Mitochondria are highly dynamic organelles that are important for many diverse cellular processes, such as energy metabolism, calcium buffering, and apoptosis. Mitochondrial biology and dysfunction have recently been linked to different types of cancers and neurodegenerative diseases, most notably Parkinson’s disease. Thus, a better understanding of the quality control systems that maintain a healthy mitochondrial network can facilitate the development of effective treatments for these diseases. In this perspective, we will discuss recent advances on two mitochondrial quality control pathways: the UPS and mitophagy, highlight how new players may be contributing to regulate these pathways. We believe the proteases involved will be key and novel regulators of mitochondrial quality control, and this knowledge will provide insights into future studies aimed to combat neurodegenerative diseases. 1. Introduction: Mitochondrial Quality Control Systems Parkinson’s disease (PD) is a neurodegenerative disease of the central nervous system that results from the loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. While environmental factors such as oxidative and nitrosative stress are responsible for the, more common, sporadic form of PD [1], there are genetic factors that contribute to the familiar (genetic) form of the disease [2]. Both forms of PD are characterized by the formation of Lewy bodies (LBs)—aggregates of various proteins including alpha-synuclein, ubiquitin, and tubulin. Although the mechanism that leads to PD pathogenesis remains elusive, studies have shown that mitochondrial dysfunction plays a role in the progression of both forms of the disease [2–4]. Mitochondria are vital for many diverse processes in the cell, such as energy metabolism, calcium buffering, and cell apoptosis. These double-membrane-bound organelles are often called the “powerhouses” of the cell because they generate the cell’s supply of energy in the form of ATP. They are also the main source of reactive oxygen species (ROS) and therefore are most susceptible to damage by oxidative stress. An accumulation of ROS can lead to mutations in mitochondrial DNA and misfolding and aggregation of proteins, which can disrupt normal functions [5]. It is known that neuronal cells are particularly vulnerable to the functional deterioration of mitochondria, primarily due to their high-energy demands. Consequently, along with PD, mitochondrial dysfunction has been linked to other neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, and the
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