Why this review matters
Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4,000 people. Although RP can be caused by changes in many different genes, people and families often face a similar clinical challenge: progressive loss of rod photoreceptors, followed over time by cone degeneration and declining central vision.
A 2026 review in Antioxidants examines a shared biological pathway that may help explain this later-stage progression across genetically diverse forms of RP. The authors focus on an interconnected process involving oxidative stress, mitochondrial injury, and inflammation—and propose that mitochondrial DNA found outside cells could eventually become a useful way to measure disease activity and treatment response.
A common pathway across many forms of RP
Genes associated with RP can affect very different retinal functions. Yet as rods die, the outer retina receives more oxygen than it can normally use. This state, called outer-retinal hyperoxia, can increase production of reactive oxygen species (ROS), chemically reactive molecules that can damage cells when present at excessive levels.
The review describes how this oxidative stress may place particular pressure on cones, the photoreceptors responsible for central, detailed, and color vision. Mitochondria—the cell structures that help produce energy—are especially vulnerable to oxidative damage. When mitochondrial function declines, cells may produce more ROS, creating a harmful cycle of oxidative stress and mitochondrial dysfunction.
This is important because the pathway is considered largely independent of the original RP-causing gene. While a gene-targeted therapy may be designed for a specific genetic subtype, approaches that reduce oxidative damage or improve mitochondrial health could potentially be relevant across multiple forms of RP.
Why mitochondrial DNA is attracting attention
Mitochondria have their own small amount of genetic material, known as mitochondrial DNA (mtDNA). When photoreceptors are damaged or die, mtDNA may be released into the space outside cells, either freely or enclosed within tiny cell-derived packages called exosomes.
Outside the mitochondria, mtDNA may act as a danger signal. The immune system can interpret it as evidence of cellular injury and activate innate immune pathways, including TLR9, cGAS-STING, and the NLRP3 inflammasome. These pathways can promote inflammation. In the retina, sustained inflammation may in turn contribute to ongoing photoreceptor stress and degeneration.
The authors describe extracellular mtDNA as a potentially “integrative” biomarker: a measurable signal that could reflect several processes at once, including oxidative stress, mitochondrial dysfunction, cell death, and innate immune activation. Rather than measuring only one part of the disease process, it might provide a broader picture of whether this damaging cascade is active.
An important gap: this has not yet been shown in people with RP
The review emphasizes a crucial limitation. Although the proposed model is biologically plausible and supported by findings across experimental settings, the steps connecting mtDNA release, inflammation, and photoreceptor death have not yet been directly demonstrated in RP itself.
In addition, extracellular mtDNA has never been quantified in the ocular fluids of people with RP. This means it is not currently a validated diagnostic test, predictor of progression, or treatment-monitoring tool. Establishing its value will require carefully designed studies measuring mtDNA in ocular samples and relating those results to retinal structure, visual function, inflammatory activity, and disease progression over time.
What this could mean for treatment research
The paper places extracellular mtDNA within a wider effort to develop treatments that address oxidative and mitochondrial stress. It discusses antioxidant and redox-modulating strategies, including clinical trials of N-acetylcysteine and elamipretide. These approaches aim, in different ways, to lessen oxidative injury or support mitochondrial function.
The review also considers therapies that could act further downstream by inhibiting the immune sensors that respond to damage-associated signals such as mtDNA. Targeting TLR9, cGAS-STING, or the NLRP3 inflammasome could, in principle, interrupt inflammatory signaling triggered by cellular damage.
A major potential role for extracellular mtDNA would be as a pharmacodynamic endpoint—a biological measurement used to show whether a treatment is affecting its intended pathway. For example, if a redox-modulating treatment reduced extracellular mtDNA, this could suggest that mitochondrial injury or cell damage is being lowered. Such a marker could help researchers evaluate candidate treatments more efficiently, particularly before changes in vision become apparent.
Looking ahead
This review does not establish extracellular mtDNA as an RP biomarker; it lays out a research framework for testing that possibility. Its central message is that RP progression may have shared, treatable biology beyond the disease-causing gene itself.
Future studies can determine whether extracellular mtDNA is detectable and informative in RP ocular fluids, whether levels change with disease activity, and whether they respond to therapies targeting oxidative stress, mitochondria, or inflammation. If validated, this marker could support a more precise way to monitor the secondary processes that threaten cone survival—and help accelerate development of treatments intended to preserve central vision across a broad range of RP genotypes.