Impaired Metabolic Flexibility in the Osteoarthritis Process: A Study on Transmitochondrial Cybrids

Abstract

Osteoarthritis (OA) is the most frequent joint disease; however, the etiopathogenesis is still unclear. Chondrocytes rely primarily on glycolysis to meet cellular energy demand, but studies implicate impaired mitochondrial function in OA pathogenesis. The relationship between mitochondrial dysfunction and OA has been established. The aim of the study was to examine the differences in glucose and Fatty Acids (FA) metabolism, especially with regards to metabolic flexibility, in cybrids from healthy (N) or OA donors. Glucose and FA metabolism were studied using D-[14C(U)]glucose and [1-14C]oleic acid, respectively. There were no differences in glucose metabolism among the cybrids. Osteoarthritis cybrids had lower acid-soluble metabolites, reflecting incomplete FA β-oxidation but higher incorporation of oleic acid into triacylglycerol. Co-incubation with glucose and oleic acid showed that N but not OA cybrids increased their glucose metabolism. When treating with the mitochondrial inhibitor etomoxir, N cybrids still maintained higher glucose oxidation. Furthermore, OA cybrids had higher oxidative stress response. Combined, this indicated that N cybrids had higher metabolic flexibility than OA cybrids. Healthy donors maintained the glycolytic phenotype, whereas OA donors showed a preference towards oleic acid metabolism. Interestingly, the results indicated that cybrids from OA patients had mitochondrial impairments and reduced metabolic flexibility compared to N cybrids.

Increased hexokinase-2 as a novel biomarker for the diagnosis and correlating with disease severity in rheumatoid arthritis

“…[ 23 ] A recent study reported that degeneration of cartilage may be triggered by metabolic disorders of glucose balance. [ 10 , 24 , 25 ] RA is a chronic systemic autoimmune disease featured with painful joint inflammation and disability. The changes in glucose metabolism are believed to contribute to disease progression of RA.…”

Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis

“…However, over the past decade, evidence has accumulated that there is an association between mtDNA haplogroups and the prevalence, progression and incidence of the disease 14 – 19 . This link has been assessed only in ex vivo studies and only with the use of in vitro transmitochondrial cybrid models 20 . Thus, the causal link between mtDNA haplotype variability and OA joint phenotype has not been studied.…”

Not all mitochondrial DNAs are made equal and the nucleus knows it

“…Co‐evolution and interaction between both genomes make it difficult to consolidate the association studies. The effects of polymorphic mtDNA excluding the divergence effects from the nDNA were first described in transmitochondrial cybrid cell lines 67–71 and then using mouse models carrying different mtDNA species under a common nuclear background 72–79 . The use of transmitochondrial cybrids has been extensively used to understand mtDNA‐nDNA compatibility as an in vitro model to study the effects of having different mtDNA species under the same nuclear background 80 .…”

“…Better cell survival under mtDNA haplotype J was associated with a downregulation of the expression of the proapoptotic gene BBC3 70 . Further analyses using a supplementary haplotype N showed that fatty acid oxidation decreased under mtDNA variants J and H in comparison with N in OA cybrid models 71 . For decades, efforts to validate mtDNA variants and their role in different diseases were made to identify‐specific treatment and diagnosis approaches.…”