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Mitochondrial Protein Alterations May Underlie Inflammatory Myopathies

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The link between mitochondria and inflammation is still unclear. But it is known is that the accumulation of defective mitochondria that should have been removed causes inflammation.


Scientists at the Institute for Research in Biomedicine (IRB), in Barcelona, report that the removal of a single mitochondrial protein in mouse muscle leads to severe inflammation throughout the body, causing the premature death of the animal. Their study (“Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency”) appears in The EMBO Journal.

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“Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-κB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death,” write the investigators.


“The effects of Opa1 deficiency on the expression NF-κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.”


Mitochondrial dynamics is one of the research lines addressed in the Complex Metabolic Diseases and Mitochondria Lab, led by Antonio Zorzano, Ph.D., a full professor at the University of Barcelona. To study this process, the scientists examined the proteins involved in mitochondrial membrane fusion— Mitofusin 1 and 2, and Opa1.


Authored by 24 researchers from various centers, the study focuses on Opa1. To examine its functions, the researchers generated a mouse deficient in Opa1 only in skeletal muscle.


“It was surprising to see how small they were and that they died after only a few months,” explains Dr. Zorzano. “This is the first time that we’ve seen that the lack of a muscle mitochondrial protein triggers an inflammatory response of this magnitude, and these observations give us further information on the relation between mitochondria and inflammation.”


There is a set of diseases known as inflammatory myopathies, of unknown origin, in which patients show chronic muscle inflammation accompanied by muscle weakness. “The results of this study suggest that mitochondrial alterations may underlie inflammatory myopathies. More research is now needed to address this possible link,” says Dr. Zorzano.

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