Reenergizing aged mitochondria to combat retinal degeneration (LB555)

Abstract

Bioenergetic failure is the major risk factor for Age‐Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). Within the eye, the delicate microvasculature of the choroid and the metabolically active retinal pigment epithelium (RPE) are especially sensitive to the stresses of age and diabetes. Using mouse models of diabetes and advanced age, we demonstrated diabetes/aging‐induced abnormalities of the mitochondria in the choroid and RPE, alterations to the choroidal microvasculature, disruption to the RPE, and an increase in inflammation markers. Treatment with the novel cardiolipin‐targeted antioxidant tetrapeptide SS‐31, after onset of diabetes or in aged mice, restored proper RPE integrity and mitochondrial morphology, as well as reduced the intrusion of neovascular tufts from the choroid through the RPE and the level of inflammation markers. Moreover, SS‐31 administration restored visual function as demonstrated by optokinetic tracking. Thus we are the first to pioneer a mitochondrial‐targeted approach for resolving feed‐forward mitochondrial damage and restoring bioenergetic capacity in the choroid and RPE, thereby preventing disease progression and restoring visual function in early AMD and DR. Grant Funding Source: Supported by the Tri‐Institutional Training Program in Vision Research (5T32EY007138‐20)

Peptide Power: Mechanistic Insights into the Effect of Mitochondria-Targeted Tetrapeptides on Membrane Electrostatics from Molecular Simulations

“…Over the last two decades, a family of synthetic mitochondria-targeted tetrapeptides (MTPs, also referred to as SS peptides) carrying a +3 charge and an alternating motif of basic and aromatic amino acids have grown to be among the most promising potential therapeutics in the pipeline. − MTPs have broadly been shown to be efficacious in restoring healthy mitochondrial function in a variety of common diseases and conditions, including all of the ones mentioned above and more. − Notably, these studies have also confirmed the safety and favorable pharmacokinetic properties in preclinical and clinical trials. These compounds are currently being evaluated in early to advanced-phase clinical trials for a range of heritable − and aging-related diseases. , …”