Cellular O2 sensing is an important biological process in health and disease. The ability to detect and respond to hypoxia is required for embryonic development, for transition from placental to lung respiration at birth, and for systemic oxygen homeostasis throughout life. In previous funding cycles we discovered that mitochondria regulate the signaling of hypoxia to the cell through the release of reactive oxygen species (ROS) from complex III, which then activate cellular protective and adaptive responses. We also developed genetic tools for assessing subcellular redox signaling and for modifying ROS generation from complex III. Inhibition of hypoxia-induced mitochondrial ROS signals by genetic deletion of the Risked Iron-Sulfur Protein (RISP) or expression of an H2O2 scavenger in the mitochondrial intermembrane space abrogated hypoxia responses in diverse cell types. Unexpectedly, deletion of RISP in the adult mouse heart induced profound remodeling characterized by a ~2.5-fold increase in heart weight and thickening of the ventricular walls, with no evidence of cellular hypertrophy. Cardiomyocyte diameter, cell morphology, and mitochondrial ultrastructure were unchanged, while immunostaining for markers of cellular proliferation (Ki67) revealed profuse distributions of labeled cells, consistent with the generatio of new cardiomyocytes. Gene array analysis during remodeling identified activation of pathways involving cytoskeletal reorganization but no signature characteristic of cardiac hypertrophy. We hypothesize that ROS signals are generated by cardiac mitochondria in response to the decrease in myocardial PO2 that occurs as the neonatal heart transitions from a fetal glycolytic program into the adult oxidative phenotype. We postulate that these ROS signals trigger the cell cycle arrest that develops by postnatal day 7. Deletion of RISP, which is required for hypoxia-induced ROS signaling, abrogates the ROS signaling and permits adult cardiomyocytes to re-enter the cell cycle. We will test these hypotheses using genetic models to manipulate mitochondrial ROS generation and signaling, identify early genes involved in the activation of this response, and determine the cellular mechanisms underlying the regulation of proliferative arrest by heart mitochondria. Finally, we will test whether reactivation of proliferation in hearts damaged by ischemia-reperfusion can be induced by modulating complex III function, allowing rescue of function through the generation of new cardiomyocytes. The results of these studies could provide a major advance in our understanding of how cell proliferation in the heart is controlled, and carry profound potential clinical significance in terms of the treatment of ischemi injury in the heart.
This project will extend previous work investigating the role of mitochondria in the oxygen sensing pathway in neonatal and adult hearts. Preliminary studies from the previous funding period reveal that hypoxia-induced mitochondrial oxidant signals regulate the proliferative arrest that develops in post-natal cardiomyocytes and continues through adulthood. We will identify the molecular mechanisms underlying this regulation, and test whether reactivation of cardiomyocyte proliferation through the modulation of mitochondrial signals can lead to the rescue of hearts damaged by ischemia, through replacement with new cardiac myocytes.
| Smith, Kimberly A; Waypa, Gregory B; Schumacker, Paul T (2017) Redox signaling during hypoxia in mammalian cells. Redox Biol 13:228-234 |
| Arulkumaran, Nishkantha; Deutschman, Clifford S; Pinsky, Michael R et al. (2016) MITOCHONDRIAL FUNCTION IN SEPSIS. Shock 45:271-81 |
| Waypa, Gregory B; Smith, Kimberly A; Schumacker, Paul T (2016) O2 sensing, mitochondria and ROS signaling: The fog is lifting. Mol Aspects Med 47-48:76-89 |
| Datta, Ankur; Kim, Gina A; Taylor, Joann M et al. (2015) Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent. Am J Physiol Lung Cell Mol Physiol 309:L369-77 |
| Sanchez-Padilla, Javier; Guzman, Jaime N; Ilijic, Ema et al. (2014) Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nat Neurosci 17:832-40 |
| Sabharwal, Simran S; Schumacker, Paul T (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer 14:709-21 |
| Ball, Molly K; Waypa, Gregory B; Mungai, Paul T et al. (2014) Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1?. Am J Respir Crit Care Med 189:314-24 |
| Schumacker, Paul T; Gillespie, Mark N; Nakahira, Kiichi et al. (2014) Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol 306:L962-74 |
| Schriewer, Jacqueline M; Peek, Clara Bien; Bass, Joseph et al. (2013) ROS-mediated PARP activity undermines mitochondrial function after permeability transition pore opening during myocardial ischemia-reperfusion. J Am Heart Assoc 2:e000159 |
| Waypa, Gregory B; Marks, Jeremy D; Guzy, Robert D et al. (2013) Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation. Am J Respir Crit Care Med 187:424-32 |
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