Mechanisms and roles of mitophagy in neurodegenerative diseases

Abstract

Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

TBK1 regulates autophagic clearance of soluble mutant huntingtin and inhibits aggregation/toxicity in different models of Huntington’s disease

“…Phosphorylation on OPTN or p62 was shown to facilitate the autophagy-dependent clearance of damaged/dysfunctional mitochondria (Matsumoto et al, 2015;Richter et al, 2016), a common defect in many neurodegenerative diseases (Rodolfo et al, 2018;Wang et al, 2019) and misfolded proteins and aggregates of proteins linked to neurodegenerative diseases, such as mutant SOD1 (Korac et al, 2013) and HTT (Matsumoto et al, 2011). TBK1-mediated enhancement of cargo/substrate recognition by the adaptors OPTN and p62, and OPTN mRNA levels were shown to be partially reduced in HD patient brain tissues (Hodges et al, 2006).…”

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

“…S3) (65). This process of mitochondrial quality control (MQC) can be impaired during aging and has been associated with major neurodegenerative disorders including AD (66, 67). Mito-mKeima has a unique spectral characteristic whereby at neutral pH or above, such as occurs in the mitochondrial matrix, excitation at 440-nm results in emission at 600-nm+, but at acidic pH, such as occurs in the lysosome, the excitation maxima shifts to 550-nm (akin to a conventional red fluorescent protein).…”

Mitochondrial Degeneration and Autophagy Associated With Delayed Effects of Radiation in the Mouse Brain

“…Dysfunctional mitochondria may be considered early features of neurodegenerative diseases (Lezi and Swerdlow, 2012). Mitochondrial homeostasis is maintained by mitophagy; once mitophagy is initiated, autophagy will be activated to remove deceased mitochondria and other organelles by lysosomes in normal functioning neurons (Wang et al, 2019). Autophagy is an intracellular degradation system which delivers cytoplasmic constituents to the lysosome, and any disruption in autophagy has been related to increased genome instability.…”