Microglial Mitophagy and Neurodegenerative Disorders

Microglial Mitophagy and Neurodegenerative Disorders

Eyitayo Adeyemi Oyindamola (Kwame Nkrumah University of Science and Technology, Ghana), Maxwell Kwadwo Agyemang (Kwame Nkrumah University of Science and Technology, Ghana), Joseph Owusu-Sarfo (Kwame Nkrumah University of Science and Technology, Ghana), Oduro Kofi Yeboah (Kwame Nkrumah University of Science and Technology, Ghana) and Newman Osafo (Kwame Nkrumah University of Science and Technology, Ghana)
Copyright: © 2020 |Pages: 41
DOI: 10.4018/978-1-7998-1317-0.ch004

Abstract

Microglia are important in the regulation of the inflammatory response in regulating the release of proinflammatory mediators in the brain. Through their phagocytic actions, microglia are significant in the CNS when it comes to the body's response to physiological insults by promoting repair of impaired brain function. They do so by engulfing and degrading microbes as well as brain-derived debris and proteins such as myelin and axonal fragments, amyloid-beta, and apoptotic cells. This mitophagic activity of microglia is of importance in neurodegeneration. In most neurodegenerative disorders, mitophagy is impaired with resultant accumulation of dysfunctional mitochondria as well as processes such as lysosomal fusion and autophagosomes. In Parkinson's and Alzheimer's for example, impaired mitophagy accounts for the build-up of α-synuclein and amyloid respectively in affected individuals. The chapter discusses extensively the link between microglia mitophagy and neurodegeration and how dysfunctional mitophagy increases the likelihood of their occurrence.
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Introduction

The mitochondrion is a membrane-bound organelle with several important roles in cellular function, including the production of adenosine triphosphate (ATP), the main energy currency of the cell, via oxidative phosphorylation, calcium homeostasis, and the metabolism of fatty and amino acids, and steroids (Wager and Russell, 2013). Notwithstanding, the mitochondrion is also the primary source of potentially damaging endogenous reactive oxygen species (ROS), which have been associated with a number of pathological pathways such as neurodegeneration, and the induction of lipid peroxidation, protein carbonyls and DNA damage (Santos et al., 2012; Murphy et al., 2011). It has been shown that the release of the cytochrome c, a hemeprotein relevant in the mitochondrial electron transport system and apoptosis, from mitochondria, triggers apoptosis under the regulation of several regulators, the most prominent being members of the B-cell lymphoma protein-2 (BCL2) family (Ow et al., 2008). ROS can induce mitochondrial permeability transition pore (mPTP) and also increase the release of cytochrome c from mitochondria, both of which results in programmed cell death (Murphy, 2008).

The removal of damaged mitochondria is essential for cell survival. Neurons, being highly specialized cells, are peculiarly liable to defects in autophagic mechanisms. These impairments in mitochondrial function and their dynamics have been identified in many neurodegenerative disorders, and modulators of both mitochondrial physiology and autophagy have presented themselves as promising therapeutic targets (Wager and Russell, 2013). Studies have demonstrated that deletion of certain pivotal autophagic genes such as ATG-7 and ATG-5 in successive post-mitotic cells enhances the formation and accumulation of cytoplasmic inclusions and induces neurodegeneration in the absence of any other pathological pathway that can also contribute to neural tissue death (Plaza-Zabala et al., 2017; Hara et al., 2006; Komatsu et al., 2006). This selective degradation of mitochondria by highly specialized autophagic mechanisms is what is termed mitophagy, and represents an important quality control mechanism in protein folding (Wager and Russell, 2013).

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