Multifaceted mitochondrial as a novel therapeutic target in dry eye: insights and interventions

Abstract

Dry eye, recognized as the most prevalent ocular surface disorder, has risen to prominence as a significant public health issue, adversely impacting the quality of life for individuals across the globe. Despite decades of extensive research into the chronic inflammation that characterizes dry eye, the intricate mechanisms fueling this persistent inflammatory state remain incompletely understood. Among the various cellular components under investigation, mitochondria-essential for cellular energy production and homeostasis-have attracted increasing attention for their role in dry eye pathogenesis. This involvement points to mechanisms such as oxidative stress, apoptosis, and sustained inflammation, which are central to the progression of the disease. This review aims to provide a thorough exploration of mitochondrial dysfunction in dry eye, shedding light on the critical roles played by mitochondrial oxidative stress, apoptosis, and mitochondrial DNA damage. It delves into the mechanisms through which diverse pathogenic factors may trigger mitochondrial dysfunction, thereby contributing to the onset and exacerbation of dry eye. Furthermore, it lays the groundwork for an overview of current therapeutic strategies that specifically target mitochondrial dysfunction, underscoring their potential in managing this complex condition. By spotlighting this burgeoning area of research, our review seeks to catalyze the development of innovative drug discovery and therapeutic approaches. The ultimate goal is to unlock promising avenues for the future management of dry eye, potentially revolutionizing treatment paradigms and improving patient outcomes. Through this comprehensive examination, we endeavor to enrich the scientific community's understanding of dry eye and inspire novel interventions that address the underlying mitochondrial dysfunctions contributing to this widespread disorder.

Fig. 1. Role of mitochondrial dysfunction in DE.

The risk factors for DE-induced mitochondrial dysfunction. Mitochondrial dysfunction increases intracellular ROS accumulation, activating the NLRP3 and NF-kB signaling pathways and the release of downstream inflammatory cytokines. Mitochondrial dysfunction increases mitochondrial permeability by inducing the expression of Bax. Cyt-c and DIABLO/Smac are released from mitochondria to the cytoplasm. Cyt-c binds and activates APAF-1 to form apoptotic bodies and activates Caspase-9- and Caspase-3-7-dependent apoptosis. DIABLO/Smac activates apoptosis by blocking IAP. Additionally, mtDNA can be released into the cytoplasm and recognized by pattern recognition receptors to initiate the inflammatory response.

Fig. 2. Mitophagy.

In cases of DE syndrome, the condition of tear hyperosmolarity acts as a critical trigger for mitochondrial reactive oxygen species (mtROS) generation and subsequent cellular energy dysfunction. This process potentially leads to the activation of the AMP-activated protein kinase/Mitochondrial Fission Factor (AMPK/MFF) pathway in Human Corneal Epithelial Cells (HCECs). Once activated, MFF plays a pivotal role in recruiting DRP1—a cytoplasmic protein—to the OMM. This recruitment is a key step in mediating both mitochondrial fission and mitophagy, processes essential for maintaining cellular health and function under stress conditions.

Fig. 3. Sorting mechanisms and biological effects of mitoEVs.

Potential Sorting Mechanisms in Donor Cells. The formed MDVs can be sorted into lysosomes via PINK1/Parkin, Tollip, or STX17 pathways; into peroxisomes through Vps35 and MAPL; and into the extracellular space via OPA1, SNX9, DRP1, or PINK1. In certain cases, MDVs budding from mitochondria may merge into multivesicular bodies (MVBs), subsequently being released into the extracellular space as mitochondrial EVs. Moreover, mitoEVs encompass novel EV subtypes, mitochondrial vesicles, and other potential pathways involved in mitoEV biogenesis that require further categorization. Diverse effects of these EVs in target cells. These EVs may exhibit metabolic regulatory functions, such as disruptions in mitochondrial biogenesis (e.g., AMPK, PGC1), mitochondrial respiration, and mtROS production, thereby mediating the receptor cell’s phenotypic changes (e.g., differentiation, apoptosis). MitoEVs also possess immunomodulatory functions, including the induction of pro-inflammatory signals (e.g., TLR and STING), cytokine release, IFN responses, and phagocytic activities in immune cells.