Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

Abstract

Oxidative stress develops as a response to injury and reflects a breach in the cell’s antioxidant capacity. Therefore, the fine-tuning of reactive oxygen species (ROS) generation is crucial for preserving cell’s homeostasis. Mitochondria are a major source and an immediate target of ROS. Under different stimuli, including oxidative stress and impaired quality control, mitochondrial constituents (e.g., mitochondrial DNA, mtDNA) are displaced toward intra- or extracellular compartments. However, the mechanisms responsible for mtDNA unloading remain largely unclear. While shuttling freely within the cell, mtDNA can be delivered into the extracellular compartment via either extrusion of entire nucleoids or the generation and release of extracellular vesicles. Once discarded, mtDNA may act as a damage-associated molecular pattern (DAMP) and trigger an innate immune inflammatory response by binding to danger-signal receptors. Neuroinflammation is associated with a large array of neurological disorders for which mitochondrial DAMPs could represent a common thread supporting disease progression. The exploration of non-canonical pathways involved in mitochondrial quality control and neurodegeneration may unveil novel targets for the development of therapeutic agents. Here, we discuss these processes in the setting of two common neurodegenerative diseases (Alzheimer’s and Parkinson’s disease) and Down syndrome, the most frequent progeroid syndrome.

Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D inDrosophilaneurons

“…We hypothesize that the ruptured mitochondria are responsible for the strong pupal lethality of neuronal Vps13D depletion. While we did not observe direct evidence of neuronal apoptosis, we consider that mitochondrial DNA and oxidized mitochondrial proteins are potent inducers of innate immune responses (West 2017), and neuro-immune interactions are increasingly being recognized as important factors in neurodegenerative disease (Picca et al 2020;Yu et al 2020). Therefore, there is interesting work ahead to understand the pathology that evolves following Vps13D loss.…”

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

“…Intriguingly, these processes are associated with adenosine triphosphate (ATP) consumption, and mitochondrial impairment is one of the earliest events in neurodegeneration, which promotes an increase of ROS. Mitochondrial dysfunction has been reported in pre-clinical models of DS and in primary cell cultures from DS individuals [ 49 , 81 , 90 , 91 ]. In particular, mitochondrial ROS overproduction has been identified in trisomic human skin fibroblasts, where it was linked to a deficiency of mitochondrial complex I, ATP synthase, ADP/ATP translocators, and adenylate kinase activities [ 92 , 93 ].…”

Genetically controlled mtDNA editing prevents ROS damage by arresting oxidative phosphorylation

“…Oxidative stress markers associate with age and all-cause mortality (Schöttker et al, 2015). Ageing is associated with high circulating levels of proinflammatory markers (Ferrucci & Fabbri, 2018), proinflammatory cytokines induce ROS production in several cell types (Yang et al, 2007), and oxidant overproduction is a candidate mechanism in neuronal damage and loss via neuroinflammation (Picca et al, 2020), a common denominator of neurodegenerative diseases (van Horssen, van Schaik, & Witte, 2019). Thus, assuming that the level of chronic O !…”