Abstract
Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria owing to their high bioenergetic demand. Mitochondrial dysfunction is therefore associated with various age-related neurodegenerative disorders such as Alzheimer’s disease (AD), wherein accumulation of damaged and dysfunctional mitochondria has been reported as an early symptom further contributing to disease progression. In AD, impairment of mitochondrial function causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating the effect of Aβ and tau pathologies, leading to synaptic dysfunction, cognitive impairment and memory loss. Although there are reports suggesting intricate parallelism between mitochondrial dysfunction and AD pathologies such as Aβ aggregation and hyperphosphorylated tau accumulation, the factors that drive the pathogenesis of either are unclear. In addition, emerging evidence suggest that mitochondrial quality control (QC) mechanisms such as mitophagy are impaired in AD. As an important mitochondrial QC mechanism, mitophagy plays a critical role in maintaining neuronal health and function. Studies show that various proteins involved in mitophagy, mitochondrial dynamics, and mitochondrial biogenesis are affected in AD. Compromised mitophagy may also be attributed to impairment in autophagosome–lysosome fusion and defects in lysosomal acidification. Therapeutic interventions aiming to restore mitophagy functions can be used as a strategy for ameliorating AD pathogenesis. Recent evidence implicates the role of microglial activation via mitophagy induction in reducing amyloid plaque load. This review summarizes the current developments in the field of mitophagy and mitochondrial dysfunction in AD.
Highlights
Alzheimer’s disease (AD) is one of the most debilitating age-induced neurodegenerative disorders affecting millions worldwide (Lane et al, 2018)
Levels of SIRT3, a mitochondrial sirtuin that has a role in p62 clustering onto ubiquitinated mitochondria and autolysosome formation, were reduced in AD (Tseng et al, 2013; Yang et al, 2015). These findings suggest that impairment in mitochondrial quality control (QC) combined with abnormal mitochondrial dynamics and biogenesis can contribute to AD pathogenesis, and targeting these pathways therapeutically may be a promising strategy for AD treatment
Any dysfunction in mitochondrial QC pathways can have a detrimental effect on cells like neurons that are critically dependent on mitochondria
Summary
Alzheimer’s disease (AD) is one of the most debilitating age-induced neurodegenerative disorders affecting millions worldwide (Lane et al, 2018). Hyperphosphorylated tau can impair mitochondrial functioning in three major ways, namely, (i) by shifting the equilibrium of mitochondrial fission– fusion towards increased fission, (ii) by impairing transport of mitochondria, and (iii) by causing dysfunction in oxidative phosphorylation and increasing ROS production (Figure 2).
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