Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are characterized by a progressive loss of selective neuron subtypes in the central nervous system (CNS). Although various factors account for the initiation and development of these diseases, accumulating evidence shows that impaired mitochondrial function is a prominent and common mechanism. Mitochondria play a critical role in neurons and are involved in energy production, cellular metabolism regulation, intracellular calcium homeostasis, immune responses, and cell fate. Thus, cells in the CNS heavily rely on mitochondrial integrity. Many aspects of mitochondrial dysfunction are manifested in neurodegenerative diseases, including aberrant mitochondrial quality control (mitoQC), mitochondrial-driven inflammation, and bioenergetic defects. Herein, we briefly summarize the molecular basis of mitoQC, including mitochondrial proteostasis, biogenesis, dynamics, and organelle degradation. We also focus on the research, to date, regarding aberrant mitoQC and mitochondrial-driven inflammation in several common neurodegenerative diseases. In addition, we outline novel therapeutic strategies that target aberrant mitoQC in neurodegenerative diseases.

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

“…Many reports have associated autophagic pathway dysfunction to neurodegeneration development [180]. Alterations of this pathway have been identified at different levels and resulted in defective autophagic proteolysis of the macromolecules/molecular complexes within the lysosomal compartment [180][181][182]. The correlation of abnormal autophagic activity in AD has been described by Nixon and co-authors [180], who emphasized the impairment of the autophagolysosomes in human AD fibroblasts and in several models of the disease [183,184].…”

Mitophagy and the Brain

“…Impaired Parkin recruitment to mitochondria is suggested to be caused by tau mediated sequestration of Parkin in the cytosol [166,173]. Defects in the activation of ULK1 and TBK1 lead to impaired mitophagy [173]. In AD, mitophagy increases or decreases depending on the part of the cell.…”

“…PD has been associated with mitophagy dysfunction since the discovery of mutations in genes involved in mitophagy causing familial PD. Mutations in PARK6 (encodes for PINK1), PARK2 (encodes for Parkin), PARK1/4 (α-synuclein), PARK7 (DJ1), PARK8 (LRRK2), PARK17 (Vsp35), and PARK9 (ATP13A2) genes are linked to familial PD [173,[186][187][188][189][190][191]. The role of PINK1, Parkin, and Vsp35 in mitophagy are well known and reviewed above.…”

“…Lysosomal dysfunction has also been implicated in ALS. Specifically, lysosomal deficits result in an abnormal accumulation of autophagic vacuoles that engulf damaged mitochondria within the motor neuron axons of G93A SOD1 ALS mice [173]. Impaired mitochondrial turnover along with the accumulation of misfolded proteins and protein aggregates contributes to ALS linked mitochondrial dysfunction and motor neuron death.…”

Neuronal Mitophagy: Friend or Foe?

“…The detailed molecular mechanisms that govern mitochondrial selective autophagy in such a highly differentiated and compartmentalized cell, as well as their relevance to neuronal physiology only now begin to be elucidated. During the last decade, mitophagy was widely studied in the context of stress and pathological conditions (Palikaras et al, 2018 ; Lou et al, 2020 ; Yan et al, 2020 ). A growing body of evidence highlights mitophagy as a physiological process that occurs constitutively at baseline levels in the nervous system.…”