal degradation. In AD, Aβ can interfere with the formation of these complexes leading to the accumulation of dysfunctional mitochondria and subsequent axonal swelling.