MFN2 contributes to metabolic disorders and inflammation in the aging of rat chondrocytes and osteoarthritis

Abstract

Objective: Metabolic disorders and inflammation of chondrocytes are major pathological changes in aging cells and osteoarthritis (OA). Recent studies demonstrated age-related mitochondrial dysfunction may be a key contributing factor in the development of OA. Mitofusin 2 (MFN2) is a key regulator of mitochondrial fusion, cell metabolism, autophagy and apoptosis. This study was performed to ascertain whether MFN2 was involved in the aging of chondrocytes and OA. Methods: Metabolic measurements were taken in rat chondrocytes between different ages (3-week, 5month, 12-month). MFN2 activity was detected in both human and rat chondrocytes during aging and OA. Then, knockdown of MFN2 with small interfering RNA (siRNA) was performed to confirm whether MFN2 contributes to metabolic changes. Lentiviruses were used to establish MFN2-overexpression/ knockdown OA models both in vivo and in vitro to confirm whether MFN2 contributes to OA progress. Further, regulatory mechanism of MFN2 was assessed and interaction between MFN2 and PARKIN was performed. Results: A metabolic shift to mitochondrial respiration was confirmed in rat chondrocytes during aging. MFN2 expression was elevated in both human and rat chondrocytes during aging and OA. Knockdown of MFN2 with siRNA reversed the age-related metabolic changes in rat chondrocytes. Overexpression of MFN2 exacerbated inflammation and OA progress, while knockdown of MFN2 ameliorated inflammation and OA progress. Further, MFN2 could be ubiquitinated by PARKIN, declined PARKIN expression during aging and OA might result in elevated MFN2 expression. Conclusions: Elevated MFN2 contributes to metabolic changes and inflammation during aging of rat chondrocytes and osteoarthritis.

Irisin Mitigates Oxidative Stress, Chondrocyte Dysfunction and Osteoarthritis Development through Regulating Mitochondrial Integrity and Autophagy

“…MFN2 signaling is increased in senescent chondrocytes and osteoarthritic cartilage. Forced MFN2 expression worsens DMM-mediated articular cartilage injury, whereas knocking down the molecule delays OA conditions [48]. The investigations into Irisin downregulation of the mitochondrial fission reaction in inflamed chondrocytes also explained the protective actions of the myokine against mitochondrial dysfunction.…”

Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development

“…Alterations in Mfn2 expression have also been observed in chronic neurodegenerative disorders, acute traumatic episodes such as stroke, and cardiometabolic diseases (Bach et al , 2003 ; Bach et al , 2005 ; Wang et al , 2009 ; Shirendeb et al , 2011 ; Marsboom et al , 2012 ; Martorell‐Riera et al , 2014 ). Given the well‐established role of Mfn2 as a regulator of mitochondrial metabolism (Bach et al , 2003 ; Sebastián et al , 2012 ; Schneeberger et al , 2013 ; Segales et al , 2013 ; Martorell‐Riera et al , 2014 ; Boutant et al , 2017 ; Tur et al , 2020 ; Xu et al , 2020 ) and the importance of mitochondrial metabolism in the physiopathology of these disorders, understanding the bioenergetic mechanism of Mfn2 may aid in the design of therapeutic approaches for disorders in which Mfn2 is involved.…”

“…Soon after the discovery of mitofusins, it was observed that expression of Mfn2 maintains mitochondrial bioenergetics more efficiently than expression of Mfn1, despite Mfn1 being more efficient at mediating mitochondrial fusion (Bach et al , 2003 ; Eura et al , 2003 ; Ishihara et al , 2004 ). Diminishment of Mfn2 expression as well as Mfn2 deletion have been shown to reduce mitochondrial respiration in different cell types (Bach et al , 2003 ; Sebastián et al , 2012 ; Schneeberger et al , 2013 ; Martorell‐Riera et al , 2014 ; Boutant et al , 2017 ; Li et al , 2019 ; Tur et al , 2020 ; Xu et al , 2020 ), including fibroblasts (Yao et al , 2019 ; Hu et al , 2020 ). However, Kawalec et al ( 2015 ) have reported increased oxygen consumption in Mfn2 KO MEFs, although they did not observe changes in RCR and found reduced MMP and mitochondrial ATP production, concluding that Mfn2 KO MEFs have impaired bioenergetics.…”

Mitophagy and Oxidative Stress: The Role of Aging

“…A similar role has been shown in murine cultured neurons [ 100 ]. In chondrocytes, an age dependent reduction of MFN2 causes a reduction in mitochondrial fission, accompanied by dysfunctional mitochondria and oxidative stress [ 101 ]. Interestingly, in this model Parkin negatively regulates the levels of MFN2, and an age-related decrease of Parkin causes a post transcriptional increase of MFN2 and hyperfused mitochondria.…”

“…MFN2 expression is higher in rat and human chondrocytes during aging and OA (osteoarthritis) [ 101 ]…”