Mitophagy and Neuroprotection

Abstract

Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new etiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies.

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…Mitochondria have been considered to play a crucial role in maintaining metabolic homeostasis, regulating apoptotic processes and oxidative energy metabolism, as well as modulating ROS production (Lou et al, 2020). SphK2 has also been found to be expressed in mitochondria in addition to being expressed in the nucleus, and evidence has suggested that SphK2 may function in the production of S1P in mitochondria (Chan and Pitson, 2013;Santos and Lynch, 2015;Ghasemi et al, 2016).…”

Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

“…Mitochondria are termed the "powerhouses" of the cell, and generate the majority of the cell's supply of adenosine triphosphate (ATP) through the oxidative phosphorylation system (OXPHOS) in which electrons produced by the citric acid cycle are transferred down the mitochondrial respiratory complexes. Neurons have particularly high and continuous energy demands so that mitochondrial function is essential for maintaining neuronal integrity and responsiveness [1][2][3][4][5][6][7]. Mitochondrial energy production fuels various critical neuronal functions, especially the ATP-dependent neurotransmission [1,3,8].…”

“…Mitophagy, a selective form of autophagy, constitutes a key pathway of mitochondrial quality control mechanisms involving sequestration of defective mitochondria into autophagosomes for subsequent lysosomal degradation [1,2,24,25]. Disruption of mitophagy has been indicated in aging and various diseases, including neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) [7,26]. This review aims to provide a thorough and timely overview of the mitophagy pathways, summarize the underlying mechanisms of mitophagy defects in AD and other age-related neurodegenerative diseases, and highlight the possible therapeutic strategies targeting mitophagy towards confronting mitochondrial dysfunction and neurodegeneration.…”

Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation

“…Autophagy has a major cytoprotective effect in neurons, since defective autophagy or mitophagy (autophagic clearance of mitochondria) is frequently observed in association with neuronal loss and cognitive decline in aging or in CNS neurodegeneration [22]. A failure to eliminate neurotoxic proteins, as a result of impaired autophagy/mitophagy, causes spontaneous neurodegeneration, while restoration of autophagy/mitophagy is neuroprotective in Alzheimer's disease [23,24].…”