Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease
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Nandaki Keshavan1,2, Lana Mhaldien3, Kimberly Gilmour3
1Metabolic Unit, Great Ormond Street Hospital, London, UK.
Objective:
Mitochondria are implicated in regulation of the innate immune response. We hypothesized that abnormalities in interferon signaling may contribute to pathophysiology in patients with primary mitochondrial disease (PMD).
Methods:
Expression of interferon stimulated genes (ISGs) was measured by real-time polymerase chain reaction (PCR) in whole blood samples from a cohort of patients with PMD.
Results:
Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently IFI27 upregulation, seen in 50% of the samples. Some patients had extremely high IFI27 levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated IFI27 gene expression and PMD, but not between IFI27 and secondary mitochondrial dysfunction, suggesting that ISG upregulation is a biomarker of PMD. In some patients with PMD, ISG abnormalities persisted on repeat measurement over several years, indicative of ongoing chronic inflammation. Subgroup analyses suggested common ISG signatures in patients with similar mitochondrial disease mechanisms and positive correlations with disease severity among patients with identical genetic diagnoses.
Interpretation:
Dysregulated interferon signaling is frequently seen in patients with PMD suggesting that interferon dysregulation is a contributor to pathophysiology. This may indicate a role for repurposing of immunomodulatory therapies for the treatment of PMDs by targeting interferon signaling. ANN NEUROL 2024;96:1185-1200.
Insights
Mitochondrial disease patients often show abnormal interferon signaling, with upregulated interferon-stimulated genes (ISGs) acting as a potential biomarker. This suggests targeting interferon pathways may offer new treatments for primary mitochondrial diseases.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- Mitochondria play a role in innate immune response regulation.
- Abnormalities in interferon signaling may contribute to primary mitochondrial disease (PMD) pathophysiology.
Purpose of the Study:
- To investigate interferon signaling in patients with primary mitochondrial disease (PMD).
- To determine if interferon-stimulated genes (ISGs) can serve as biomarkers for PMD.
Main Methods:
- Real-time PCR was used to measure ISG expression in whole blood from PMD patients.
- Analysis included correlation with disease severity and genetic diagnoses.
Main Results:
- 75% of PMD patients exhibited upregulated ISG expression, most commonly IFI27.
- Elevated IFI27 gene expression significantly correlated with PMD, not secondary mitochondrial dysfunction.
- Persistent ISG abnormalities indicated chronic inflammation in some patients.
Conclusions:
- Dysregulated interferon signaling is common in PMD, contributing to disease pathophysiology.
- ISG upregulation may serve as a biomarker for PMD.
- Repurposing immunomodulatory therapies targeting interferon signaling could be beneficial for PMD treatment.
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