Mitochondrial Dynamics and Parkinson's Disease: Focus on Parkin

Abstract

Significance: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. To provide more effective medical therapy for PD, better understanding of the underlying causes of the disease is clearly necessary. Recent Advances: A broad range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Supporting this, mutations in several PD-linked genes are directly or indirectly linked to mitochondrial dysfunction. In particular, recent discoveries have identified parkin, whose mutations are causative of recessive parkinsonism, as a key regulator of mitochondrial homeostasis. Critical Issues: Parkin appears to be involved in the entire spectrum of mitochondrial dynamics, including organelle biogenesis, fusion/fission, and clearance via mitophagy. How a single protein can regulate such diverse mitochondrial events is as intriguing as it is amazing; the mechanism underlying this is currently under intense research. Here, we provide an overview of mitochondrial dynamics and its relationship with neurodegenerative diseases and discuss current evidence and controversies surrounding the role of parkin in mitochondrial quality control and its relevance to PD pathogenesis. Future Directions: Although the emerging field of parkin-mediated mitochondrial quality control has proven to be exciting, it is important to recognize that PD pathogenesis is likely to involve an intricate network of interacting pathways. Elucidating the reciprocity of pathways, particularly how other PD-related pathways potentially influence mitochondrial homeostasis, may hold the key to therapeutic development. Antioxid. Redox Signal. 16, 935-949.

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…In fact, the inhibition of the Aβ-ABAD interaction has been shown to reduce Aβ accumulation and to improve mitochondrial function in transgenic mice and neuroblastoma cells (Lim et al, 2011;Yao et al, 2011). ABAD converts estrone to estradiol, a key antioxidant compound for neurone survival whose intracellular levels are decreased due to the interaction between Aβ and ABAD, a phenomenon that may contribute to Aβ-induced toxicity (Yang et al 2007;Lim et al, 2011). In addition, ABAD is a component of the mitochondrial RNAse P involved in the processing of immature mitochondrial tRNAs (Holzmann et al, 2008).…”

“…Finally, the high-temperature requirement A2 protein (HTRA2) is the last player in the field of PD. Mutations in this gene may increase the risk of PD, and increased ROS levels and altered mitochondrial morphology have been described in several cellular models of HTRA2 dysfunction (for a review see Lim et al, 2011). In addition, it seems to be an inductor of autophagy , but the precise role of this protein in PD, mitochondrial dynamics and autophagy is still unclear.…”

Cytosolic PTEN-induced Putative Kinase 1 Is Stabilized by the NF-κB Pathway and Promotes Non-selective Mitophagy

“…Recent studies have revealed that two genes, whose mutations are linked to familial parkinsonism, i.e. parkin (encoding a ubiquitin ligase) and PINK1 (encoding a serine/ threonine kinase), are important for mitophagy (1). According to the proposed model (2), a key initial event that occurs upon mitochondrial depolarization is the selective accumulation of PINK1 on the outer membrane of the damaged organelle.…”

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

“…The action of the PARKIN-PINK1 complex is to regulate mitochondrial morphogenesis and remove damaged mitochondria through a form of ALS (50,51). Mutations in PINK1 are associated with mitochondrial dysmorphogenesis and dysfunction, which are also characteristics of Parkinson's disease (52,53). In diabetic embryopathy, the aggregation of Parkin may perturb mitochondrial dynamics and protein quality control, thereby leading to embryonic malformations (15).…”