As a Professor of Mitochondrial Biology I have a keen interest in the post-transcriptional gene expression in the human organelle. My motivation as a scientist is to uncover and understand the basic molecular mechanisms that govern mitochondrial RNA metabolism and in these endeavours I collaborate closely with Prof Bob Lightowlers. More recent projects are increasing my interactions with Prof Rob Taylor and Dr Rita Horvath as well other members of the Wellcome Trust Centre in Newcastle.
Our work on protein synthesis in human mitochondria has been enhanced by interactions with our collaborators across mitochondrial groups in Europe and Canada (including Prof Vera Bianchi, Padova; Dr Nathalie Bonnefoy, CNRS Paris; Profs Maria Falkenberg and Klaus Gustafsson, Gothenberg; Prof Laura Frontali, Roma; Prof Nils-Goran Larsson, Koln; Prof Jan Smeitink, The Netherlands; Prof Eric Shoubridge, Montreal). Our collaborations also extend into non-mitochondrial groups to improve our understanding of protein synthesis including past, present and projected interactions with Prof Warren Tate (New Zealand), Prof Tatsu Abo (Japan), Prof John Atkins (USA) and Prof Andrew Crosby (Exeter).
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 the respiratory complexes and the ATP synthase. In addition to the mRNAs the genome also encodes the 22tRNAs and 2 rRNAs that are required for this intra-mitochondrial protein synthesis.
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 function of this tail is not yet certain. In bacteria it enhances decay, whilst in the eukaryote cytosol it is bound by poly(A) binding proteins and promotes both stability and translation.
Since the mitochondrial genome cannot yet be manipulated we have used cell lines with identified mutations to try and answer some of these questions. Most of the mt-mRNAs require polyadenylation to generate the Stop codon. 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 poly(A) tail confers stability to the aberrant transcript.
Our work is presently focussed on identifying the mitochondrial nucleases and mt-RNA-binding proteins involved in the mechanism described above as well as those involved in the normal decay pathway and characterising their specificity. We are also looking at the ways in which the organelle can exert a level of ‘Quality Control’ and the protein factors that are likely to be responsible for this activity.
Within our department the link between pure and clinical research is very strong and described above. 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.
Awards, honours and professional service
Biochemical Society’s Theme Panel I – Genes
Biochemical Society’s ‘Local Ambassador’
Member of Pathological Society since 2008
Member of Biochemical Society since 2000
Wellcome Trust Research Career Development Fellowship, February 1999 – 2003
The Don Beaven Travelling Fellowship
Christchurch School of Medicine, University of Otago, New Zealand, February 1998
Sir Henry Wellcome Commemorative Award for Innovative Research, June 1997
Ph.D. Regulation of the Homeostasis of Cytochrome c Oxidase
University of Newcastle upon Tyne, England, May 1995
M.Sc. Biochemistry and Molecular Biology, Institute of Molecular Biology
University of Oregon, Oregon, USA,1989 – 1990
Post Graduate Certificate in Education, Institute of Education
University of London, London, England, 1983 – 1984
B.Sc. (Hons) Biological Science, University of East Anglia, Norwich, England, 1980 – 1983
Recent key Publications
Rorbach J, Gao F, Powell CA, D’Souza A, Lightowlers RN, Minczuk M, Chrzanowska-Lightowlers ZM, 2016. Human mitochondrial ribosomes can switch their structural RNA composition. Proc Natl Acad Sci U S A. 13(43):12198-12201.
Spåhr H, Rozanska A, Li X, Atanassov I, Lightowlers RN, Chrzanowska-Lightowlers ZM, Rackham O, Larsson NG, 2016. SLIRP stabilizes LRPPRC via an RRM-PPR protein interface. Nucleic Acids Res. 44(14):6868-82
Mate Maus, Mario Cuk, Bindi Patel, Jayson Lian, Mireille Ouimet, Ulrike Kaufmann, Jun Yang, Rita Horvath, Hue-Tran Hornig-Do, Zofia Chrzanowska-Lightowlers, Kathryn J. Moore, Ana Maria Cuervo, Stefan Feske. Store-operated Ca2+ entry (SOCE) controls induction of lipolysis and the transcriptional reprogramming to lipid metabolism. Cell Metabolism In Press
Tai H, Wang Z, Gong H, Han X, Zhou J, Wang X, Wei X, Ding Y, Huang N, Qin J, Zhang J, Wang S, Gao F, Chrzanowska-Lightowlers ZM, Xiang R, Xiao H, 2017. Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Autophagy. 13(1):99-113.
Zaganelli S, Rebelo-Guiomar P, Maundrell K, Rozanska A, Pierredon S, Powell CA, Jourdain AA, Hulo N, Lightowlers RN, Chrzanowska-Lightowlers ZM, Minczuk M, Martinou JC, 2017. The Pseudouridine Synthase RPUSD4 is an essential component of Mitochondrial RNA Granules. J Biol Chem. Jan 12. pii: jbc.M116.771105. doi: 10.1074/jbc.M116.771105. [Epub ahead of print]
Oláhová M, Hardy SA, Hall J, Yarham JW, Haack TB, Wilson WC, Alston, CL, He L, Aznauryan E, Brown RM, Brown GK, Morris AAM, Mundy H, Broomfield A, Barbosa IA, Simpson MA, Deshpande C, Moeslinger D, Koch J, Stettner GM, Bonnen PE, Prokisch H, Lightowlers RN, McFarland R, Chrzanowska-Lightowlers ZMA, Taylor RW, 2015. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French Canadian population. Brain, 138(12) 3503-19.
Wilson, WC, Hornig-Do H-T, Bruni F, Chang JH, Jourdain AA, Martinou J-C, Falkenberg M, Spåhr H, Larsson N-G, Lewis RJ, Hewitt L, Baslé A, Cross HE, Tong L, Lebel RR, Crosby AH, Chrzanowska-Lightowlers ZMA*, Lightowlers RN*, 2014. A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression. Hum. Mol. Genet. 2014;23:6345-6355.
Hornig-Do H-T, Montanari A, Rozanska A, Tuppen HA, Almalki AA, Abg-Kamaludin DP, Frontali L, Francisci S, Lightowlers RN*, Chrzanowska-Lightowlers ZMA*, 2014. Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt-tRNA mutations. EMBO Mol. Med. 2014;6:183-193.
Jourdain AA, Koppen M, Wydro M, Rodley CD, Lightowlers RN, Chrzanowska-Lightowlers ZMA, Martinou JC, 2013. GRSF1 Regulates RNA Processing in Mitochondrial RNA Granules. Cell Metab. 17:399-410.
Temperley R, Richter R, Dennerlein S, Lightowlers RN*, Chrzanowska-Lightowlers ZMA*, 2010. Hungry codons promote frameshifting in human mitochondrial ribosomes. Science. 327:301
Richter R, Rorbach J, Pajak A, Smith PM, Wessels H J, Huynen MA, Smeitink J A, Lightowlers RN*, Chrzanowska-Lightowlers ZMA*, 2010. A functional peptidyl tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome. EMBO J. 29:1116-1125.
2018. OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect.  EMBO Mol Med.,
2018. Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.  Hum Mutat 39(4):563-578,
2018. Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.  Hum Mol Genet 27(10):1743-1753,
2017. Using mitoribosomal profiling to investigate human mitochondrial translation.  Wellcome Open Res 2:116,
2017. Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies.  Am J Hum Genet 101(4):525-538,
2017. Human mitochondrial ribosomes can switch structural tRNAs - but when and why?  RNA Biol 14(12):1668-1671,
2017. The human RNA-binding protein RBFA promotes the maturation of the mitochondrial ribosome.  Biochem J 474(13):2145-2158,
2017. Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2.  Protein Sci 26(8):1505-1516,
2017. Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism.  Cell Metab 25(3):698-712,
2017. Human mitochondrial nucleases.  FEBS J 284(12):1767-1777,
2017. Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence.  Autophagy 13(1):99-113,
2017. Pathogenic variants in HTRA2 cause an early-onset mitochondrial syndrome associated with 3-methylglutaconic aciduria.  J Inherit Metab Dis 40(1):121-130,
2017. The process of mammalian mitochondrial protein synthesis.  Cell Tissue Res 367(1):5-20,
2017. The Pseudouridine Synthase RPUSD4 Is an Essential Component of Mitochondrial RNA Granules.  J Biol Chem 292(11):4519-4532,
2016. Human mitochondrial ribosomes can switch their structural RNA composition.  Proc Natl Acad Sci U S A 113(43):12198-12201,
2016. SLIRP stabilizes LRPPRC via an RRM-PPR protein interface.  Nucleic Acids Res 44(14):6868-82,
2015. MTO1 mediates tissue specificity of OXPHOS defects via tRNA modification and translation optimization, which can be bypassed by dietary intervention.  Hum Mol Genet 24(8):2247-66,
2015. A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency.  Eur J Hum Genet 23(7):935-9,
2015. LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.  Brain 138(Pt 12):3503-19,
2015. Response to "Ribosome Rescue and Translation Termination at Non-standard Stop Codons by ICT1 in Mammalian Mitochondria".  PLoS Genet 11(6):e1005227,
2015. Adult Onset Leigh Syndrome in the Intensive Care Setting: A Novel Presentation of a C12orf65 Related Mitochondrial Disease.  J Neuromuscul Dis 2(4):409-419,
2014. Overcoming stalled translation in human mitochondria.  Front Microbiol 5:374,
2014. A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression.  Hum Mol Genet 23(23):6345-55,
2014. Mitochondrial protein synthesis: figuring the fundamentals, complexities and complications, of mammalian mitochondrial translation.  FEBS Lett 588(15):2496-503,
2014. Salvaging hope: Is increasing NAD(+) a key to treating mitochondrial myopathy?  EMBO Mol Med 6(6):705-7,
2014. Human mitochondrial leucyl tRNA synthetase can suppress non cognate pathogenic mt-tRNA mutations.  EMBO Mol Med 6(2):183-93,
2014. Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.  Biochim Biophys Acta 1842(1):56-64,
2014. The role of the mitochondrial ribosome in human disease: searching for mutations in 12S mitochondrial rRNA with high disruptive potential.  Hum Mol Genet 23(4):949-67,
2013. Interactions between peptidyl tRNA hydrolase homologs and the ribosomal release factor Mrf1 in S. pombe mitochondria.  Mitochondrion 13(6):871-80,
2013. REXO2 is an oligoribonuclease active in human mitochondria.  PLoS One 8(5):e64670,
2013. Human pentatricopeptide proteins: only a few and what do they do?  RNA Biol 10(9):1433-8,
2013. Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency.  Biochim Biophys Acta 1832(8):1304-12,
2013. GRSF1 regulates RNA processing in mitochondrial RNA granules.  Cell Metab 17(3):399-410,
2012. Recombinant human MDM2 oncoprotein shows sequence composition selectivity for binding to both RNA and DNA.  Int J Oncol 40(3):851-9,
2012. Structure based hypothesis of a mitochondrial ribosome rescue mechanism.  Biol Direct 7:14,
2012. The mystery of mitochondrial RNases.  Biochem Soc Trans 40(4):865-9,
2012. Exploring our origins--the importance of OriL in mtDNA maintenance and replication.  EMBO Rep 13(12):1038-9,
2011. Termination of protein synthesis in mammalian mitochondria.  J Biol Chem 286(40):34479-85,
2011. Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency.  Brain 134(Pt 1):183-95,
2010. Hungry codons promote frameshifting in human mitochondrial ribosomes.  Science 327(5963):301,
2010. Targeting of the cytosolic poly(A) binding protein PABPC1 to mitochondria causes mitochondrial translation inhibition.  Nucleic Acids Res 38(11):3732-42,
2010. A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome.  EMBO J 29(6):1116-25,
2010. Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy.  Biochim Biophys Acta 1802(6):539-44,
2010. Human mitochondrial mRNAs--like members of all families, similar but different.  Biochim Biophys Acta 1797(6-7):1081-5,
2010. Terminating human mitochondrial protein synthesis: a shift in our thinking.  RNA Biol 7(3):282-6,
2010. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect.  Am J Hum Genet 87(1):115-22,
2010. Human ERAL1 is a mitochondrial RNA chaperone involved in the assembly of the 28S small mitochondrial ribosomal subunit.  Biochem J 430(3):551-8,
2010. The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families.  Brain 133(10):2952-63,
2010. Defective mitochondrial mRNA maturation is associated with spastic ataxia.  Am J Hum Genet 87(5):655-60,
2010. Translation termination in human mitochondrial ribosomes.  Biochem Soc Trans 38(6):1523-6,
2009. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.  Brain 132(Pt 11):3165-74,
2009. Fine mapping of interactions between eEF1alpha protein and 3'UTR of metallothionein-1 mRNA.  Biochem Biophys Res Commun 386(1):82-8,
2008. Overexpression of human mitochondrial valyl tRNA synthetase can partially restore levels of cognate mt-tRNAVal carrying the pathogenic C25U mutation.  Nucleic Acids Res 36(9):3065-74,
2008. The human mitochondrial ribosome recycling factor is essential for cell viability.  Nucleic Acids Res 36(18):5787-99,
2008. PPR (pentatricopeptide repeat) proteins in mammals: important aids to mitochondrial gene expression.  Biochem J 416(1):e5-6,
2008. Polyadenylation and degradation of mRNA in mammalian mitochondria: a missing link?  Biochem Soc Trans 36(Pt 3):517-9,
2007. mtRF1a is a human mitochondrial translation release factor decoding the major termination codons UAA and UAG.  Mol Cell 27(5):745-57,
2006. Production of transmitochondrial cybrids containing naturally occurring pathogenic mtDNA variants.  Nucleic Acids Res 34(13):e95,
2006. Sporadic intragenic inversion of the mitochondrial DNA MTND1 gene causing fatal infantile lactic acidosis.  Pediatr Res 59(3):440-4,
2005. Annexin A2 binds to the localization signal in the 3' untranslated region of c-myc mRNA.  FEBS J 272(2):413-21,
2005. Serum-deprivation stimulates cap-binding by PARN at the expense of eIF4E, consistent with the observed decrease in mRNA stability.  Nucleic Acids Res 33(1):376-87,
2004. A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome.  Eur J Hum Genet 12(6):509-12,
2004. Functional polypeptides can be synthesized from human mitochondrial transcripts lacking termination codons.  Biochem J 377(Pt 3):725-31,
2004. Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells.  Hum Mol Genet 13(20):2519-34,
2004. Messenger RNA stability in mitochondria: different means to an end.  Trends Genet 20(6):260-7,
2004. Sporadic mitochondrial myopathy due to a new mutation in the mitochondrial tRNASer(UCN) gene.  Neuromuscul Disord 14(7):417-20,
2003. Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria.  Hum Mol Genet 12(18):2341-8,
2003. A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency.  Mol Genet Metab 79(2):124-8,
2003. Mu class glutathione S-transferase mRNA isoform expression in acute lymphoblastic leukaemia.  Br J Haematol 120(1):80-8,
2002. Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis.  Brain 125(Pt 7):1522-33,