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Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes


Mitochondria and mitochondrial DNA (mtDNA) variation are now recognized as important factors in the development of osteoarthritis (OA). Mitochondria are the energy powerhouses of the cell, and also regulate different processes involved in the pathogenesis of OA including inflammation, apoptosis, calcium metabolism and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Mitochondria contain their own genetic material, mtDNA, which evolved through the sequential accumulation of mtDNA variants to enable humans to adapt to different climates. The ROS and reactive metabolic intermediates that are by-products of mitochondrial metabolism are regulated in part by mtDNA and are among the signals that transmit information between mitochondria and the nucleus. These signals can alter nuclear gene expression and, when disrupted, affect a number of cellular processes and metabolic pathways, leading to disease. mtDNA variation influences OA-associated phenotypes, including those related to metabolism, inflammation and even ageing, as well as nuclear epigenetic regulation. This influence also enables the use of specific mtDNA haplogroups as complementary diagnostic and prognostic biomarkers of OA.

Key points

  • Both mitochondrial dysfunction and variation in mitochondrial DNA (mtDNA) contribute to cartilage degeneration and are implicated in the pathogenesis of osteoarthritis (OA).

  • mtDNA influences the interactions between the nucleus and mitochondria through intracellular signalling pathways, such as production of reactive oxygen species (ROS) and reactive metabolic intermediates from mitochondrial metabolism.

  • Mitochondria have regulatory roles in OA pathogenesis including bioenergetics metabolism, inflammatory responses, apoptosis, ageing-related responses, ROS production and calcium metabolism.

  • mtDNA variation, through individual groups of mtDNA characterized by particular mtDNA polymorphisms (mtDNA haplogroups) modulates critical cell functions including ATP production, oxygen consumption, generation of ROS and mitochondrial and nuclear gene expression.

  • mtDNA haplogroups are associated with the prevalence, incidence and progression of knee OA in various populations, and with comorbidities closely related to various OA phenotypes.

  • mtDNA variation affects the development of OA phenotypes and contributes to the low-grade chronic inflammation and other molecular processes underlying these phenotypes.

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The authors’ work is supported by Fondo de Investigación Sanitaria (grants CIBERCB06/01/0040-Spain, RETIC-RIER-RD16/0012/0002, PRB2-ISCIII-PT13/0001, PI12/0329 and PI16/02124 to F.J.B. and grant PI14/01254 to I.R.P.) integrated in the National Plan for Scientific Program, Development and Technological Innovation 2013–2016 and funded by the ISCIII-General Subdirection of Assessment and Promotion of Research-European Regional Development Fund (FEDER) “A way of making Europe”. I.R.P. is supported by Contrato Miguel Servet-Fondo de Investigación Sanitaria (CP12/03192). F.J.B. is supported in part by Programa Intensificacion ISCIII (INT16/00222).

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the article and contributed to reviewing and editing of the manuscript before submission.

Correspondence to Francisco J. Blanco or Ignacio Rego-Pérez.

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Further reading

Fig. 1: The connection between mitochondrial genetics and the pathogenesis of OA.
Fig. 2: Models to study the effects of mtDNA variation.
Fig. 3: Mitochondrial function influences OA phenotypes.