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J Clin Invest. 2019 May 16;130:2841-2855. doi: 10.1172/JCI98890.

Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis.

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Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University of Tübingen, Tübingen, Germany.
Institute of Biochemistry and Molecular Biology, Ulm University, Ulm, Germany.
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
CEDOC Chronic Diseases Research Center, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Central Facility for Electron Microscopy, Ulm University, Ulm, Germany.
Department of General Pediatrics, University Hospital Muenster, Muenster, Germany.


About 1% of all newborns are affected by congenital heart disease (CHD). Recent findings identify aberrantly functioning cilia as a possible source for CHD. Faulty cilia also prevent the development of proper left-right asymmetry and cause heterotaxy, the incorrect placement of visceral organs. Intriguingly, signaling cascades such as mTor that influence mitochondrial biogenesis also affect ciliogenesis, and can cause heterotaxy-like phenotypes in zebrafish. Here, we identify levels of mitochondrial function as a determinant for ciliogenesis and a cause for heterotaxy. We detected reduced mitochondrial DNA content in biopsies of heterotaxy patients. Manipulation of mitochondrial function revealed a reciprocal influence on ciliogenesis and affected cilia-dependent processes in zebrafish, human fibroblasts and Tetrahymena thermophila. Exome analysis of heterotaxy patients revealed an increased burden of rare damaging variants in mitochondria-associated genes as compared to 1000 Genome controls. Knockdown of such candidate genes caused cilia elongation and ciliopathy-like phenotypes in zebrafish, which could not be rescued by RNA encoding damaging rare variants identified in heterotaxy patients. Our findings suggest that ciliogenesis is coupled to the abundance and function of mitochondria. Our data further reveal disturbed mitochondrial function as an underlying cause for heterotaxy-linked CHD and provide a mechanism for unexplained phenotypes of mitochondrial disease.


Cardiology; Development; Genetic variation; Mitochondria; Organogenesis

[Available on 2019-10-01]
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