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EASTBIO Understanding the rules of mitochondrial nucleic acid escape in innate immune activation

  • Full or part time
  • Application Deadline
    Sunday, January 05, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Mitochondria are the ‘power-stations’ of our cell, providing energy for cellular function. Mitochondria have evolved from ancient bacteria that invaded our cells a billion of years ago and have ‘integrated’ into our biological system in an endosymbiotic relationship. As such, mitochondria still carry some features of bacterial origin, including a closed circular DNA as genetic material and prokaryotic gene expression process. This begs the question of how do cells not detect mitochondria as “foreign” and mount an immune response against them. Indeed, at a cost of this symbiotic relation the cell has evolved certain pathways to maintain homeostasis. Recently we have discovered such a novel evolutionary conserved pathway that prevents the formation of toxic double-stranded RNA (dsRNA) inside mitochondria1. Bidirectional transcription of mitochondrial DNA generates two long polycistronic RNA of which one is mainly noncoding and is rapidly degraded by the combined action of RNA helicase SUV3 and exonuclease PNPase. This action is essential to prevent formation of mitochondrial dsRNA (mtdsRNA) which otherwise has deleterious consequences as exemplified by activation of antiviral innate immune response in patients carrying hypomorphic mutations in PNPase. Underpinning this immune response is the unresolved issue of how mtdsRNA escapes outside of the mitochondria thereby triggering such a potent response.

This PhD studentship will focus on investigating the mechanism of how mitochondrial nucleic acids, in particular mtdsRNA, escapes the double-membrane compartments of mitochondria in pathophysiological settings. This study will be at the intersection of mitochondrial biology and innate immunity with an evolutionary perspective.

In the first part of the PhD project the student will develop various tools to monitor mtdsRNA by live cell imaging for a time lapse study using super-resolution microscopy. This will include differential labelling of mitochondrial membranes and investigating its dynamics and ultrastructural features that determines mtdsRNA release. This will also emphasize on identifying involvement of various mitochondrial channels or pores in such a process. This is a powerful approach that we have previously applied to understand mitochondrial DNA release in apoptotic stimuli2.

In second part, we will take biochemical approaches to understand the function of PNPase in mtdsRNA accumulation and its escape. We will engineer various variants of PNPase using CRISPR knock-in that abolish RNA exonuclease activity without affecting other functions so as to dissect out its role in mtdsRNA accumulation vs its escape. Biochemical approaches of protein-protein interaction and RNA-protein interactome will be used to understand this complexity.

Download application and reference forms via: http://www.eastscotbiodtp.ac.uk/how-apply-0

Applications: Completed application form along with your supporting documents should be sent to our PGR student team at

References: Please send the reference request form to two referees. Completed forms for this IGMM project should be returned to by the closing date: 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.

Funding Notes

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References

1. Dhir A, Dhir S, Borowski L, Jimenez L, Teitell M, Rötig A, Crow YJ, Rice GI, Duffy D, Tamby C et. al.: Mitochondrial double stranded RNA triggers antiviral signalling in humans. Nature. 2018 Aug;560 (7717): 238-242 (PMID:30046113).

2. Riley JS, Quarato G, Cloix C, Lopez J, O'Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, Wheeler AP, Oberst A, Ryan KM, Tait SW: Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018 Sep 3;37(17) (PMID:30049712).

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