The consequences of mitochondrial dysfunction and upregulated glycolysis on innate and adaptive immune responses

Abstract

Mitochondrial dysfunction occurs in response to a variety of causes. It leads to partial or complete inhibition of oxidative phosphorylation and, consequently, to the upregulation of fermentative glycolysis which remains the main or only energy-producing pathway. Mitochondrial dysfunction leads also to the release of several mediators, mainly oxidized mitochondrial DNA (mtDNA), reactive oxygen species (ROS) and adenosine triphosphate (ATP) molecules which have potent stimulatory effects on the innate immune system. In parallel, also upregulated glycolysis has immunomodulatory effects which are mediated by glycolytic enzymes or metabolites. In most cases these effects are unrelated to their role in metabolism and are referred to as non-canonical, “moonlighting” functions. In this article we propose that the immunomodulatory effects of upregulated glycolysis integrate those induced by the mediators released from damaged mitochondria (oxidized mtDNA, ROS, ATP). While many of these effects are immunostimulatory and act on both the innate as well as the adaptive immune system, some are immunosuppressive. The latter are likely induced in order to avoid excessive immunostimulatory effects with possible pathological consequences. Eventually, we address the relationship between upregulated fermentative glycolysis and another response promoted by dysfunctional mitochondria, i.e. the integrated stress response.