Relationship Between β-Amyloid and Mitochondrial Dynamics

Abstract

Mitochondria as dynamic organelles undergo morphological changes through the processes of fission and fusion which are major factors regulating their functions. A disruption in the balance of mitochondrial dynamics induces functional disorders in mitochondria such as failed energy production and the generation of reactive oxygen species, which are closely related to pathophysiological changes associated with Alzheimer's disease (AD). Recent studies have demonstrated a relationship between abnormalities in mitochondrial dynamics and impaired mitochondrial function, clarifying the effects of morphofunctional aberrations which promote neuronal cell death in AD. Several possible signaling pathways have been suggested for a better understanding of the mechanism behind the key molecules regulating mitochondrial morphologies. However, the exact machinery involved in mitochondrial dynamics still has yet to be elucidated. This paper reviews the current knowledge on signaling mechanisms involved in mitochondrial dynamics and the significance of mitochondrial dynamics in controlling associated functions in neurodegenerative diseases, particularly in AD.

Keywords: Alzheimer’s disease; Mitochondrial dynamics; Mitochondrial dysfunction; Oxidative stress; β-Amyloid (Aβ).

Fig. 1

Regulation of mitochondrial dynamics. Mitochondria change the morphology through fission and fusion. Mitochondrial fission involves three steps; first, Drp1 translocates from cytosol to the mitochondria with the help of Fis1, Mid49/51, and Mff, which function as a receptor for Drp1. Subsequently, Drp1 assembles and forms oligomer ring-like structures. Finally, membrane constriction via GTP hydrolysis splits one mitochondrion into two mitochondria. Mitochondrial fusion consists of outer and inner mitochondrial membrane process. Two Mfn isoforms, Mfn1/2, are required for outer membrane fusion, which forms homo- and hetero-oligomeric complex. Opa1 mediates the fusion of inner membrane and thereby making elongated mitochondria. Drp1 dynamin-related protein, Fis1 fission protein 1, Mid49/51 mitochondrial dynamics proteins of 49 and 51 kDa, Mff mitochondrial fission factor, Mfn1/2 mitofusin 1/2, Opa1 optic atrophy 1

Fig. 2

Mitochondrial dynamics in cell death. Altered mitochondrial structure triggers cell death due to structural and functional disturbances. Mitochondrial fission induces the formation of MOMP and regulates cristae remodeling through Drp1 mediated or Opa1 processing, which destabilizes the cristae junction and facilitates the release of pro-apoptotic factors including Cyt C, AIF, and Endo G. Mitochondrial fragmentation induces ROS generation by attenuating the activity of ETC. The increased levels of ROS production lead to oxidative stress, causing ATP depletion, ΔΨm collapse, and mtDNA mutations followed by mitochondrial dysfunction, which eventually leads to cell death. Cyt C cytochrome C, AIF apoptosis inducing factor, EndoG endonuclease G, IMM inter mitochondrial membrane, OMM outer mitochondrial membrane, MOMP mitochondrial outer membrane permeabilization, ROS reactive oxidative species, mtDNA mitochondrial DNA, ΔΨm mitochondrial membrane potential

Fig. 3

Interaction between Aβ and mitochondrial dynamics on mitochondrial dysfunction. a Effect of extracellular Aβ. Extracellular Aβ oligomers either directly or indirectly interact with cell surface receptors (for example, mGluR, NMDAR, AMPAR), and enhance the calcium level by increasing the calcium entry and releasing stored calcium ions from the ER. Perturbations of calcium signaling lead to mitochondrial fragmentation by regulating the activity of kinase and phosphatase. Increment in calcium levels mediates the activation of PTMs in mitochondrial dynamic proteins. b Effect of intracellular Aβ. RAGE, α7nAChR, TOM, and TIM complex induce the entry of Aβ. Intracellular Aβ modulates mitochondrial morphology and function by interacting with mitochondrial proteins. Intracellular accumulated Aβ oligomers decrease the proteolytic activity and regulate the expression and the PTM of mitochondrial dynamic proteins, resulting mitochondrial fission. Excessive mitochondrial fission induced by extracellular and intracellular Aβ impairs mitochondrial function and contributes to AD pathogenesis. mGluR metabotropic glutamate receptor, NMDA N-methy l-D-aspartate, AMPAR amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor, ER endoplasmic reticulum RAGE receptor for advanced glycation end products, α7nAChR α7 nicotinic acetylcholine receptor, PTM post-translational modification