Sometimes errors occur during embryonic development, leading the wrong arrangement of organs. Heterotaxy patients also often suffer from severe heart defects. Researchers at the University of Ulm have now investigated the molecular causes of these heart defects: it appears that mitochondria play a special role in this process.
In the human body, all organs have a predetermined place. If this arrangement is disrupted during embryonic development, severe malformations such as heart defects may occur. Researchers from the German University of Ulm and their international colleagues have now looked into the genetic and molecular causes of heart defects in such heterotactic patients, focusing in particular on mitochondria.
Cilia (singular form: cilium) ensure that the heart and other organs are not just literally in the right place. It is now scientifically proven that these antenna-like structures on the surface of certain cells regulate the later asymmetric arrangement of human organs very early in human development.
However, within a small proportion of the population (1:15,000), embryonic development goes somewhat wrong. In the optimal case, all organs are located in a mirror-inverted form, and no health problems arise. However, the arrangement of the organs can also get completely mixed up and those affected develop a so-called heterotaxy (also referred to as Situs ambiguus, heterotaxia): Such patients often suffer from severe heart defects, which in many cases have to be operated on immediately after birth. Now researchers have discovered that mitochondria have a decisive influence on the formation of these cilia. Thus, they seem to play an indirect role in the development of heterotaxy-associated heart defects.
Specifically, the scientists were able to show that heterotaxy patients have a considerably lower number of mitochondria in their blood cells. In addition, they have more frequently detected a severe gene mutation in the affected individuals that leads to impaired mitochondrial function compared to healthy subjects.
In the zebrafish model, the influence of mitochondria in the development of asymmetry and heart defects was also confirmed: "Zebrafish embryos in which mitochondria are inhibited or increasingly active show significantly more heart malformations than control groups," explained Melanie Philipp, who worked for many years at the Institute of Biochemistry and Molecular Biology at the University of Ulm.
But how do cilia and mitochondria interact in the development of asymmetry defects? Using electron microscopy, the international research group has actually detected a physical connection in the form of a microtubule bridge between the cell power plants and cilia.
Furthermore, in fibroblasts of the skin of heterotaxy patients and zebrafish embryos, they were able to show that the length of the cilia was inversely correlated with the mitochondrial function: cells with a lower mitochondrial function have longer cilia. Their ability to function, however, is clearly limited in comparison to normal-length cilia.
Zebrafish embryos, in which genetic alterations of heterotaxy patients are simulated, also develop both asymmetry and ciliary defects. The scientists draw a clear conclusion from the sum of these results: "During embryonic development and long before a heart has formed, mitochondria have a decisive influence on cilia and later heart development".