Mitochondrial DNA: a proinflammatory ‘enemy from within’ during HIV infection?

Abstract

Mitochondria are crucial in cell life, as they are the main intracellular source of energy, and have a main role in cell death as they contain molecules able to trigger apoptosis. However, mitochondria can also release molecules called ‘damage-associated molecular patterns' (DAMPs) that trigger a potent innate immune response and cause inflammation through the engagement of the Toll-like receptors (TLR). During human immunodeficiency virus (HIV) infection, a proinflammatory status is present that is not completely explained by the activity of the virus per se, or by the effective immune response against the virus. However, the presence of significant amounts of DAMPs of mitochondrial origin, such as extracellular plasmatic mtDNA, in the peripheral blood of subjects with HIV infection suggests that part of the inflammation typical of such infection could be because of the activity of these molecules, and thus opens new therapeutic perspectives. Mitochondria are intracellular organelles involved in a wide range of processes, as they are the main source of cellular energy, in the form of ATP, are deeply involved in the regulation of programmed cell death, in the homeostasis of intracellular calcium, and are the site of several biosynthesis pathways. Furthermore, they are the main source of reactive oxygen species. Mitochondria derive from ancestral endosymbiont bacteria; as a reminiscence of such origin, they contain several copies of a circular genome, the mtDNA, which encodes key proteins of the oxidative phosphorylation system. Like bacterial proteins, those synthetized within mitochondria contains formyl-methionin, and their degradation origin chemotactic formyl peptides,1 which behave as danger signals and can activate inflammasome.2 When cells are coping with a massive insult that is potentially harmful for the entire organism, mitochondria release into the cytoplasm molecules able to trigger cell death, such as cytochrome-c or apoptosis-inducing factor.