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Staff Profile

Professor Zofia Chrzanowska-Lightowlers

Professor of Mitochondrial Biology

Background

Introduction

My research focuses on gene expression in the human mitochondrion. The organelle has its own genome and the transcribed RNA is translated in organello. My work aims to identify and understand the molecular mechanisms underlying these processes. We are currently identifying and isolating factors that are important for modulating post-transcriptional regulation in the human mitochondrion. Main questions we are addressing include: What are the rescue mechanisms that act on stalled mitoribosomes? How is mt-RNA targetted for degradation ? What elements affect mitoribosome progression through the transcript ?  Where does translation of each transcript take place at a suborganellar level ?

Roles and Responsibilities

Director of the Institute of Neuroscience (2017 - 2019)
Deputy Director MRes (2003 - current)
Chair Curriculum Committee (MRes) (2003 - current)

Programme lead for MRes Mitochondrial Biology and Medicine

Qualifications

BSc (Hons) Biological Sciences, University of East Anglia
PGCE, University of London
MSc, University of Oregon
PhD, University of Newcastle

Research

Research Interests

The mitochondrion is an organelle found in all nucleated cells of higher eukaryotes. It is the site of oxidative phosphorylation and contains its own genome that encodes 13 proteins, which are essential components of these respiratory complexes. In addition to the mRNAs the genome also encodes the 22 tRNAs and 2 rRNAs that are required for this intra-mitochondrial protein synthesis. Our work is focussed on unravelling the nuances of gene expression in mammalian mitochondria.

It is the fate of these mitochondrial mRNA species that we are investigating. Although much is known about the turnover of cytosolic and bacterial transcripts, until very recently almost nothing was clear about the mitochondrial RNA species. Do they behave as their bacterial ancestors or follow the example of the cytosol in which they reside ? What is the normal decay mechanism and what are the enzymes responsible for carrying out these activities ? We have identified that in contrast to yeast, the mammalian mt-transcripts are polyadenylated but the full function of this tail is not yet certain. In addition to completing the stop codon for 7 open reading frames, it affects transcript stability in specific but different ways for the individual mtDNA encoded transcripts. Since the mitochondrial genome cannot yet be manipulated we have used cell lines with identified mutations to try and answer some of these questions. By using a cell line that has a 2 base pair microdeletion the resulting mRNA loses the termination codon, we have identified a ‘non-stop’ decay mechanism and shown that in this situation the inhibition of translation confers stability to the aberrant transcript.

Our work includes investigations into the mitochondrial nucleases and mt-RNA-binding proteins involved in the mechanism described above as well as those involved in the normal deadenylation and decay and characterising their specificity.

We have spent many years investigating the release factors and recycling factors. Although we have learned a great deal the precise function played by mtRF1 and C12orf65 still elude the field, and the role of ICT1 that is not incorporated in the mitoribosome also remains enigmatic. It is however, very likely that these factors are responsible for terminating translation under specific circumstances.

Within our department the link between pure and clinical research is very strong. Many of the neurological conditions that patients present with affect their mitochondrial DNA. In some instances this would be predicted to affect the subsequent transcription and translation. This provides the opportunity to study the differences in the homeostasis of mitochondrial mRNA in controls versus disease.

Postgraduate Supervision

I currently supervise 5 postgraduate PhD students and am tutor to undergraduate and MRes students.

Funding

The Wellcome Trust and the EU currently support the ongoing research in my laboratory

Keywords

RNA metabolism, mitochondrial RNA, degradation, mitochondrial gene expression, polyadenylation, stability

Teaching

Undergraduate Teaching

I have hosted final Honours year undergraduates in my lab for their research project work for over 20 years.


Postgraduate Teaching

I am the Deputy Director for the suite of MRes courses in Medical and Molecular Biosciences.

I am also the Chair of the Curriculum Committee and Director for Admissions and Recruitment.

I am programme director for and teach on the MRes in Mitochondrial Biology and Medicine.


I host Erasmus students from numerous European countries as well as MRes project students in my group.

I am responsible for a number of home, EU and International PhD students that I supervise. 

I have served on the Management Committee for Training for the NIHR funded BRC/BRU programme.

I am involved in the assessment and marking of MBBS, MSci, BSc and MRes student courses.


Publications