Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemiareperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane. Ischemic AKI occurs in many clinical settings, including shock, sepsis, and cardiovascular surgery, and it leads to increased mortality in critically ill patients. 1 Ischemia-reperfusion injury is also a critical issue in organ transplantation, where it can result in delayed graft function, and is a major risk factor for chronic allograft nephropathy. 2,3 Tissue injury occurs during ischemia as a result of ATP depletion. The rapid drop in ATP leads to cytoskeletal changes in tubular epithelial cells, because ATP is required for actin polymerization, 4 resulting in breakdown of the brush border, loss of cell-cell contact, disruption of barrier function, and cell detachment. 5 These cytoskeletal changes are reversible if the duration of ischemia is brief and ATP recovery occurs rapidly on reperfusion. Mitochondrial function is pivotal to the recovery of ATP in proximal tubular cells, because they have minimal glycolytic capacity and must rely on oxidative phosphorylation for ATP synthesis. However, ATP recovery is often delayed on reperfusion, because ischemia results in loss of cristae membranes and mitochondrial swelling. 6,7 The recovery of ATP can be further compromised by mitochondrial permeability transition (MPT) during

Diabetic retinopathy is characterized by progressive vision loss and the advancement of retinal micoraneurysms, edema and angiogenesis. Unfortunately, managing glycemia or targeting vascular complications with anti-vascular endothelial growth factor agents has shown only limited efficacy in treating the deterioration of vision in diabetic retinopathy. In light of growing evidence that mitochondrial dysfunction is an independent pathophysiology of diabetes and diabetic retinopathy, we investigated whether selectively targeting and improving mitochondrial dysfunction is a viable treatment for visual decline in diabetes. Measures of spatial visual behavior, blood glucose, bodyweight and optical clarity were made in mouse models of diabetes. Treatment groups were administered MTP-131, a water-soluble tetrapeptide that selectively targets mitochondrial cardiolipin and promotes efficient electron transfer, either systemically or in eye drops. Progressive visual decline emerged in untreated animals before the overt symptoms of metabolic and ophthalmic abnormalities were manifest, but with time, visual dysfunction was accompanied by compromised glucose clearance, and elevated blood glucose and bodyweight. MTP-131 treatment reversed the visual decline without improving glycemic control or reducing bodyweight. These data provide evidence that visuomotor decline is an early complication of diabetes. They also indicate that selectively treating mitochondrial dysfunction with MTP-131 has the potential to remediate the visual dysfunction and to complement existing treatments for diabetic retinopathy.

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)

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The major risk factors for Age‐Related Macular Degeneration (AMD) are age and oxidative stress. Aging is associated with bioenergetic failure, especially of the metabolically active retinal pigment epithelium (RPE), which is required for phagocytic function of photoreceptor outer segments. A2E and lipid peroxides in lipofuscin can increase the feed‐forward loop of oxidative damage to mitochondria in the RPE. Here, we propose a novel approach for resolving feed‐forward mitochondrial damage with the mitochondria‐targeted peptide SS‐31. With its strong antioxidant properties and ability to promote electron transport in aging mitochondria, we show optimization of ATP synthesis and minimization of oxidative stress. We created an age‐relevant RPE model using complex I inhibitors and A2E or lipid peroxide (tBHP) and demonstrated relevant energetic failure. SS‐31 treatment restored ATP synthesis, antioxidant capacity and phagocytic function of the RPE. Moreover, SS‐31 treatment in aged mice and rats improved visual acuity as measured by optokinetic tracking. Thus, our novel mitochondria‐targeted approach will preserve RPE mitochondrial function and will potentially prevent or delay progression of early AMD.