The Emerging Role of Mitochondrial Dysfunction in the Pathogenesis of Idiopathic Inflammatory Myopathies

Abstract

Increasing evidence points towards mitochondria as crucial players in the initiation and progression of auto-immune and degenerative disorders, to which impaired cell metabolism is but a facet of the subjacent etiopathogenesis. This review aims to introduce the reader to essential concepts of mitochondrial abnormalities in idiopathic inflammatory myopathy (IIM), underscoring inclusion-body myositis and dermatomyositis. Far surpassing the initial simplistic view of being responsible for energy generation, mitochondria have gathered attention regarding their role in inflammatory processes, being able to fuel autoimmunity, as shown by the presence of anti-mitochondrial antibodies (AMAs) in up to 10% of IIM patients. As cellular respiration takes place, mitochondrial metabolites might help to shape the pro-inflammatory milieu in affected muscle, beyond generating reactive oxygen species, which are well-recognized inducers of damage-associated molecular patterns. A series of mitochondrial components might facilitate the sterile activation of pro-inflammatory cells and the production of several cytokines responsible for enhancing auto-immune responses. Marked variation in the mitochondrial genome has also been reported in IIM patients. As such, we summarize key historical and recent advances linking aberrations and instabilities of mitochondrial DNA to impaired muscle function. Besides discussing mitochondrial dysfunction as an essential part of IIM development, we also highlight possible associations between presence of AMAs and a particular phenotype of IIM, with its own characteristic clinical and radiological pattern. Finally, we present promising treatment approaches targeting mitochondria, while briefly discussing experimental models for gaining deeper insight into the disease process, and ultimately leading to novel drug development.

Figure 1

Clinical and Radiological Phenotype of Anti-mitochondrial Antibody-positive Idiopathic Inflammatory Myopathies. CT, computed tomography; MRI, magnetic resonance imaging. Created with Biorender.com.

Figure 2

Main Proposed Mechanisms of How Mitochondria Influence the Pathophysiology of Idiopathic Inflammatory Myopathies. AMA-M2, anti-mitochondrial antibodies against the E2 subunit of the 2-oxo acid dehydrogenase complex; ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; DM, dermatomyositis; FGF-21, fibroblast growth factor 21; fMet, N-formylated methionine peptides; GDF-15, growth differentiation factor-15; IBM, inclusion-body myositis; IFN, interferon; IIM, idiopathic inflammatory myopathy; mtDNA, mitochondrial DNA; PBC, primary biliary cholangitis; SNPs, single nucleotide polymorphisms. Created with Biorender.com.