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What causes sudden infant death syndrome?

Researchers used induced pluripotent stem cells to determine a genetic cause of sudden infant death syndrome.

Sudden infant death syndrome or SIDS is the sudden and unexplained death, usually during a period of sleep, of a seemingly healthy child. It is the leading cause of infant mortality in developed countries. Three main risk factors can make a child more vulnerable to these attacks. The first is the stage of a child’s development, SIDS usually affects children under the age of one. This relates to the development of the parts of a child’s nervous system that are responsible for regulating respiration, sleep cycles and heart rate. The second risk factor is an environmental stressor that places a child at higher risks of asphyxia. Sleeping position (prone or on their side), soft bedding, bed sharing, infection, prenatal smoke or alcohol exposure and prematurity are all risk factors for SIDS. The third risk factor is an intrinsic vulnerability or a genetic variant. Genetic variants in genes that are involved in the central nervous system, metabolism, cardiac function and immune system can all contribute to an increased risk of SIDS.

The heart of metabolism

On a cellular level, metabolism is really important when it comes to SIDS, particularly fatty acid oxidation in heart cells (cardiomyocytes). The heart needs a continuous and high amount of energy to pump efficiently. In a prenatal heart, glucose and lactate are the nutrients that are broken down to provide energy for contraction. When a baby is born their diet changes to breast milk, which contains high amounts of fats and lipids. The child’s heart cells switch to fatty acid oxidation as a means of getting the energy it needs. This process takes place in the mitochondria and twenty-five proteins are responsible for breaking down these fats. Mitochondrial trifunctional protein (MTP) is one of the enzymes that is essential for this process. When there is a mutation in the gene (HADHA) that produces MTP it prevents the protein from being made and this can result in arrhythmia (irregular heartbeats). Often children with these mutations suffer from SIDS. The exact mechanism of how this genetic mutation may cause SIDS is not well understood.

Modelling MTP deficiencies in stem cells

In a recent US study published in Nature Communications, researchers used human induced pluripotent stem cells as a model to study what happens to cells when they have a mutation in the HADHA gene. The researchers used the CRISPR/Cas9 system to introduce mutations into the HADHA gene of human-induced pluripotent stem cells. The team used three cell lines, they had a cell line with a healthy gene that produced normal MTP, a cell line with a mutation that prevented MTP from being made and finally a cell line that that could only produce a small amount of MTP. The scientists then encouraged the cells to mature (differentiate) so they would become cardiomyocytes. They made sure that the cells with the mutations followed a normal developmental process by analyzing cell size and contractile force generated by cell (twitching). They also looked at the RNA of each cell type by doing a transcriptome analysis and single-cell sequencing to make sure cells were maturing correctly.

Mutations in the HADHA gene affect metabolism

Using these mature cardiomyocytes the scientists went on to examine the differences between the mutant cell lines (little to no MTP produced) and the healthy cell lines. First, they looked at the total oxygen consumption rate of each cell type and found that in cells that didn’t have MTP there was a decrease in the maximum oxygen consumption rate of the cell, this meant that the MTP deletion may affect the function of the mitochondria in these cells. The researchers thought there may be an issue with how fatty acids are broken down in the mitochondria which may cause the arrhythmia that results in SIDS. They went on to investigate whether or not the mutated cells had arrhythmia when beating. The scientists showed that the cells that had the mutations beat slower and the time between beats was variable.

Fatty acid oxidation is disrupted

The research team was interested in investigating the mitochondria as metabolism appeared to be an important difference between the healthy and mutant cell lines. They went on to investigate the structure and function of the mitochondria using fluorescent imaging. They were able to show that when mutant cells were fed fatty acids the deletion of MTP caused a build-up of fatty acids in the mitochondria. This means that the fatty acids are not being processed to produce energy but instead packaged for storage. What they noticed was the mitochondria were rounded and collapsed, but did not burst. This made the team wonder if the HADHA mutation could affect cardiolipins. Cardiolipins are a major component of the mitochondrial inner membrane. The scientists measured the amounts of different lipids within the mutant and healthy cell lines and found that the mutant cells had increased abundance of lighter chain cardiolipins and a decrease of heavier chain cardiolipins. The scientist speculated that this difference may contribute to the mitochondrial defects and erratic heartbeats seen in the mutant cells.

The work of these researchers paves the way forward for the development of new drugs and treatments. “But there is now hope, because we’ve found a new aspect of this disease that will innovate generations of novel small molecules and designed proteins, which might help these patients in the future.”, said Dr Hannele Ruohola-Baker, lead author on the study, in a press release.

 

Written by Tarryn Bourhill MSc, PhD Candidate

 

References:

1 Baruteau, A.-E., Tester, D. J., Kapplinger, J. D., Ackerman, M. J. & Behr, E. R. Sudden infant death syndrome and inherited cardiac conditions. Nature Reviews Cardiology 14, 715 (2017).

2 Houten, S. M., Violante, S., Ventura, F. V. & Wanders, R. J. The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annual review of physiology 78, 23-44 (2016).

3 Ivey, K. N. & Srivastava, D. MicroRNAs as regulators of differentiation and cell fate decisions. Cell stem cell 7, 36-41 (2010).

4 Miklas, J. W. et al. TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nature Communications 10, 1-21 (2019).

5  Gray, L. New genetic link found for some forms of SIDS, <https://www.eurekalert.org/pub_releases/2019-10/uowh-ngl101019.php> (2019).

 

Image by Michal Jarmoluk from Pixabay

Tarryn Bourhill MSc PhD Candidate
Tarryn Bourhill MSc PhD Candidate
Tarryn has a Master’s degree in Molecular Medicine from the University of the Witwatersrand, South Africa. She is currently pursuing a PhD in Molecular Biology and Biochemistry at the University of Calgary. Tarryn specializes in cancer, oncolytic viral therapy and stem cell research. She is passionate about scientific communication and enjoys turning complicated ideas into approachable and engaging conversations. In her spare time, Tarryn is a keen baker and a photography enthusiast.
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