10 Chapter 1 organelles have not been deeply characterized they involve physical contact sites, diffusion processes, and vesicular transport24–26. Given the close interplay between the two organelles, it has been suggested that alterations in one of them (either in biogenesis, proliferation or metabolism) might potentially have an effect on the other27. In the case of peroxisomes, several studies have reported that diseases affecting peroxisomal fatty acid metabolism28, peroxisomal biogenesis29 and peroxisomal redox activity30 also had a negative effect on mitochondrial health. This phenomenon was also observed in hepatocytes of a liver-specific knockdown of PEX5. L-Pex5−/− mice showed alteration of the mitochondrial inner membrane, increased oxidative stress and depletion of mitochondrial DNA31. On the other hand, it remains unknown if primary mitochondrial diseases also cause peroxisomal dysfunction. These findings not only support the notion of a tight interplay between both organelles, but also point towards potential compensatory mechanisms between the two organelles. Given the importance of both mitochondria and peroxisomes in the metabolism of fatty acids, it is understandable that defects in either one of these organelles might have serious health repercussions. Disruptions in normal fatty acid metabolism caused by nutritional and genetic disorders Imbalances in different biochemical processes involved in fatty acid metabolism cause a vast range of human diseases. The origin of these imbalances can be either genetic (inborn errors of metabolism) or environmental factors and contextual conditions (such as nutrition and/or malnutrition). Different nutritional stressors can have an important impact on the metabolism of macronutrients. There are multifactorial diseases which are caused by a combination of multiple genetic and dietary factors, of which none is in itself pathogenic. A common example of an acquired, multifactorial metabolic disease is NonAlcoholic Fatty Liver Disease (NAFLD), known as one of the most prevalent chronic liver diseases. NAFLD is associated with different risk factors such as diabetes type II, obesity and metabolic syndrome32,33. A contrasting example of another disease that leads to fatty liver associated with disturbances in fatty metabolism is undernutrition 34–38. Interestingly, illustrating the complexity of this topic, moderately-low protein diets without malnutrition, have been shown to increase lifespan and metabolic health in mice39,40.
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