TABLE 1.

Summary of mitochondria-targeted therapeutic strategies for primary open-angle glaucoma.

Therapeutic strategy	Mechanism of action	Strengths	Limitations
Exercise	- Increased physical activity reduces reactive oxygen species (ROS), promotes enzymatic activity for cellular respiration, increases mitochondrial biogenesis and mitophagy, and enhances neurotrophic factors and cerebral pathways	- Low cost	- Greater efficacy studies needed to confirm neuroprotection in glaucoma-
		- Accessible	Lack of clinical trials
		- Non-invasive	- Unclear standardization of recommendations and consistent delivery of treatment
		- Protective against other risk factors such as diabetes
Diet and nutrition	- Altering diet and food intake (ketone-based diet, low-fat diet, Mediterranean diet, vitamin supplementation) or adjusting quantity of caloric intake	- Low cost	- Greater efficacy studies needed to confirm neuroprotection in glaucoma
		- Accessible	- Lack of clinical trials
	- Improves abnormal protein accumulation, neurotoxicity, energy utilization, inflammation, ROS production, and overall mitochondrial dysfunction	- Non-invasive	- Difficult to adhere to in real-world scenarios
		- Protective against other risk factors such as diabetes	- Strict diets can cause inadequate nutrition balances
Antioxidant supplementation	- Enzymatic or non-enzymatic antioxidants to counter oxidative stress	- Low cost	- Difficult to achieve specific and concentrated subcellular delivery into mitochondrial organelle
	- Decreased proinflammatory cytokines in the retina and optic nerve	- Accessible	- Improved standardized methods of effective antioxidant supplementation and augmentation strategies needed
	- Increased retinal ganglion cell (RGC) survival and axonal transport	- Non-invasive	- Larger sample clinical trials necessary to confirm efficacy in humans
	- May work synergistically with trophic factors to rescue RGCs	- Positive results in animal and human small sample trials
Stem cell transplantation	- Direct stem cell replacement of diseased RGCs	- Neuroprotective potential for surviving RGCs	- Expensive
	- Mesenchymal stem cell transplantation promotes survival of RGCs through neurotrophic factors, growth factors, and other neuroprotective cytokines	- Neuroregenerative potential for degenerated RGCs	- Invasive
	- Stem cell replacement of trabecular meshwork cells improves aqueous humor outflow and RGC neuroprotection	- Demonstrated potential for integration with preserved functionality	- Sparse human clinical trials in glaucoma that show equivocal results
			- Challenges in cell purification and protocol
			- Unclear risks and benefits regarding the origin of different stem cell transplant sources
Exposure to hypoxia	- Low-dose intermittent hypoxia exposure preconditions neuroprotective cellular responses, increases antioxidant production, promotes hypoxia-inducible factors expression, and protects RGCs against future hypoxic stress	- Strengthens adaptive neuroprotection response that sustains past initial treatment exposure	- Lack of clinical trials in glaucoma
		- Potential for post-injury treatment exposure to have positive effects via adaptive cellular plasticity	- Unclear standardization of recommendations and treatment protocol
Gene therapy	- Targeted alteration of a multitude of genes can act by upregulating expression of healthy DNA, proteins, and mitochondria or by downregulating pathogenic mutant forms	- Several genetic associations with POAG have been identified	- Expensive
		- Potential for high-risk loci alteration prior to disease onset or progression
		- Highly individualized care	- Invasive
	- Genes associated with glaucoma pathogenesis and progression have been identified at various steps throughout the pathway of disease	- Clinical utilization of genetic screening in families	- Early stages of human studies in glaucoma
		- Distinct anatomy of the ocular system conducive to gene therapy	- Improved DNA vector design for effective delivery of genetic material needed
Mitochondrial transplantation	- Restores mitochondrial function and cell structure	- Multiple routes of administration possible to achieve desired results	- Expensive
			- Invasive
	- Increases the proportion of healthy mitochondria within a heteroplasmic state	- Successful uptake in human induced pluripotent stem cell-derived RGCs	- Persistent challenges in functional integration and incorporation of mitochondrial material
		- Ability to produce neuroprotective and altering results in brain neural tissue	- Need for more glaucoma-specific studies
Light therapy	- Enhances mitochondrial energy production, enzymatic activity, cell signaling, neurobiogenesis, and neuronal growth	- Low cost	- May not be suitable for patients with photosensitivity
		- Accessible
	- Prevents dendritic pruning and RGC degeneration	- Non-invasive	- Unclear treatment protocol standardization
		- Innate characteristics of ocular and mitochondrial systems conducive to light therapy
		- Demonstrated results in various ocular pathologies	- Lack of clinical trials