Linking energy state to redox environment through mitochondrial redox circuits

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Cody D Smith (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Mitochondria are the primary producers of intracellular H2O2, an oxidant signaling molecule that has gained attention for its role in normal physiological processes and disease etiologies such as skeletal muscle insulin resistance and type 2 diabetes. Understanding the factors that govern the rate of mitochondrial H2O2 emission is critical to developing therapeutic strategies that might mitigate H2O2-induced disease progression while simultaneously enabling cytosolic redox homeostasis and proper cell function. Lipid catabolism through the [beta]-oxidation pathway is a known source of mitochondrial H2O2 generation and implicated in the development of skeletal muscle insulin resistance based on its association with high-fat diets. The goal of this dissertation was 2-fold: 1) To investigate how mitochondrial H2O2 emission due to [beta]-oxidation is regulated by inherent redox circuits with the matrix antioxidant system in skeletal muscle; and 2) To identify the bioenergetic consequences and resulting redox environment associated with increased [beta]-oxidation flux and the development of skeletal muscle insulin resistance. To accomplish these goals, wild-type and genetically altered mouse models were used for experimentation at the whole body, muscle, and mitochondrial level. Multiple redox circuits were discovered in skeletal muscle mitochondria linking [beta]-oxidation-induced H2O2 production to both membrane potential ([Delta][Psi]m)-dependent and independent sources of NADPH, the cofactor ultimately responsible for powering antioxidant activity. Collectively, these redox circuits regulated the rate of mitochondrial H2O2 emission by ensuring sufficient NADPH production to maintain a constant 70-80% antioxidant efficiency, regardless of the [beta]-oxidation-flux rate. Therefore, when flux through [beta]-oxidation was increased, thus elevating the mitochondrial energy state and rate of H2O2 production, redox circuitry enabled proportionally increased NADPH generation in order to reduce the same fraction of H2O2 as with lower energy states. Thus, an increased energy state due to increased [beta]-oxidation-flux resulted in an increased, yet proportional rate of mitochondrial H2O2 emission. In this way, redox circuits regulate the rate of mitochondrial H2O2 emission depending on changes in energy state. At high energy states due to elevated [beta]-oxidation flux, the increased rate of mitochondrial H2O2 emission further induced a more oxidized cytosolic redox environment, consistent with the insulin resistant phenotype observed in genetic models. Hence, redox circuitry further links mitochondrial energy state with activation/deactivation of specific redox-sensitive signaling pathways leading to changes in protein and cellular function.

Additional Information

Publication

Dissertation

Language: English

Date: 2016

Keywords

NADPH, insulin, lipid, diabetes, NNT, H2O2, energy, i2-oxidation

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