# No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases

## TL;DR

This study shows that cultured skin fibroblasts from mitochondrial disease patients are useful for studying interferon signaling, but abnormal signaling and mitochondrial DNA/RNA leakage are not consistently linked.

## Contribution

The study reveals inconsistent interferon signaling and weak correlation with mitochondrial DNA/RNA leakage in mitochondrial disease patient fibroblasts.

## Key findings

- Only 43% of patients’ fibroblasts showed increased interferon-stimulated gene scores.
- No correlation was found between elevated interferon response and cytosolic mitochondrial DNA/RNA leakage.
- Cytosolic mtDNA and mtRNA accumulation varied and showed little correlation with interferon signaling scores.

## Abstract

Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon‐stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease‐causing genes. Control fibroblasts showed a strong expression of interferon‐stimulated genes in response to interferon, but only 43% of patients’ fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients’ fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.

Investigation of IFN signaling in cultured skin fibroblasts from patients with genetically confirmed mitochondrial diseases of diverse origins revealed that altered IFN signaling is an inconsistent feature of these disorders. Cytosolic accumulation of mtDNA and mtRNA was variably detected and showed little correlation with ISG scores.