Sepsis affects over 750,000 people per year in the United States and kills over a third of these patients. As such, it has proved to be one of the greatest challenges to modern medicine. The cellular and molecular events underlying the evolution of tissue injury and organ dysfunction during sepsis are under active investigation and promise to guide the development of therapeutics. As of now the treatment of sepsis is limited to treatment of the underlying infection and supportive care, without much of a individualized approach. An area of intense recent focus is bioenergetics, the mitochondria, and metabolomics. Mitochondrial responses are now known to orchestrate downstream cell signaling responses and outcomes, and thus greatly influence organ function and outcomes. Others and we demonstrate that in the setting of sepsis, signals to the mitochondria to regulate mitochondrial respiration and signaling from the mitochondria to regulate inflammatory responses are not only important in the early response to sepsis, but also critical to the recovery of the cell. Our preliminary data show that sepsis patients have a profile of injured mitochondria. Additionally, that aging is associated with decreased mitochondrial reserve and less dynamic responses. Mitochondrial health and the ability to adapt to stimuli are crucial to the survival of organisms during stress. We show that during this response mitochondrial respiration is altered and that the mitochondrion orchestrates this response by initiating adaptive signaling responses. As a result mitochondria may become dysfunctional, and processes to mitigate this, including removal of damaged mitochondria by autophagic cell signaling (controlled removal of the organs) leads to decreased cell injury. Additionally reconstitution of a healthy mitochondrial population via mitochondrial biogenesis is necessary to ensure survival. Based upon this we hypothesize the following: The baseline `health' of the mitochondrial network and the ability to adapt through robust mitochondrial dynamic responses are critical to limit inflammation, tissue injury, and organ dysfunction in sepsis. We will test this hypothesis by addressing the following specific aims:
Specific Aim 1. To determine how bioenergetics/mitochondrial health influences organ injury and outcomes in sepsis.
Specific Aim 2. To examine how mitophagy/biogenesis inducing therapies can be harnessed for therapeutic benefit in sepsis. Our laboratory has been investigating organ injury in sepsis and the role of mitochondrial signaling. These novel studies will add insight into organ dysfunction in sepsis, have the promise of allowing determination of at risk patients and a personalized approach to sepsis treatment, and will help guide the development of therapeutics.
The development of sepsis from infection is a leading cause of death worldwide. The development of multiple organ dysfunction secondary to sepsis/infection accounts for most of these deaths; however, our understanding of the processes that lead to organ dysfunction/failure and the subsequent development of therapeutics that effectively reverse or prevent the processes have been limited. In the proposed study, we will investigate how mitochondria as the source of energy and mitochondrial signaling are central to the control of inflammation and the development of adaptive responses to prevent organ injury in sepsis. The study focuses on the role of mitochondria as a `cellular rheostat' that then elicits responses to allow cells and tissues to adapt to the septic insult by preventing bioenergetic failure, cell death, and organ dysfunction.
