Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage

Bubb, K; Holzer, Tatjana; Nolte, Janica L.; Krüger, Marcus; Wilson, Richard; Schlötzer‐Schrehardt, Ursula; Brinckmann, Jürgen; Altmüller, Janine; Aszódi, Attila; Fleischhauer, Lutz; Clausen‐Schaumann, Hauke; Probst, Kristina; Brachvogel, Bent

doi:10.1016/j.jbc.2021.101224

Cited by 22 publications

(16 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The highly ordered structure of the ECM endows articular cartilage unique functional properties of cushioning and lubricating joints. Notably, mice with impaired MT electron transport chain proteins had altered ECM composition, resulting in increased cartilage stiffness 37 . MT are highly plastic organelles that undergo morphological and functional changes in response to synthetic and bioenergetic demands 38 .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

Fahey

Bennett

Thomas

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Articular cartilage has limited healing capacity and no drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Mesenchymal stromal cell (MSC)-based regenerative therapies for OA are increasingly common, but questions regarding their mechanisms of action remain. Our group recently reported that although cartilage is avascular and relatively metabolically quiescent, injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. MSCs are known to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known to induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When exposed to mechanically injured cartilage, MSCs localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

Fahey

Bennett

Thomas

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Also, clinical studies indicated that cyclosporin A may help to slow COL6-RD progression by correcting the mitochondrial dysfunction [ 43 , 44 , 45 ]. In addition, single-cell (sc) RNA-sequencing analysis demonstrated that mitochondrial respiratory chain dysfunction is a key factor that can alter ECM integrity and mechanostability [ 46 ]. We also detected Golgi apparatus fragmentation and morphological modifications in COL6-RD patient-derived fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy

Castroflorio

Berná

López-Márquez

et al. 2022

IJMS

View full text Add to dashboard Cite

Collagen VI-related disorders (COL6-RD) represent a severe form of congenital disease for which there is no treatment. Dominant-negative pathogenic variants in the genes encoding α chains of collagen VI are the main cause of COL6-RD. Here we report that patient-derived fibroblasts carrying a common single nucleotide variant mutation are unable to build the extracellular collagen VI network. This correlates with the intracellular accumulation of endosomes and lysosomes triggered by the increased phosphorylation of the collagen VI receptor CMG2. Notably, using a CRISPR-Cas9 gene-editing tool to silence the dominant-negative mutation in patients’ cells, we rescued the normal extracellular collagen VI network, CMG2 phosphorylation levels, and the accumulation of endosomes and lysosomes. Our findings reveal an unanticipated role of CMG2 in regulating endosomal and lysosomal homeostasis and suggest that mutated collagen VI dysregulates the intracellular environment in fibroblasts in collagen VI-related muscular dystrophy.

show abstract

“…The highly ordered structure of the ECM endows articular cartilage unique functional properties of cushioning and lubricating joints. Notably, mice with impaired MT electron transport chain proteins had altered ECM composition, resulting in increased cartilage stiffness (34). MT are highly plastic organelles that undergo morphological and functional changes in response to synthetic and bioenergetic demands (35).…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Fahey

Bennett

Thomas

et al. 2022

Preprint

View full text Add to dashboard Cite

Avascular soft tissues of the skeletal system, including articular cartilage, have limited healing capacity, in part due to their low metabolic activity. No drugs are available that can prevent or slow the development of osteoarthritis (OA) after joint injury. Therefore, mesenchymal stromal cell (MSC)-based regenerative therapies are increasingly common in the treatment of OA, but questions regarding their clinical efficacy and mechanisms of action remain unanswered. Our group recently reported that mitochondrial dysfunction is one of the earliest responses of cartilage to injury, resulting in chondrocyte death, extracellular matrix degeneration, and ultimately OA. MSCs have been found to rescue injured cells and improve healing by donating healthy mitochondria in highly metabolic tissues, but mitochondrial transfer has not been investigated in cartilage. Here, we demonstrate that MSCs transfer mitochondria to stressed chondrocytes in cell culture and in injured cartilage tissue. Conditions known induce chondrocyte mitochondrial dysfunction, including stimulation with rotenone/antimycin and hyperoxia, increased transfer. Stressed chondrocytes increased expression of genes related to inflammation and senescence, further supporting the link between mitochondrial dysfunction and transfer. MSC-chondrocyte mitochondrial transfer was blocked by non-specific and specific (connexin-43) gap-junction inhibition. When MSCs were exposed to mechanically injured cartilage they localized to areas of matrix damage and extended cellular processes deep into microcracks, delivering mitochondria to chondrocytes. This work provides insights into the chemical, environmental, and mechanical conditions that can elicit MSC-chondrocyte mitochondrial transfer in vitro and in situ, and our findings suggest a new potential role for MSC-based therapeutics after cartilage injury.Significance StatementRecent evidence suggests that although articular cartilage is avascular and relatively metabolically quiescent, acute injury induces chondrocyte mitochondrial dysfunction, driving cartilage degradation and OA. We present the first evidence that MSCs donate mitochondria to articular chondrocytes undergoing mitochondrial dysfunction in vitro and in situ. These findings support a new role for MSCs in the context of cartilage injury and OA, and intercellular mitochondrial transfer may represent a new biological approach to augment mitochondrial capacity in injured chondrocytes. This work establishes multiple experimental models to study MSC mitochondrial donation for the treatment of OA and related degenerative diseases of avascular orthopedic tissues.

show abstract

Mitochondrial respiratory chain function promotes extracellular matrix integrity in cartilage

Cited by 22 publications

References 54 publications

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

Mesenchymal stromal cells donate mitochondria to articular chondrocytes exposed to mitochondrial, environmental, and mechanical stress

The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy

Mesenchymal Stromal Cells Donate Mitochondria to Articular Chondrocytes Exposed to Mitochondrial, Environmental, and Mechanical Stress

Contact Info

Product

Resources

About