Mitochondrial Dysfunction and Oxidative Stress in Alzheimer's Disease

Abstract

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer's disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca²⁺ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

Keywords: Alzheimer’s disease; fission; fusion; mitochondria; mitophagy; oxidative stress.

FIGURE 1

Representation of ROS-induced mitochondrial abnormalities in AD. ROS production or impaired antioxidant system results in the cellular redox balance to oxidative imbalance and cause ROS overproduction. ROS generated during cellular respiration has detrimental effects on mitochondria and neuronal function. Increased ROS causes reduction of mitochondrial ΔΨm and ATP generation through negatively affecting mitochondrial energy stores, disturbance in energy metabolism, and compromised dynamics and mitophagy. ROS further causes an increase in caspase activity and initiates apoptosis. On the other hand, ROS overproduction causes inhibition of phosphatase 2A (PP2A), which also activates glycogen synthase kinase (GSK) 3β causing tau hyperphosphorylation and neurofibrillary tangles accumulation.

FIGURE 2

Schematic representation of the mitochondrial Ca²⁺ dysregulation in AD. Mitochondria participate in intracellular Ca²⁺ signaling as modulators, buffers, and sensors; excessive Ca²⁺ taken up by mitochondria can lead to cell death, i.e., mitochondrial Ca²⁺ overload, results in increased ROS production, ATP synthesis inhibition, mitochondrial permeability transition pore (mPTP) opening, the release of cytochrome c, activation of caspases, and apoptosis.

FIGURE 3

Schematic diagram depicting defects of mitochondrial dynamics (fission and fusion) and mitophagy mechanism in AD. Mitochondria are dynamic, and they undergo frequent changes in shape, size, number, and location to maintain mitochondrial biology and quality control. Actions of outer membrane Drp1 control mitochondrial fission. Drp1 is recruited by mitochondrial fission factor (Mff), mitochondrial fission 1 protein (Fis1), mitochondrial dynamics protein 49/51 (MiD49/51) to promote the mitochondrial fission process. On the other hand, Mitochondrial fusion is regulated by mitofusin (Mfn) 1 and 2 and optical atrophy protein 1 (OPA1). This allows for the exchange of material (matrix components and damaged mitochondrial DNA), as well as promoting a balance in bioenergetic properties (e.g., mitochondrial membrane potential ΔΨm). These fission/fusion processes also involve mitophagy mechanisms (removal of damaged mitochondria) to maintain quality control. When mitochondria become damaged due to cellular stress, sustained depolarization of their inner membrane occurs, resulting in the loss of ΔΨm, which stabilizes PINK1 at the outer membrane to initiate mitophagy. In AD, due to excessive ROS burden on neurons, impaired fission/fusion balance occurs, resulting in defective mitophagy.

FIGURE 4

Summary of physiological and pharmacological interventions and molecular targets to improve mitochondrial function in AD. We highlight several strategies that can contribute to mitochondrial health, such as exercise and a healthy diet, inhibition of excessive mitochondrial fragmentation and ROS, and improving fusion, biogenesis, transport, and mitophagy using various compounds, as potential strategies for AD prevention.