Mitochondrial Genetics and Epigenetics in Osteoarthritis

Abstract

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 OA-related 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 bi-directional 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.

Keywords: epigenetics; genetics; methylation; mitochondria; osteoarthritis.

Figure 1

The interactions between the nucleus and mitochondria that take place inside articular chondrocytes give rise to epigenetic modifications that are mediated by mitochondrial DNA haplogroups. As a consequence, different haplogroup-associated methylation patterns condition key processes related to the development of OA. Permission is granted for publication of this figure as a modified version of the figure that appeared on page A17 of the July 2019 issue of Arthritis & Rheumatology (Clinical Connections).