Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

Abstract

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. 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.

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…Moreover, the accumulation of the glial fibrillary acidic protein (GFAP) indicated neuroinflammation ( Fig 1D), which was further substantiated by the increased expression of the proinflammatory cytokines and NF-jB target genes Tnfa, Il-1b, Asc, and Myd88 in retinas of 6-week-old NYKO mice ( Fig 1E). These findings are reminiscent of inflammatory responses observed in muscular OPA1 deficiency (Rodriguez-Nuevo et al, 2018). Similar to this model, we observed increased expression of Fgf21 ( Fig 1F).…”

Fibroblast growth factor 21 controls mitophagy and muscle mass

“…On one hand, FGF21 has gained attention for being a potential therapeutic protein for obesity and type 2 diabetes because it stimulates the oxidation of fatty acids, the production of ketone bodies, and inhibits lipogenesis . On the other hand, several reports indicate a pathophysiological role for FGF21: (i) it promotes bone loss and reduces bone mineral density; (ii) FGF21 is a stress‐induced myokine, which is released under conditions of starvation, ER stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging . We have recently shown that chronic elevation of muscle‐derived circulating FGF21 leads to systemic inflammation, precocious senescence, and premature death .…”

“…In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver . In contrast, muscle‐dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging . Moreover, FGF21 is a stress‐induced myokine that has been proposed as a specific serum biomarker of muscle‐specific mitochondrial disorders .…”

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

“…96 This was cGASindependent and may have been TLRdependent. 96 Mitochondria in OPA1 knockdown cells appear more fragmented than the untreated cells 96 and may mimic the swing towards fission experienced during some microbial infections. Thus, some forms of mitochondrial disruption may deliver a TLR9-driven priming signal for the NLRP3 inflammasome.…”

“…93 TLR9 recognises unmethylated CpG in the endosomal system, 94,95 including that of mitochondrial origin following mitochondrial disruption. [96][97][98][99] CpG recognition by TLR9 provides a signal 1 for NLRP3 activation, transcriptionally upregulating inflammasome-required genes under NF-jB control 100,101 (Figure 3b). The mitochondrial dynamics that drive disruption and exposure of mtDNA to TLR9 are varied and unclear, yet some evidence implicates defective fission/fusion dynamics.…”