Mitochondrial Diseases and Immunity

Summary

Mitochondria are specialised cell organelles which transform nutrients into energy. Mitochondria are made from proteins coded by DNA present inside mitochondria (mtDNA) and in the cell nucleus (nDNA), and mutations in either genome can cause mitochondrial diseases.1 Mitochondrial diseases affect the skeletal muscle, peripheral nerves, brain or other organs and there are no effective cures. 

Clearance of damaged mitochondria is crucial for maintaining cellular homeostasis, especially in terminally differentiated cells with no or slow renewal rates. It has been shown that mtDNA leakage activates cGAS-stimulator of interferon genes (STING) promoting inflammation in aged cells. Similar changes were also detected in the polymerase gamma mutant mice2 and in a few special forms of mitochondrial diseases (ATAD3A mutations)3. 

Recently, the secretion of mitochondria in extracellular-vesicles (mtEVs)has been indicated as a form of quality control when autophagic function is affected and it can be triggered by mitochondrial damage4. Released mtDNA has also been associated with replicative stress and it can be further eliminated through endosomal trafficking.

This data shows that as part of mitochondrial quality control, mitochondrial cargo, including mtDNA, can be eliminated from the cells through vesicles. However, the extent of this phenomenon and its relevance in primary mitochondrial disease has not been addressed. The increase in secreted mitochondrial cargo in MDVs may be relevant in mitochondrial diseases and can modulate cellular mechanisms contributing to the disease progression.

Project aims

The aim of this project is to study the relevance of mt-EVs and the activation of the immuneresponse in primary mitochondrial diseases. The project will use state-of-the-art cellular models of mitochondrial disease (iPSC derived neuronal and muscle cells and brain organoids) and validate the results in samples obtained from patients with mitochondrial disease. 

References 

1. Gorman, G.S., et al. Mitochondrial diseases. Nat Rev Dis Primers 2016;2:16080. 

2. Kang Y, et al. Ancestral allele of DNA polymerase gamma modifies antiviral tolerance. Nature. 2024 Apr;628(8009):844-853 

3. Lepelley A., et al. Enhanced cGAS-STING-dependent interferon signalling associated with mutations in ATAD3A. J Exp Med 2021;218(10):e20201560 

4. König T, McBride HM. Mitochondrial-derived vesicles in metabolism, disease, and aging. Cell Metab. 2024;36(1):21-35. 

Contact details

Professor Rita Horvath, rh732@medschl.cam.ac.uk - Neurology

Co-supervisor: Dr Daniel Lagos.

Opportunities

This opportunity is open to PhD applicants.