The absence of a single mitochondrial protein causes severe inflammation

The absence of a single mitochondrial protein causes severe inflammation

The link between mitochondria and inflammation is still unclear. But it is known that the accumulation of defective mitochondria, which should have been removed, causes inflammation. Scientists now demonstrate 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. This study has been published in the EMBO Journal.

Opa1 is a mitochondrial fusion protein. It serves to fuse the internal membranes of mitochondria. Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Although present in all cells and tissues (except white blood cells), mitochondria are particularly abundant in muscle and liver, and their main function is to convert the energy in food into energy for cells. Mitochondria are highly dynamic; they join and separate, and grow and shrink constantly. These processes are known as mitochondrial dynamics.

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 the author.The article describes the animal phenotype and explains that the removal of Opa1 exclusively from skeletal muscle fibre triggers a severe inflammatory process that spreads from the muscle fibre throughout the body. The inflammatory response halts growth and shortens the lifespan of the animal. The scientists also describe the main molecular components of the cell signalling pathway that activates the inflammatory response in muscle.

The 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.

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. 

"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," says the author.