9 1 General Introduction functions, which vary between different organisms and even between different organs in a single organism8. Some of the metabolic functions of peroxisomes include lipid metabolism, hydrogen peroxide metabolism, synthesis of ether lipids and bile acids, glyoxylate detoxification, and in trypanosomatids even glycolysis89. Impairments in peroxisomal function can lead to severe diseases, highlighting the importance of these organelles. Peroxisomal disorders can be divided in peroxisomal biogenesis disorders (PBDs) and single-enzyme deficiencies. Peroxisomal biogenesis disorders are autosomal recessive inherited disorders caused by a defect in any of the PEX genes8. These genes encode for proteins (peroxins) taking part in peroxisomal biogenesis. Peroxisomal biogenesis disorders affect peroxins involved in either the import of peroxisomal proteins10,11,in peroxisomal division12–14or de novo formation15,16. These disorders lead to multiple metabolic dysfunctions. Single-enzyme deficiencies are caused by impairments or defects of any enzyme involved in specific peroxisomal metabolic pathways (e.g. ABCD1, ACOX1, AMACR, etc.). Unlike PBDs, singleenzyme deficiencies only affect specific metabolic functions. One key function of peroxisomes, and the main point of interest of this thesis, is fatty acid metabolism. Peroxisomes are able to metabolize several types of fatty acids, including very long chain fatty acids (VLCFA), branched chain fatty acids (BCFA) and even medium-chain fatty acids17. Moreover, peroxisomes are also capable of oxidizing mono- and poly-unsaturated fatty acids18. To do so, peroxisomes can perform both α- and β-oxidation with a very broad range of substrates. Although peroxisomal β -oxidation is similar to the mitochondrial pathway, peroxisomes are equipped with their own set of enzymes in charge of metabolizing both straight-chain acyl-CoA to Acetyl-CoA as well as 2-methylbranched-chain acyl-CoAs, into propionyl-CoA and Acetyl-CoA18. The interplay between peroxisomes and mitochondria In recent times, it has become clear that peroxisomes and mitochondria display a functional interplay, key for different metabolic processes19–21. Reactive oxygen species (ROS) are molecules formed during different cellular processes that contribute to aging processes. While essential for cell signaling, when accumulated ROS can cause oxidative damage22. As an example of the interaction between peroxisomes and mitochondria, we could highlight their combined role in ROS homeostasis 23. Another relevant example in the context of this thesis is the oxidation of fatty acids in order to maintain lipid homeostasis. While the mechanisms of interaction between these two
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