Loss of mitochondrial respiration alters mechanical properties of the cartilage

A group of researchers headed by Professor Dr. Bent Brachvogel, Head of Experimental Neonatology at the Faculty of Medicine and University Hospital Cologne, have identified regulatory mechanisms of tissue organization that was earlier unknown.

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Along with other scientists from Brachvogel’s group, the first author of the current research and licensed pharmacist Kristina Bubb analyzed alterations in the so-called extracellular matrix (ECM).

The researchers identified a connection between the mitochondrial respiratory chain (a series of reactions in cells) and the balance of the ECM. The research “Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage” was published in the Journal of Biological Chemistry.

The leading cause of chronic pain and loss of mobility globally is musculoskeletal diseases. Chronic pain and loss of mobility substantially restrict people’s quality of life. Most times, early childhood disorders or age-related changes in the extracellular matrix results in dysfunctions and long-term chronic diseases of the musculoskeletal system. An alteration in the ECM can, for instance, cause osteoporosis and arthrosis.

ECM, is a tissue present in-between cells in the intercellular space, mostly in the connective tissue. It is developed by the cells, embeds them, and creates the stabilizing framework of the tissue. As there is only a little knowledge on the connections between disturbances in the ECM and musculoskeletal diseases, specific treatment options are not available at present.

The scientists found that the mitochondrial respiratory chain in cartilage tissue performs a major role in preserving ECM balance (homeostasis). The respiratory chain is part of the energy metabolism of cells—a series of biochemical reactions occurring in the mitochondria, the “power houses of the cells”—responsible for energy generation in organisms.

This impacts the integrity and mechanical stability of the ECM in cartilage, and presumably in numerous other tissues.

The scientists illustrated that dysfunction of the mitochondrial respiratory chain in cartilage is linked to a postnatal delay in skeletal growth employing a model organism. To further analyze the molecular relationships, the researchers employed advanced measurement and sequencing techniques.

They employed a combined approach of high-resolution scRNA sequencing, electron microscopy, and mass spectrometry, to analyze cartilage-specific inactivation of respiratory chain function. The scientists found that loss of mitochondrial respiration results in tissue disorganization and expansion, along with stiffening of the cartilage matrix.

This is due to weakened metabolic signaling, which secondarily modified the composition and mechanical properties of the cartilage.

The scientists state that these results are a vital milestone for an enhanced understanding of musculoskeletal diseases. They can bring forth the formation of novel diagnostic and therapeutic approaches in the medium and long term.  Professor Brachvogel is also the spokesperson of the research team FOR2722 “New molecular factors of musculoskeletal extracellular matrix homeostasis” funded by the German Research Foundation (DFG).

The energy metabolism of the cell is very important for the production of the extracellular matrix, but the interactions between these components have not been sufficiently understood so far. We have demonstrated for the first time the importance of the mitochondrial respiratory chain as an essential energy supplier for extracellular matrix homeostasis in cartilage.”

Dr Bent Brachvogel, Professor and Head, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne

“Our research has identified the mitochondrial respiratory chain as a new therapeutic target for treating a defective extracellular matrix in degenerative cartilage disease,” remarks Kristina Bubb.

The precise molecular connections between cellular energy metabolism, EZM homeostasis, and the formation of musculoskeletal diseases can be explained based on the research results. The observations can be incorporated into the formation of novel treatment strategies for degenerative diseases of the musculoskeletal system in the future.