Mitochondria supply the somatic cells with energy. They play an important role in organ development., | Sebastian Kaulitzki © | Sebastian Kaulitzki


Failure in the Cell’s Powerhouses

How the Body Gets Lost while Assembling the Organs

Scientific name of the study

Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis.

Our heart beats on the left side. Technically. In rare cases, a displacement of the organs occurs. In certain cases, they are completely disarranged. Medical experts refer to this condition as heterotaxy. A research team has now come as close to the causes as never before. The study took place at the Competence Network for Congenital Heart Defects and was led by pharmacist Melanie Philipp, who is based at the University of Ulm.

Our heart develops as early as the early embryonic period. The development proceeds in several stages. It involves highly complex biochemical and molecular biological processes in our somatic cells. These also help the cells to assign the appropriate position in the body to each organ. In rare cases, an incorrect placement of the organs within the body occurs. This affects about one in 15,000 newborns. In the best case, the organs end up in a mirror-inverted arrangement without leading to any significant health problems. If the organs end up being completely disarranged, however, this leads to so-called heterotaxy: the newborns affected by this condition often have severe heart defects. In many cases, these require instant surgery. What exactly is happening there? Why is it that the cells seem to get lost? Addressing this question in a joint international project, researchers at the University of Ulm discovered new correlations.

Failure in the Cell’s "Powerhouses?"

During the embryonic period, there are tiny antennas on the cell’s surface that are responsible for the heart and organs to end up in the right place, that is, to be arranged asymmetrically to each other in the body. According to the current state of research, these cell organelles, also referred to as cilia, control the placement of the organs as early as in the early embryonic period. In a long-term study that took place in cooperation with the Competence Network for Congenital Heart Defects, an international research team has now discovered significant evidence that the mitochondria in the somatic cells influence the cilia’s development. The research team was led by Melanie Philipp and Martin Burkhalter. The tiny organelles that are only a few micrometers long (0,5-10 µm), seem to be involved in the development of the organs’ disarrangement. They are also referred to as the cell’s powerhouses since they supply the cells with energy, among other things.

In this light, scientists from the universities of Ulm, Tübingen, Indiana (Indianapolis, USA), Lisbon (Universidade Nova de Lisboa), of the Competence Network for Congenital Heart Defects, as well as the university hospitals of Hamburg-Eppendorf and Münster found out that the blood cells of heterotaxy patients show a much smaller number of mitochondria than those of healthy patients. Furthermore, certain mutations that lead to an impaired function of the mitochondria were detected more frequently in those affected.

Using the Example of the Zebrafish

Also in animal models, the scientists were able to prove that the cell’s powerhouses were involved in the development of heterotaxy. In this context, they made use of the transparent embryos of zebrafish: “After hindering the mitochondria’s function or activity, the zebrafish embryos showed organ displacements and heart malformations more frequently than the control groups, whose mitochondria were unaffected in their work,” Melanie Philipp states, explaining the results. After spending many years at the University of Ulm, she meanwhile teaches and researches at the University of Tübingen.

Bridge between “Antennas” and “Powerhouse”

But how exactly do the cilia’s and the mitochondria’s activities combine in the case of such a malformation? Is there a connection? With the help of a microscope, the researchers were in fact able to detect a physical connection between the “antennas” and the “powerhouses.” “Picture it as if it were a small bridge. It consists of tubular protein objects, so-called microtubules,” Melanie Philipp says, explaining the image the researchers found.

Impaired “GPS”

At the same time, the scientists found further significant evidence as a result of analyzing DNA samples of heterotaxy patients, as well as of zebrafish model studies. As could be shown, the length of the antenna-like cilia is influenced by the “cell’s powerhouses”: The cells’ surfaces showed longer cilia in the cases of a reduced mitochondria function. Their proper functioning was significantly limited as compared to “healthy” cilia. The same process could be observed in zebrafish embryos in whose cell material the researchers had implanted the genetic mutations of heterotaxy patients: The zebrafish embryos developed both defects in the cilia and dislocated organs. “All findings indicate that the very interaction of mitochondria and cilia creates some kind of the body’s own GPS for arranging the organs. The development of a displacement of organs during the embryonic development apparently involves genetically caused biochemical communication processes that have a fatal influence on the organs’ development and location; this happens even before the heart development,” biologist Martin Burkhalter (University of Tübingen) states, summarizing the conclusions of the research team.

Forward-thinking for Diagnostics and Treatment

The researchers assume that their findings have the potential to simplify the diagnostics of organ displacements and associated secondary diseases. In the long term, they might additionally contribute to an improvement of treatment options. “So far, we have only been able to assign inheritable diseases to malfunctioning cilia. Now we know that the mitochondria also play a vital role. Accordingly, we are now able to also address the systematic creation of a proper functioning of mitochondria in both research and development. This finding has the potential to be a crucial factor for the treatment of heterotaxy, as well as of other hereditary diseases,” Martin Burkhalter states.

Made Possible by Donated Samples from the National Register

The research project was funded by the German Research Foundation (DFG) and the Boehringer Ingelheim Ulm University Biocenter (BIU). Furthermore, the project was supported by the National Institutes of Health (NIH) and the Indiana University School of Medicine. Among other factors, the research was made possible by the samples donated by the participants of the National Register for Congenital Heart Defects that is based at the Competence Network for Congenital Heart Defects. The latter is funded by the German Centre for Cardiovascular Research (DZHK).

  • Scientific Details of the Study

    Learn more about the study design, material and methods, as well as the background of the study:


    • 16.5.2019

      Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis.

      Burkhalter MD, Sridhar A, Sampaio P, Jacinto R, Burczyk MS, Donow C, Angenendt M, , Hempel M, Walther P, Pennekamp P, Omran H, Lopes SS, Ware SM, Philipp M

      The Journal of clinical investigation 130, 2841-2855, (2019). Show this publication on PubMed.


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