Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages

Abstract

Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.

Evolution of peroxisomes illustrates symbiogenesis

“…Controls include: inhibiting succinate oxidation with dimethyl malonate, blocking ROS production with rotenone (a complex I inhibitor), or expressing an alternative oxidase to oxidize QH 2 . As expected, they all abolish the pro-inflammatory phenotype [30]. Surprisingly, in a Drosophila brain study, RET induced ROS formation by Complex I could delay ageing [31], by activating a range of eukaryotic anti-oxidant measures.…”

“…All in all, Q redox status acts as a metabolic sensor to adjust the electron transport chain to the high F/N ratio associated with beta oxidation [29]. Mills et al describe the involvement of F/N (QH 2 /Q) ratios in macrophage activation [30]. Upon lipopolysaccharide stimulation, macrophages shift to glycolysis but also increase succinate levels.…”

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

“…Indeed, a greater proportion of ccRCC CD8 TIL had hyperpolarized mitochondria than control CD8 T cells from healthy donors (Figure 6B). Hyperpolarized mitochondria can be a source of ROS in macrophages (43), and ccRCC CD8 TIL also had high levels of mitochondrial ROS ( Figure 6C). Total cellular or cytoplasmic ROS, however, were decreased in ccRCC CD8 TIL relative to control T cells ( Figure 6D).…”

The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?

“…In fact, it seems that uncoupling is tightly controlled by the immune system and inflammation generally suppressing it [128,129]. One of the ways this seems to happen is that it repurposes succinate dehydrogenase, at least in macrophage mitochondria, from generating energy to producing ROS, a process associated with an increased membrane potential and decreased uncoupling and enhanced glycolysis to provide the energy [130]. This "repurposing" of mitochondria has long been observed and seems to be part of a more general inflammatory strategy [7].…”