Fatty acids induce mitochondrial fragmentation in human macrophages
Ekaterina Zezina, Ryan Snodgrass, Bernhard Brüne, Dmitry Namgaladze* Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
Saturated fatty acids promote expression and secretion of inflammatory cytokines in macrophages. This pro-inflammatory skewing contributes to development of inflammatory microenvironment and insulin resistance in obese adipose tissue. How mitochondria influence the responses of macrophages to fatty acids is incompletely understood. Here we investigated the impact of fatty acids on mitochondrial dynamics in primary human macrophages. We observe that free fatty acids, independently of their saturation, induce mitochondrial fragmentation, which is reversible upon fatty acid removal. Mitochondrial fragmentation was not associated with a loss of mitochondrial quantity or function. We provide evidence that fatty acid-evoked fragmentation involves the activity of dynamin-related protein 1 whereas fusion machinery remains unaltered. At the same time, endoplasmic reticulum stress and the loss of mitochondrial membrane potential due to uncoupled respiration induced by fatty acids do not modulate mitochondrial dynamics in macrophages. Fatty acids promote mitochondrial accumulation of phospholipid biosynthetic intermediates associated with altered mitochondrial dynamics. Analyzing inflammatory responses of macrophages to saturated fatty acids upon inhibition of mitochondrial fragmentation, we show that mitochondrial fragmentation may prevent excessive inflammatory responses towards saturated fatty acids.
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