Role of mitochondrial complex IV in acute O2 sensing by carotid body glomus cells

• Grant number: 23/02930-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): August 20, 2023
• Effective date (End): June 19, 2024
• Field of knowledge: Biological Sciences - Biophysics - Cellular Biophysics
• Principal Investigator: Davi José de Almeida Moraes
• Grantee: Pedro Favoretto Spiller
• Supervisor: José López-Barneo
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: Instituto de Biomedicina de Sevilla (IBIS), Spain
• Associated to the scholarship: 20/03955-5 - Effects of sustained hypoxia on the electrophysiological properties and purinergic signaling of the carotid chemoreceptors of rats, BP.DD

Abstract

Cardiorespiratory adaptations to hypoxia are essential for cell survival. The main organs sensitive to O2 in mammals are the carotid bodies (CBs), which are organs highly sensitive to oxygen (O2) and mediate hyperventilation in response to sustained hypoxia (SH). CBs contains glomus cells that express channels for K+ whose inhibition by hypoxia leads to the release of neurotransmitters. The neurotransmitters activate nerve fibers, whose the first synapse is located in the brainstem, to produce cardiovascular and respiratory adjustments. While mitochondrial proteins have been implicated in oxygen sensing by glomus cells, the mechanism underlying their mitochondrial sensitivity to hypoxia compared to other cells is unknown. Here, we hypothesize that mitochondrial complex IV actively participates in the adaptations of glomus cells to short-term SH and detection of acute changes in O2 pressure. To test this hypothesis, we will analyze in different mice models of mitochondrial complex IV subunits conditional deletion (Cox4i2, Ndufa4l2, Cox8b and Higd1c) in comparison with control (WT) mice: a) the participation of mitochondrial complex IV subunits in the pulmonary ventilation, cellular and molecular adaptations of glomus cells to short-term SH; b) the effects of acute hypoxia and hypercapnia on the pulmonary ventilation; c) the effects of acute hypoxia on neurosecretory response of glomus cells in CBs slices; d) the effects of acute hypoxia on mitochondrial signaling (NADH and ROS) and cytosolic [Ca2+] in dispersed glomus cells, and; e) the electrical properties and the responses to hypoxia of dispersed glomus cells. The data to be obtained with the development of this Research Project will allow us to advance in the better understanding of the cellular and molecular mechanisms involved in the important ventilatory adaptations, mediated by the peripheral chemoreceptors, in response to acute and sustained reductions of the O2 in mice. (AU)