Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson's Disease and Huntington's Disease

Abstract

In recent years, several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease (PD) and Huntington's disease (HD). Despite distinct clinical and pathological features, these two neurodegenerative diseases share critical processes, such as the presence of misfolded and/or aggregated proteins, oxidative stress, and mitochondrial anomalies. Even though the mitochondria are commonly regarded as the “powerhouses” of the cell, they are involved in a multitude of cellular events such as heme metabolism, calcium homeostasis, and apoptosis. Disruption of mitochondrial homeostasis and subsequent mitochondrial dysfunction play a key role in the pathophysiology of neurodegenerative diseases, further highlighting the importance of these organelles, especially in neurons. The maintenance of mitochondrial integrity through different surveillance mechanisms is thus critical for neuron survival. Mitochondria display a wide range of quality control mechanisms, from the molecular to the organellar level. Interestingly, many of these lines of defense have been found to be altered in neurodegenerative diseases such as PD and HD. Current knowledge and further elucidation of the novel pathways that protect the cell through mitochondrial quality control may offer unique opportunities for disease therapy in situations where ongoing mitochondrial damage occurs. In this review, we discuss the involvement of mitochondrial dysfunction in neurodegeneration with a special focus on the recent findings regarding mitochondrial quality control pathways, beyond the classical effects of increased production of reactive oxygen species (ROS) and bioenergetic alterations. We also discuss how disturbances in these processes underlie the pathophysiology of neurodegenerative disorders such as PD and HD.

Mitochondrial integrity in neurodegeneration

“…In a transgenic mouse model of HD, they found that the structure of complex II was affected early in HD, and overexpressing complex II reduced the effects of mutated Htt on striatal neurons, relieving them from neuronal dysfunction. In other studies, this reduction in complex II was accompanied by a reduction in ATP production, as insufficient oxidative phosphorylation results in a disruption of mitochondrial metabolism …”

“…In other studies, this reduction in complex II was accompanied by a reduction in ATP production, as insufficient oxidative phosphorylation results in a disruption of mitochondrial metabolism. 86,88 The effect of mutant Htt on mitochondrial dynamics has also become a key focus in HD research. HD patients were found to have an imbalance in mitochondrial dynamics proteins, in postmortem tissue taken from the striatum of HD patients.…”

Miro: A molecular switch at the center of mitochondrial regulation

“…As a critical component of axonal mitochondrial transport, Miro occupies a central role in regulating mitochondrial position and turnover, a process critical to the health of neurons . In this section, we will discuss the link between Miro and mitochondrial biology with neurodegeneration.…”

Tollip coordinates Parkin‐dependent trafficking of mitochondrial‐derived vesicles

“…Mitochondrial quality control pathways are essential to maintain their proper function and ensure overall cell health and survival. Dysfunction in these pathways is associated with several human pathologies, such as neurodegenerative disease and cardiomyopathy (Campos et al , ; Franco‐Iborra et al , ). Mitophagy, the autophagic degradation of damaged mitochondria (Lemasters, ), is one of the most well‐studied mechanisms of mitochondrial quality control and is an important pathway aimed at sequestering whole, damaged mitochondria to ensure their degradation in lysosomes.…”