Molecular Mechanisms Underlying the Role of Mitophagy in Neurodegeneration

Molecular Mechanisms Underlying the Role of Mitophagy in Neurodegeneration

Abhilasha Ahlawat (Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India), Meenakshi Kaira (Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India), Vaibhav Walia (Faculty of Pharmacy, DIT University, Dehradun, India) and Munish Garg (Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, India)
Copyright: © 2020 |Pages: 25
DOI: 10.4018/978-1-7998-1317-0.ch003

Abstract

Mitophagy is a selective autophagy process in which damaged or surplus mitochondria are removed to sustain normal homeostasis. The efficient removal of damaged or stressed mitochondria is crucial for cellular health. Recent literature emphasizes the role of PINK1-Parkin pathways in the pathogenesis process of various neurodegenerative disorders. Further, mitophagy has shown potential therapeutic activity in treating neurodegenerative diseases. Thus, mitophagy might be important in the field of pharmacotherapeutics. In the present chapter, the authors explain mitophagy, mitophagy signaling pathways, as well as mechanisms and roles of mitophagy in various neurodegenerative disorders.
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Introduction

Mitochondria are the organelle mainly involved in the production of energy, regulation of metabolism and cell death (Ding and Yin, 2012). The process of removal of defected/damaged mitochondria from the cell is known as mitophagy. Mitophagy is related to the autophagy of mitochondria and was first termed by Lemasters (Lemasters, 2005). Mitophagy plays a crucial role in mitochondrial disruption and neurodegenerative disorders (Ding and Yin, 2012). In mitophagy, the mitochondria to be removed are packed into autophagosomes followed by the fusion with lysosomes and leading to complete mitochondrial degradation (Xie et al., 2011). Pathways involved in the regulation of mitophagy are classified either as ubiquitin-dependent or ubiquitin-independent (Khaminets et al., 2016). Mitophagy is further classified as basal (progressive mitochondrial housekeeping that recycles old and damaged organelles), stress-induced (extracellular stress signals affecting mitochondrial physiology which may trigger mitochondrial clearance) or programmed (gets activated in various cell types during development) (Sekine and Youle, 2018). Mitophagy impairment alters mitochondrial function and leads to aggregation of nonfunctioning organelles further causing cellular and tissue damage (Durcan and Fon, 2015). Various stimuli contribute to mitophagy through various signaling pathways in different cellular aspects (Palikaras et al., 2017). Basal mitophagy is known to be independent of PINK1 in metabolically active tissues (McWilliams et al., 2018). Mitophagy mediated by starvation or hypoxia is partially independent of the typical macroautophagy process (Hirota et al., 2015).

Neurons are found to be more vulnerable to mitophagic impairment as seen in various neurodegenerative disorders (Martinez-Vicente, 2017). Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) share common pathology marked by the neuronal loss which may further lead to various physical and cognitive dysfunction in patients. These disorders have aggregated neurotoxic proteins and dysfunctional mitochondria in common that alter the cellular homeostasis and neuronal function. Removal of these neurotoxic proteins and dysfunctional organelles is important for neuronal homeostasis. Any impairment in the removal process alters neuronal homeostasis and plays a role in the development of these neurodegenerative disorders (Rodolfo et al., 2018).

Mitochondrial dysregulation and defective mitophagy have been associated with neurodegenerative disorders. Mutations in the PINK1 and Parkin genes are responsible for PD (Valente et al., 2004). In AD, amyloid beta-derived diffusible ligands cause mitochondrial splitting and mitophagy (Ryu et al., 2015). In HD, the mutant huntingtin is known to induce mitophagy (Khalil et al., 2015). In ALS, mitochondrial dysfunction is seen where ubiquitinated mitochondria’s targeting to autophagosomes is reduced further contributing to the development of ALS (Benatar, 2007).

So, the proper degradation of dysfunctional mitochondria through mitophagy is important for maintaining mitochondrial quality and quantity in neurons. Thus, mitophagy has found to play a crucial role in aforementioned disorders (Martinez-Vicente, 2017). So, in the present chapter, authors describe the multifaced role of mitophagy in neurodegenerative disorders.

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