Mitophagy: An Emerging Target in Ocular Pathology

Abstract

Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

Figure 1.

Transmission electron microscopy (TEM) of human mitochondria. (A) Normal, functional, mitochondria display densely packed cristae and no inclusion bodies and often have an average size (0.5–1.0 µm in length) with a discoid shape. (B) Dysfunctional mitochondria display abnormal or unfolded cristae (arrowhead), cristae dropout (asterisk), and inclusion bodies (arrow) and may have smaller or larger than average sizes with a rounded shape.

Figure 2.

Mitophagy protein signaling mechanisms. (A) PINK1/parkin-mediated mitophagy. Following the stabilization of PINK1 to the OMM, possibly by BNIP3, parkin is recruited to the OMM, resulting in the phosphorylation of parkin by PINK1. This event then triggers parkin to polyubiquitinate an OMM protein (VDAC), which then recruits a phagophore through proteins p62 and LC3. Interactions between the polyubiquitinated OMM protein and LC3/p62 initiate the mitophagy process. (B) Non-parkin-mediated mitophagy is initiated through proteins on the OMM (FUNDC1, NIX, or BNIP3) that bind directly to LC3 on the phagophore membrane, initiating the mitophagy process. (C) Non-parkin, syntaxin 17 (STX17)-mediated mitophagy occurs when the expression of FIS1 is downregulated, allowing for the accumulation of STX17 proteins on the OMM. The accumulation of STX17 proteins on the OMM recruits ATG14, which interacts with LC3 on the phagophore membrane.