Background and Significance

Cell organelles are key players in maintaining of physiological homeostasis of cells and organs. The scope how we gather interplay of metabolic control mechanism in cellular setting has undergone a major revision during the last years. In reference to human health, several inherited diseases are known that are caused by malfunction of cell organelles and they contribute also to pathophysiology of almost all acquired human diseases.

A large number of studies have demonstrated significance of the polyunsaturated fatty acids (PUFAs) for human health. In spite of international research and progress many key aspects on molecular mechanisms translating PUFA sensing into changes in gene expression have remained largely enigmatic. As one approach to shed light on the responses of animals to PUFAs, we have generated a mouse line defective in mitochondrial dienoyl-CoA reductase (Decr), which is a key enzyme required for mitochondrial break-down of PUFAs, with an outcome of accumulation of PUFAs in these mice. The Decr null mutant mice are asymptomatic until exposed to fasting, during which they switch on ketogenesis, but simultaneously develop hypoglycemia and the mice do not tolerate cold. These observations highlight the necessity of Decr and the breakdown of unsaturated fatty acids in the transition of intermediary metabolism from the fed to the fasted state.

Major recent discoveries on many previously unknown or neglected aspects of mitochondrial physiology and biochemistry have brought these organelles into the spotlight of research interest in the field of life sciences. These discoveries include mechanisms of mitochondrial fusion and fission events, linkage of mitochondrial fusion events to the progression of the cell cycle, mitochondrial-nuclear crosstalk, mitochondrial DNA replication, transcription and translation, iron-sulfur cluster biogenesis, aging, mitophagy, the role of mitochondria in apoptosis and mitochondrial inheritance as a tool for the tracking of maternal lineages. Among the recently recognized features of mitochondrial functions is their ability to synthesize fatty acids in an acyl carrier protein (ACP)-dependent manner. The failure in mitochondrial fatty acid synthesis (mtFAS) in yeast leads to loss of mitochondrial respiratory function and to defective mitochondrial RNA processing and there is mounting evidence pointing to an essential function of mtFAS for well-being of mammals. Recently pieces of evidences have been emerging which link the mtFAS pathway to diseases in mammals. Our report on the development of cardiomyopathy in mice overexpressing Etr1 established a possible connection between mtFAS and heart disease. It has been recently demonstrated that compromised mtFAS results in dysfunction of mitochondrial respiration and accelerated aging in genetically modified mice. Furthermore, compromising protein lipoylation and respiratory complex I result in cell death in cultured human embryonic kidney 293T cells upon shutdown of ACP.  The expression of 17βHSD8, encoding a subunit in 3-ketoacyl reductase (KAR1), was severely repressed in kidney and liver.

 

Last updated: 28.10.2016