Mitochondria-Targeted Peptide Accelerates ATP Recovery and Reduces Ischemic Kidney Injury

Abstract

The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury. Acute kidney injury (AKI) develops in 5% of hospitalized patients and is associated with significant morbidity. Ischemia is the most common cause of AKI. Despite our current knowledge of the pathophysiology underlying renal ischemia-reperfusion (IR) injury, pharmacologic interventions have not reduced the mortality and morbidity associated with AKI.Rapid recovery of ATP after ischemia is essential for cell survival after IR injury. A profound reduction in intracellular ATP occurs early after onset of ischemia and leads to cytoskeletal derangements, membrane alterations, and cell death by apoptosis and necrosis. 1 Disruption of the cytoskeleton leads to redistribution of integrins and Na ϩ ,K ϩ -ATPase from the basal membrane, resulting in detachment of viable cells from the basement membrane and impairment of Na ϩ reabsorption. The mode of cell death depends on the duration of ischemia and the region of the nephron. Cell death is usually restricted to the outer medullary region where oxygen tension drops precipitously at the corticomedullary junction. 2 The proximal tubules are particularly susceptible to IR injury because they have minimal glycolytic capacity and must rely on mitochondrial metabolism for ATP synthesis. [3][4][5] Ischemia causes damage to all components of the mitochondrial electron transport chain (ETC), resulting in decreased oxidative phosphorylation upon reperfusion. 6 In addition, mitochondria are the primary source of reactive oxygen species (ROS). 6,7 Mitochondria can undergo further damage upon reperfusion because of mitochondrial permeability transition (MPT). During ischemia, elevated mitocho...

Tolerance of the Human Kidney to Isolated Controlled Ischemia

“…These findings dramatically contrast to those seen in animal models, which showed greater severity and extent of these changes after being subjected to shorter durations of ischemia than were most patients in our cohort. 31,32,35,36 Consistent with the limited apical structural damage, basal b1 integrin, which is highly sensitive to ischemia in animal models and to hypoxia of isolated tubules, 21,22 was almost unaffected. In maximally hypoxic isolated tubules, immunodetectable phosphotyrosine is entirely lost and then recovers during reoxygenation as a function of ATP availability.…”

“…Tubule injury produced by ischemia or hypoxia is sensitively reflected by alterations of actin and integrins. 21,22 Cellular ATP depletion decreases protein tyrosine phosphorylation. 22,23 Intercellular adhesion molecule-1 (ICAM-1) is an important early mediator of the inflammatory component of ischemic AKI.…”

Cellular and Molecular Mechanisms of AKI

“…Whereas efforts to target ROS in postischemic AKI with generic antioxidants have been unsuccessful, promising preclinical results have been attained with mitochondrially targeted antioxidantscompounds that achieve mitochondrial accumulation of antioxidant activity either by a chemical modification (e.g., MitoQ) or by tethering to a targeting peptide (e.g., SS-31). 29,30 Opening of the MPT pore is a key event. The MPT is composed of several proteins and its opening permits the passage of small molecules and water between the mitochondrial matrix and the cytoplasm.…”

Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury

“…Despite the proportionally high blood flow to the kidney, specific delivery of a therapeutic compound to the kidney has been limited. [21][22][23][24] We designed a targeting strategy to deliver the SOD mimetic tempol to specific sites by making use of the selective expression of the folate receptor in the renal proximal tubules. Folic acid is an essential vitamin with a high affinity for the folate receptor, which maintains folate homeostasis.…”