Effect of Systemic Triphenylphosphonium on Organ Function and Oxidative Stress

Abstract

Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP1) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP1 on mitochondrial integrity. Male rats were anesthetized and TPP1 (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later. Rats were exsanguinated 2-hours postinjection. Cardiac, pulmonary, hepatic, splenic, and renal tissues were analyzed for inflammation, lipid peroxidation, endogenous antioxidant activity, cytokine expression, and mitochondrial function. In vitro modeling was performed using freshly isolated hepatocytes subjected to 8-hours hypoxia/30-minutes reoxygenation in the absence or presence of TPP1. TPP1 increased lipid peroxidation in the liver, lung, and kidney as well as antioxidant activity in the liver, kidney, and spleen. Conversely, antioxidant activity decreased in the lung with TPP1. In addition, TPP1 altered hepatic inflammatory mediators. In vitro, TPP1 attenuated oxygen consumption and, when combined with hypoxic injury, depolarized mitochondrial membranes in hepatocytes. TPP1 induces systemic responses associated with oxidative stress and worsening pathologies in animals. Caution should be exercised when employing TPP1 for therapeutics.