The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease

Abstract

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.

Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis

“…Therefore, the present finding might indicate the accumulation of proteolytic peptides within mitochondria, thus suggesting the activation of mitochondrial proteases such as the intermembrane space protease HTRA2/OMI. 36,37 Interestingly, HTRA2 was associated with a familial Parkinsonism (PARK13), although mutations were also found in healthy subjects. 8 The different activity of mitochondrial proteases with respect to the treatments could also explain the complex behavior displayed by the mitochondrial chaperone mortalin.…”

Metformin promotes mitophagy in mononuclear cells: a potential in vitro model for unraveling metformin's mechanism of action

“…These polyubiquitinated signals recruit p62/SQSTM1, a ubiquitin‐binding autophagic adaptor protein that delivers the ubiquitinated mitochondrial cargo to autophagosomes via interacting with microtubule‐associated protein light chain 3 (LC3; also known as MAP1LC3A), thereby promoting selective autophagy. Furthermore, the fusion of autophagosomes with lysosomes to form autolysosomes is mediated by lysosome‐associated membrane protein‐2 (LAMP2), eventually resulting in the degradation of mitochondrial cargo along with LC3‐II and p62 by lysosomal hydrolases, indicating active autophagic flux …”

“…Furthermore, the fusion of autophagosomes with lysosomes to form autolysosomes is mediated by lysosome-associated membrane protein-2 (LAMP2), eventually resulting in the degradation of mitochondrial cargo along with LC3-II and p62 by lysosomal hydrolases, indicating active autophagic flux. 7 Metformin (1,1-dimethylbiguanide), a potent antihyperglycemic agent, is the preferred first-line drug in the management of type 2 diabetes mellitus (T2DM). It exerts its pleiotropic effects via the activation of AMPK (5ʹ-AMP-activated protein kinase), which is a ubiquitously expressed serine/threonine protein kinase that regulates cell growth, proliferation, and improves insulin sensitivity via increased translocation of glucose transporter 4.…”

A candidate factor that interacts with RF2, a restorer of fertility of Lead rice-type cytoplasmic male sterility in rice

“…1 for mice), which is reported to be associated with ubiquitin ligases and proteasomes (Ko et al [ 2004 ]). Although a ubiquitin proteasome proteolysis system has not been reported in mitochondria, we could not rule out the possibility that RIF2 is involved in ubiquitin-proteasome proteolysis of impaired mitochondrial proteins after their translocation to the outer membrane as reported for quality control of human mitochondria (Shanbhag et al [ 2012 ]). In this case, a CMS-causing protein would be a target of degradation for fertility restoration.…”