Mitochondrial Perturbation in Alzheimer's Disease and Diabetes

Abstract

Mitochondria are well-known cellular organelles that play a vital role in cellular bioenergetics, heme biosynthesis, thermogenesis, calcium homeostasis, lipid catabolism, and other metabolic activities. Given the extensive role of mitochondria in cell function, mitochondrial dysfunction plays a part in many diseases, including diabetes and Alzheimer's disease (AD). In most cases, there is overwhelming evidence that impaired mitochondrial function is a causative factor in these diseases. Studying mitochondrial function in diseased cells vs healthy cells may reveal the modified mechanisms and molecular components involved in specific disease states. In this chapter, we provide a concise overview of the major recent findings on mitochondrial abnormalities and their link to synaptic dysfunction relevant to neurodegeneration and cognitive decline in AD and diabetes. Our increased understanding of the role of mitochondrial perturbation indicates that the development of specific small molecules targeting aberrant mitochondrial function could provide therapeutic benefits for the brain in combating aging-related dementia and neurodegenerative diseases by powering up brain energy and improving synaptic function and transmission.

Keywords: Alzheimer disease; Diabetes; Mitochondrial dysfunction; Neuronal toxicity; Synaptic degeneration aging.

Fig. 1

Effect of Aβ on CypD-involved mPTP formation. Aβ-cyclophilin D interaction mediates impairments in axonal mitochondrial transport due to an increase in the opening of CypD-mediated mitochondrial permeability transition pore (mPTP). This leads to the disruption of Ca²⁺ balance and increases the production/accumulation of reactive oxygen species (ROS). Elevation of Ca²⁺ and oxidative stress activates the downstream p38 MAP kinase signaling pathway, thus contributing to mitochondrial dysfunction.

Fig. 2

Effect of AD on mitochondrial dynamics. AD-induced mitochondrial respiratory function abnormality orchestrates ROS generation and accumulation and subsequently activates ERK signal transduction. Activation of ERK signaling disrupts mitochondrial dynamics and results in altered DLP1 and Mfn2 expression, which eventually leads to mitochondrial dysfunction. Inhibition of DLP1 or Mfn2 expression attenuates AD- or MCI-derived mitochondrial and neuronal dysfunction (Mdivi-1, an inhibitor for DLP1).

Fig. 3

The cellular factors and related pathways contribute to Aβ-mediated mitochondrial defects and synaptic damage. Aβ accumulation perturbs mitochondrial transport and dynamics, cell signaling, synaptic mitochondrial structure and function, leading to decreased energy metabolism/ATP production, deregulation of calcium homeostasis, perturbed cell signaling cascades, altered key enzymes associated with mitochondrial respiratory chain, induced oxidative stress, and, eventually, synaptic injury and cognitive decline.