During recent years, the significant influence of mitochondria on osteoarthritis (OA), the most common joint disease, has been consistently demonstrated. Not only mitochondrial dysfunction but also mitochondrial genetic polymorphisms, specifically the mitochondrial DNA haplogroups, have been shown to have an important influence on different OArelated features, including the prevalence, severity, incidence, and progression of the disease. This influence could probably be mediated by the role of mitochondria in the regulation of different processes involved in the pathogenesis of OA, such as energy production, the generation of reactive oxygen and nitrogen species, apoptosis, and inflammation. The regulation of these processes is at least partially controlled by the bidirectional communication between the nucleus and mitochondria, which permits the regulation of adaptation to a wide range of stressors and the maintenance of cellular homeostasis. This bi-directional communication consists of an "anterograde regulation" by which the nucleus regulates mitochondrial biogenesis and activity and a "retrograde regulation" by which both mitochondria and mitochondrial genetic variation exert a regulatory signaling control over the nuclear epigenome, which leads to the modulation of nuclear genes. Throughout this mini review, we will describe the evidence that demonstrates the profound influence of the mitochondrial genetic background in the pathogenesis of OA, as well as its influence on the nuclear DNA methylome of the only cell type present in the articular cartilage, the chondrocyte. This evidence leads to serious consideration of the mitochondrion as an important therapeutic target in OA.
Objective. To analyze the influence of mitochondrial genome variation on the DNA methylome of articular cartilage. Methods. DNA methylation profiling was performed using data deposited in the NCBI Gene Expression Omnibus database (accession no. GSE43269). Data were obtained for 14 cartilage samples from subjects with haplogroup J and 20 cartilage samples from subjects with haplogroup H. Subsequent validation was performed in an independent subset of 7 subjects with haplogroup J and 9 with haplogroup H by RNA-seq. Correlated genes were validated by real-time polymerase chain reaction in an independent cohort of 12 subjects with haplogroup J and 12 with haplogroup H. Appropriate analyses were performed using R Bioconductor and qBasePlus software, and gene ontology analysis was conducted using DAVID version 6.8.Results. DNA methylation profiling revealed 538 differentially methylated loci, while whole-transcriptome profiling identified 2,384 differentially expressed genes, between cartilage samples from subjects with haplogroup H and those with haplogroup J. Seventeen genes showed an inverse correlation between methylation and expression. In terms of gene ontology, differences in correlations between methylation and expression were also detected between cartilage from subjects with haplogroup H and those with haplogroup J, highlighting a significantly enhanced apo ptotic process in cartilage from subjects with haplogroup H (P = 0.007 for methylation and P = 0.019 for expression) and repressed apoptotic process in cartilage from subjects with haplogroup J (P = 0.021 for methylation), as well as a significant enrichment of genes related to metabolic processes (P = 1.93 × 10 −4 for methylation and P = 6.79 x 10 −4 for expression) and regulation of gene expression (P = 0.012 for methylation) in cartilage from subjects with haplogroup H, and to developmental processes (P = 0.015 for methylation and P = 8.25 x 10 −12 for expression) in cartilage from subjects with haplogroup J.Conclusion. Mitochondrial DNA variation differentially associates with the methylation status of articular cartilage by acting on key mechanisms involved in osteoarthritis, such as apoptosis and metabolic and developmental processes.
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