Role of Optineurin in the Mitochondrial Dysfunction: Potential Implications in Neurodegenerative Diseases and Cancer

Abstract

Optineurin (Optn) is a 577 aa protein encoded by the Optn gene. Mutations of Optn are associated with normal tension glaucoma and amyotrophic lateral sclerosis, and its gene has also been linked to the development of Paget’s disease of bone and Crohn’s disease. Optn is involved in diverse cellular functions, including NF-κB regulation, membrane trafficking, exocytosis, vesicle transport, reorganization of actin and microtubules, cell cycle control, and autophagy. Besides its role in xenophagy and autophagy of aggregates, Optn has been identified as a primary autophagy receptor, among the five adaptors that translocate to mitochondria during mitophagy. Mitophagy is a selective macroautophagy process during which irreparable mitochondria are degraded, preventing accumulation of defective mitochondria and limiting the release of reactive oxygen species and proapoptotic factors. Mitochondrial quality control via mitophagy is central to the health of cells. One of the important surveillance pathways of mitochondrial health is the recently defined signal transduction pathway involving the mitochondrial PTEN-induced putative kinase 1 (PINK1) protein and the cytosolic RING-between-RING ubiquitin ligase Parkin. Both of these proteins, when mutated, have been identified in certain forms of Parkinson’s disease. By targeting ubiquitinated mitochondria to autophagosomes through its association with autophagy related proteins, Optn is responsible for a critical step in mitophagy. This review reports recent discoveries on the role of Optn in mitophagy and provides insight into its link with neurodegenerative diseases. We will also discuss the involvement of Optn in other pathologies in which mitophagy dysfunctions are involved including cancer.

<p>Mitofusin1 Is a Major Mediator in Glucose-Induced Epithelial-to-Mesenchymal Transition in Lung Adenocarcinoma Cells</p>

“…35 More importantly, activation of Pink and the E3 ubiquitin ligase Parkin leads to recruitment of the autophagy receptors that contain the LC3interacting region motif; these receptors bind to the LC3B-II form to initiate autophagy and mitophagy. 36 Consistent with the notion, in this study, we reported that glucose stimulation promotes autophagy by increasing the crosstalk between MFN1 and Pink which are key promoters of EMT and serve as regulators in LAD. The expression of Fis1 and Parkin is unaffected by MFN1 interference.…”

Molecular recognition of M1-linked ubiquitin chains by native and phosphorylated UBAN domains

“…Also, upon tumor necrosis factor (TNF)-α stimulation, ABIN-1 is recruited to the TNF receptor 1 (TNFR1) resulting in the recruitment of A20 and deubiquitination of RIP kinase 1 [13,14]. OPTN is involved in diverse cellular functions [15].…”

Glaucoma-Associated Mutations in the Optineurin Gene Have Limited Impact on Parkin-Dependent Mitophagy

“…Furthermore, more than 20 mutations in the OPTN gene have been reported as causal mutations leading to ALS, a fatal neurologic disorder accompanied by degeneration of both upper motor neurons in the motor cortex of the brain and lower motor neurons in the brainstem and spinal cord. 14 These OPTN mutations are present in both familial and sporadic forms of ALS. 14 A total of more than 40 mutations have been reported for POAG and ALS, and are located throughout the OPTN gene ( Fig.…”

“…14 These OPTN mutations are present in both familial and sporadic forms of ALS. 14 A total of more than 40 mutations have been reported for POAG and ALS, and are located throughout the OPTN gene ( Fig. 1A).…”