Abstract WP352: Mitochondrial Electron Transport Support as a New Mechanism of Action of Carbon Nano-particles in the Treatment of Stroke
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Introduction: Mitochondrial damage, including electron leakage and oxidative stress, likely contributes to stroke pathophysiology and is a potential therapeutic target. We recently reported robust protection when non-toxic graphene-derived PEGylated hydrophilic carbon clusters (PEG-HCCs) were administered at a realistic time point in severe reversible stroke rodent models (Front Neurol 2018). We attributed this efficacy to their high capacity, catalytic antioxidant features (PNAS 2015). Here we report a new action, the shuttling of electrons between mitochondrial constituents, consistent with their unique electrochemistry. Methods: We examined the redox chemistry of PEG-HCCs interaction with mitochondrial constituents, the reductants NAD(P)H, ascorbic acid and their targets, cytochrome C (CytC) and the mitochondrial viability indicator, resazurin. Subcellular distribution was visualized with deconvolution microscopy. In-vitro protection against mitochondrial toxins was assessed. Results: PEG-HCCs showed a broad redox wave ranging from -0 to -1500 V similar to the endogenous shuttle ubiquinone. They dramatically catalyzed the reduction of resazurin and CytC by NAD(P)H and ascorbic acid through a ternary complex. PEG-HCCs were co-localized with mitochondrial membranes within 5 min of incubation in cultured neurons (Fig. blue: nucleus; green: mitochondria; yellow: colocalized PEG-HCCs). PEG-HCCs give protection in-vitro from mitochondrial complex toxins including sodium cyanide (NaCN) (5 mM NaCN 54% of baseline viability vs 104% with PEG-HCCs + NaCN; p=0.0065). Conclusions: These experiments indicate PEG-HCCs are able to support electron shuttling as a potential mechanism of sustaining mitochondria after injury. In-vitro studies indicate cells can be protected from mitochondrial toxins. Work is ongoing to identify the functional groups that facilitate this shuttling effect to optimize their potential as stroke therapies.
