Mitochondrial and metabolic evaluation of COVID-19 patients: new predictive factors and therapeutic targets – MIMETIC

Since last December, the coronavirus disease 2019 (COVID-19) affected more than 23 million people, causing more than 800,000 deaths. The clinical spectrum of COVID-19 goes from asymptomatic to multiorgan dysfunction requiring ICU (Intensive Care Unit) admission. Although a very few drugs might be promising, a better understanding of the pathophysiology is required to identify new therapeutic targets. Moreover, to properly orientate patients to the best unit and to prevent the ICU saturation, identifying early predictive markers could improve patient care and unit organization. Levels of plasmatic lactate reflect total metabolic function of the human body. Lactate has been described as an independent marker that could objectively predict mortality in patients with sepsis and data from our team indicate that lactate is also a predictive factor for mortality of patients suffering from COVID-19. However, lactate elevation may also be considered as a late marker of organ dysfunction, metabolic alterations and mitochondrial impairment. Identification of upstream and early metabolic and mitochondrial alterations could represent better readouts with higher predictive value and pave the way to new therapeutic strategies.
In addition to get new knowledge of the pathophysiology, we aim to identify metabolic and mitochondrial markers predictive of COVID-19 patient evolution in order to improve patient sorting, to anticipate optimal treatment and relieve ICU. These objectives address the “Pathophysiology of the Disease” axis of the ANR call AAP RA COVID-19, and especially the “history of the disease” and the “new therapeutic targets”.
We will use samples from retrospective and prospective COVID-19 patient cohorts from Lille Hospital. Plasma metabolites and accumulation of glycogen and lipids in post-mortem tissues will be evaluated to assess metabolic alterations (Months M1-M4 of the project). Immunohistochemistry and electron microscopy of post-mortem tissues (M1-M4), RTqPCR and western-blot targeting mitochondrial population control quality pathways (M2-M10), mitochondrial potential, respiration, Warburg-like glycolysis and acidification, and ROS generation on peripheral blood mononuclear cells (M2-M10) will characterize mitochondrial alterations. All the data will be analyzed by statisticians (M5, M11) to determine whether these parameters can be considered as risk factors of bad outcome for COVID-19 patients. We expect two publications (M6, M12).
We expect to identify metabolic and/or mitochondrial parameters that will give a better understanding of the pathophysiology, unravel new therapeutic targets and discover new biomarkers that could be immediately used in the clinic to improve patient care and orientate patients to the most adapted unit.