Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases

Tatjana Holzer; Kristina Probst; Julia Etich; Markus Auler; Veronika Georgieva; Björn Bluhm; Christian Frie; Juliane Heilig; Anja Niehoff; Julian Nüchel; Markus Plomann; Jens Seeger; Hamid Kashkar; Olivier Baris; Rudolf Wiesner; Bent Brachvogel

doi:10.1083/jcb.201809056

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Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases

Tatjana Holzer ^{1, 2} Kristina Probst ^{1, 2} Julia Etich ^{1, 2} Markus Auler ^{1, 2} Veronika Georgieva ^{1, 2} Björn Bluhm ^{1, 2} Christian Frie ^{1, 2} Juliane Heilig ^{3, 4} Anja Niehoff ^{3, 4} Julian Nüchel ² Markus Plomann ² Jens Seeger ⁵ Hamid Kashkar ^{5, 6, 7} Olivier Baris ⁸ Rudolf Wiesner ^{6, 7, 8} Bent Brachvogel ^{1, 2}

1 Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne

2 Center for Biochemistry, Faculty of Medicine, University of Cologne

3 Institute of Biomechanics and Orthopedics, German Sport University Cologne

4 Cologne Center for Musculoskeletal Biomechanics, University of Cologne

5 Institute for Medical Microbiology, Immunology, and Hygiene, Faculty of Medicine, University of Cologne

6 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne

7 Center of Molecular Medicine Cologne, University of Cologne

8 Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Faculty of Medicine, University of Cologne

Abstract : In childhood, skeletal growth is driven by transient expansion of cartilage in the growth plate. The common belief is that energy production in this hypoxic tissue mainly relies on anaerobic glycolysis and not on mitochondrial respiratory chain (RC) activity. However, children with mitochondrial diseases causing RC dysfunction often present with short stature, which indicates that RC activity may be essential for cartilage-mediated skeletal growth. To elucidate the role of the mitochondrial RC in cartilage growth and pathology, we generated mice with impaired RC function in cartilage. These mice develop normally until birth, but their later growth is retarded. A detailed molecular analysis revealed that metabolic signaling and extracellular matrix formation is disturbed and induces cell death at the cartilage-bone junction to cause a chondrodysplasia-like phenotype. Hence, the results demonstrate the overall importance of the metabolic switch from fetal glycolysis to postnatal RC activation in growth plate cartilage and explain why RC dysfunction can cause short stature in children with mitochondrial diseases.

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https://hal.univ-angers.fr/hal-02348135
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