【Literature Review】 Mitochondria-Targeted HDAP2 Protects Retinal Ganglion Cells and Enhances Intraocular Pressure Tolerance in DBA/2J Mice
Release time:
2026-06-10
Mitochondria-Targeted HDAP2 Protects Retinal Ganglion Cells and Enhances Intraocular Pressure Tolerance in DBA/2J Mice
Research Background:
Glaucoma is the leading cause of irreversible blindness, primarily due to the progressive degeneration of retinal ganglion cells (RGCs) and their axons. Elevated intraocular pressure (IOP) is a major risk factor; however, a significant proportion of glaucoma patients continue to experience RGC loss and progressive visual field defects even after IOP is successfully lowered. This highlights the urgent need for therapeutic strategies that can enhance RGC tolerance to elevated IOP. Mitochondrial dysfunction is a key pathogenic mechanism linking elevated IOP to RGC degeneration. This study aimed to investigate whether HDAP2, a novel high-density aromatic peptide that binds to cardiolipin to stabilize the mitochondrial membrane, could exert neuroprotective effects on RGCs in the DBA/2J mouse model.
Methods:
Four-month-old DBA/2J mice were administered the novel peptide HDAP2 (3 mg/kg, intraperitoneal injection, every other day) for a continuous period of 8 months. IOP was monitored monthly using the TonoLab rebound tonometer specifically designed for mice and rats (Icare Finland Oy, Helsinki, Finland) to document IOP exposure levels. RGC survival was assessed by RBPMS staining and cell counting in retinal wholemounts, as well as by axon counting in toluidine blue-stained semi-thin sections of the optic nerve.
The novel peptide HDAP2 was synthesized by a commercial company (GenScript, Piscataway, NJ, USA) and verified by high-performance liquid chromatography (HPLC) and mass spectrometry, with a purity of >96%. The peptide targets mitochondria and binds to cardiolipin on the inner mitochondrial membrane to maintain mitochondrial membrane potential under oxidative stress conditions.
Results:
At comparable levels of IOP exposure, the retinas of HDAP2-treated mice retained approximately 49% more RGCs compared to untreated controls (P = 0.0063; F(2, 59) = 5.524). Under mild IOP exposure, HDAP2 preserved 58% more RGCs; under high IOP conditions, RGC survival was 180% higher than in untreated mice. Kaplan–Meier analysis revealed that HDAP2 raised the IOP threshold for severe RGC loss by 29 mmHg and reduced the risk of severe RGC degeneration to 1/4.6 of that in the untreated group. The optic nerve axons in the treatment group were also well preserved, with axonal morphology showing no significant difference from the control group. No significant alterations in axon size distribution were observed among treatment groups, suggesting that HDAP2 provides comparable protection across different RGC subtypes.
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Conclusion:
The findings of this study carry significant clinical implications. Current therapeutic strategies for glaucoma are almost exclusively focused on lowering IOP; however, many patients continue to experience progressive vision loss even when IOP is well controlled. Standard treatment typically achieves only a 20%–30% reduction in IOP, equivalent to a decrease of approximately 4–8 mmHg⁴²⁻⁴⁴.
In contrast, HDAP2 raised the threshold for severe RGC loss by 29 mmHg. This protective effect is comparable in magnitude to conventional therapy, yet its mechanism is achieved through direct neuroprotection rather than IOP reduction.
This effect translates to a 4.6-fold reduction in the risk of severe visual impairment (from 46.2% to 15.6%), a difference with clear clinical value.
Across various levels of IOP exposure, HDAP2 simultaneously protected both RGCs and axons, and enhanced tolerance to IOP. These results suggest that HDAP2 may serve as a complementary therapeutic approach to IOP-lowering treatments, with potential applicability in normal-tension glaucoma as well as treatment-refractory glaucoma.
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