Highlights d Macrophages adopt a transient metabolic state in response to TLR4 activation d MyD88 and TRIF synergistically facilitate signaling-driven changes in metabolism d Increases in glycolysis and ATP-citrate lyase activity foster histone acetylation d ATP-citrate lyase governs gene induction of a distinct LPS responsive gene set

L-3,4-Dihydroxyphenylalanin (l-DOPA or levodopa) is currently the most used drug to treat symptoms of Parkinson’s disease (PD). After crossing the blood–brain barrier, it is enzymatically converted to dopamine by neuronal cells and restores depleted endogenous neurotransmitter levels. l-DOPA is prone to auto-oxidation and reactive intermediates of its degradation including reactive oxygen species (ROS) have been implicated in cellular damage. In this study, we investigated how oxygen tension effects l-DOPA stability. We applied oxygen tensions comparable to those in the mammalian brain and demonstrated that 2% oxygen almost completely stopped its auto-oxidation. l-DOPA even exerted a ROS scavenging function. Further mechanistic analysis indicated that l-DOPA reprogrammed mitochondrial metabolism and reduced oxidative phosphorylation, depolarized the mitochondrial membrane, induced reductive glutamine metabolism, and depleted the NADH pool. These results shed new light on the cellular effects of l-DOPA and its neuro-toxicity under physiological oxygen levels that are very distinct to normoxic in vitro conditions.

Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.