Glaucoma is the leading cause of irreversible blindness and affects more than 60 million people worldwide, of which nearly 10% of cases are estimated to result in blindness (Quigley and Broman, 2006; Ulhaq, 2020a; Ulhaq and Soraya, 2020). Although lowering intraocular pressure (IOP) can alleviate glacoma symptoms, it does not necessarily impede the progression of optic nerve head (ONH) and retinal ganglion cell (RGC) degeneration (Edwards et al., 2020; Noh et al., 2013; Ulhaq et al., 2021a, Ulhaq et al., 2022). The exact factors contributing to RGC and axon degeneration in glaucoma are still not fully understood. However, there is compelling evidence in the literature suggesting that mitochondrial abnormalities play a significant role in the development of this disease (Hvozda Arana et al., 2021; Vallabh et al., 2022). Upon onset of the elevated IOP, the ON exhibited lower ATP levels as well as a significant loss of mitochondrial cristae (Baltan et al., 2010; Coughlin et al., 2015; Harun-Or-Rashid et al., 2018). Moreover, because the nerve fiber layers of the ONH and the sensory retina primarily consist of unmyelinated axons (Mehmood et al., 2021), higher energy consumption is required to maintain the ion concentration gradients across the axonal membrane and to facilitate the proper functioning of the neurons (Neishabouri and Faisal, 2011). Consequently, a substantial presence of mitochondria is observed in the prelaminar region of the optic nerve axons (Carelli et al., 2004). Therefore, energy deprivation due to mitochondrial dysfunction and metabolic stress may contribute to the degeneration of axons in glaucoma.

The modulation of energy production by mitochondria occurs through several pathways, including the tricarboxylic acid (TCA) cycle, fatty acid β-oxidation (FAO), and oxidative phosphorylation (OXPHOS) (Nsiah-Sefaa and McKenzie, 2016). Our previous study (Ulhaq et al., 2023a) and others (Fu et al., 2021; Guo et al., 2022; Tyni et al., 2002) demonstrated that disruption of FAO pathways leads to energy deficiency and ferroptosis in the eye, which ultimately causes retinal dysfunction. Genetic and genome-wide association studies (GWAS) have also confirmed associations between impaired lipid pathways with glaucoma pathology (Khawaja et al., 2016; Wiggs, 2015), highlighting the possibility of β-oxidation failure in glaucomatous individuals. Although the level of long-chain fatty acids in the optic nerve (ON) between control and glaucomatous patients varied (Chauhan et al., 2019), an earlier study reported elevation of long-chain unsaturated fatty acids among glaucoma patients (Rong et al., 2017). Such discrepancy emphasizes the need for further investigation into the biological basis of lipidomic changes in glaucomatous neurodegeneration.

Due to the highly oxidizing microenvironment of mitochondria, excessive amounts of reactive oxygen species (ROS) are often generated. In such conditions, the cell relies on its antioxidant defense system to neutralize and regulate the levels of ROS (Fu et al., 2021). Therefore, impairment in the mitochondrial oxidative phosphorylation (OXPHOS) pathway results in ROS overproduction, which in turn leads to oxidative stress and the development of multiple retinal disorders, including glaucoma (Noh et al., 2013). Indeed, robust evidence indicates a significant increase in oxidative DNA damage within the trabecular meshwork (TM) of glaucomatous individuals (Saccà et al., 2005; Wu et al., 2022). Although it has been proposed that variations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes could contribute to aberrant mitochondrial structure and function, there is extensive documentation highlighting the significance of mtDNA variants as a crucial cellular component in numerous neurodegenerative disorders, including glaucoma (Lascaratos et al., 2012; Mambo et al., 2003). The higher susceptibility of mtDNA towards damage relative to nDNA is likely due to the absence of DNA protection by histones and its close proximity to reactive oxygen species (ROS) generated by the mitochondrial respiratory chain (Wu et al., 2015). In addition, mtDNA deletion is frequently detected in the TM of glaucomatous eyes (Izzotti et al., 2011). While numerous studies suggest that alterations in mtDNA contribute to the pathogenesis of glaucoma, the results across studies remain equivocal. Hence, in this present study, a meta-analysis was conducted to explore a possible association between complex mitochondrial dysfunction due to variants in mtDNA with glaucoma susceptibility. The potential involvement of β-oxidation defects in glaucoma was also assessed by evaluating the acylcarnitine (AC) level from the polled studies and knocking down its corresponding enzyme for AC production in the zebrafish model.