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.

Keywords: autophagy; autophagy receptor; cancer; mitophagy; neurodegenerative diseases; pathologies.

Figure 1

The role of mitophagy in physiology and human pathologies. Mitophagy plays an important role in maintaining mitochondria homeostasis including quality control of mitochondria and cell metabolism, as well as in regulating various aspects of cellular function, such as development/differentiation, cell death, and immunity/inflammation. These roles are critical to prevent developing human diseases linked to organ failure (heart muscle, skeletal muscle, liver, and pancreas) or to age-related dysfunctions (cancer, neurodegenerative diseases).

Figure 2

Schematic representation of the structural domains of the non-mitochondrial autophagy receptors involved in mitophagy. Each domain is represented, scaled according to its aa position [except for NBR1 and Tax1 binding protein 1 (TAX1BP1)] and delimitations are indicated. Abbreviations: HLX, helix-loop-helix; CC, coiled-coil; LZ, leucine zipper; ZF, zinc finger; LIR, LC3-interacting region; NOA, NEMO-optineurin (Optn)-ABIN domain; SKICH, SKIP carboxyl homology domain; CLIR, non-canonical LC3-interacting region; GALBI, galectin-8 binding region; LIM-L, Lin11, Isl-1, and Mec-3 (LIM)-like domain; PB, Phox and Bemp1 domain; TB, TRAF6-binding domain; KIR, Keap1-interacting region; UBD, ubiquitin-binding domain; J, α-helical J domain; O, homodimerization domain. Known preferential affinities of the autophagy receptors for the different ubiquitin chain types are presented according to the following references: Optn (37, 38); nuclear dot protein 52 (39); p62 (40, 41); NBR1 (42, 43), and TAX1BP1 (44, 45).

Figure 3

Schematic representation of the overall process of mitophagy [adapted from Ref. (36)]. (A) PINK1 import and accumulation mechanisms into mitochondria. PINK1 detects mitochondrial damage via selective proteolysis. Continuous import and the degradation cycle explain the undetectable levels of PINK1 on healthy mitochondria. Upon damage, import into the inner membrane is blocked leading to accumulation of uncleaved PINK1 on the outer mitochondrial membrane. Abbreviations: TOM, translocase of the outer mitochondrial membrane complex; TIM, translocase of the inner mitochondrial membrane complex; MPP, mitochondrial processing peptidase; PARL: presenilin-associated rhomboid-like protein. (B) Positive feedback ubiquitination cycles induced by Parkin and Ub chains on damaged mitochondria. Mitochondria-recruited PINK1 phosphorylate Ub chains conjugated to mitochondrial proteins, including CISD1 and MNF2 (shown here), as well as cytosolic Parkin, subsequently recruited to mitochondria. Activated Parkin can elongate Ub chains that can be, in turn, phosphorylated by PINK1. (C) Recruitment and activation of autophagy receptors during Parkin/PINK1-mediated mitophagy. Autophagy proteins, including adaptors [Optineurin (Optn), nuclear dot protein 52 (NDP52), p62, and Tax1 binding protein 1 (TAX1BP1) presented] and regulators (TANK-binding kinase-1, TBK1) are recruited to the mitochondria. TBK1-phosphorylation of autophagy adaptors can enhance their Ub-binding activities and promote the recruitment of the light chain 3 (LC3)-labeled isolation membrane. (D) Autophagosome biogenesis during mitophagy. Formation of autophagophore vesicle surrounding damaged mitochondria is a multi-independent process. (i) Optn and NDP52 mediate initiation and elongation of autophagosomes (at ER-mitochondria contact sites for example) via recruitment of complexes containing ULK1, PI3K, WIPI1, and DFCP1. (ii) Autophagy receptors also mediate recruitment of LC3/GABARAP family members to promote expansion of the isolation membrane. (iii) Finally, Rab-GAPs, TBC1D15, and TBC1D17, localized to mitochondria via interaction of Fis1 can regulate proper autophagosomal formation by modulating Rab7 activity.

Figure 4

Mapping of the neurodegenerative disease-associated mutations of Optineurin (Optn). Localization of the disease-associated polymorphisms and mutations of human Optn protein is shown (as described in Table 1). Mutations associated with POAG and juvenile open-angle glaucoma are indicated in red, while mutations linked to amyotrophic lateral sclerosis are in green. Optn contains multiple protein interaction domains that are important for its localization and its mitophagy-related function. The regions of human Optn that have been involved in the interaction with its different partners are represented as thick bars with their delimitations.