Defects of mitochondrial gene expression in human disease

Figure | Three-dimensional model of human mitochondrial tRNA methyltransferase TRMT5, with residues mutated in patients affected with mitochondrial disease indicated in red.

Much of our understanding of mitochondria has come from studying rare mitochondrial disorders. Thanks to multiple collaborations with clinical groups worldwide, we have been analysing key aspects of mitochondrial genome regulation in samples derived from patients affected with mitochondrial disease. This analysis is a source of valuable insights into the pathomechanisms of human disease, and also into basic mitochondrial molecular genetics. Furthermore, our collaborative studies provide patients with genetic disease with a molecular diagnosis for prevention (prenatal genetic diagnosis) and counseling [1] [2].

Currently, we are focused on investigating:

Interdependence of mitochondrial RNA processing and translation. We study the ELAC2 gene, coding for an RNase Z responsible for 3’-end processing of mt-tRNAs, in patients with cardiomyopathy, lactic acidosis, and complex I deficiency. We found accumulated mt-RNA precursors in patient-derived cells. Despite normal levels of correctly processed transcripts, mitochondrial translation was impaired in cells carrying ELAC2 mutations. This research highlights the importance of maintaining a correct balance between precursor and mature mt-RNAs for proper gene expression in mitochondria, and these aspects will be investigated further [3].

Importance of post-transcriptional modification of mitochondrial RNA for correct expression of mtDNA-encoded genes. We have been analysing three mt-tRNA modifying enzymes: (i) GTPBP3, mutations in which lead to a combined OXPHOS deficiency, cardiomyopathy, lactic acidosis and encephalopathy[4] and (ii) TRMT5, mutations in which were associated with OXPHOS deficiency and lactic acidosis [5]. (iii) NSUN3, vatiants in which are associated with combined OXPHOS deficiency, external ophtalmoplegia and lactic acidosis [6] . Our studies highlight that defects in mitochondrial translation resulting from incorrect post-transcriptional modification of mt-tRNAs are an important contributory factor to the spectrum of human mitochondrial disease [7] [1].

Aspacts of mitochondrial genome maintenance. We identified an orphan gene MGME1 (mitochondrial genome maintenance exonuclease 1, C20orf72) mutated in patients with a mitochondrial syndrome characterised by ocular myopathy, extreme emaciation and respiratory failure associated with mtDNA depletion and large-scale rearrangements. We showed that MGME1 encodes a mitochondrial protein belonging to the PD-(D/E)XK nuclease superfamily, and that MGME1 cleaves single-stranded DNA and processes DNA (and RNA-DNA) flap substrates. Cells from affected individuals show impaired mtDNA replication. This study has demonstrated that MGME1-mediated mtDNA processing is essential for mitochondrial genome maintenance [8] [9].


  1. Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ & Minczuk MA (2015) Mitochondrial transcript maturation and its disorders. J Inherit Metab Dis 38, 655-80
  2. Nicholls TJ, Rorbach J & Minczuk MA (2013) Mitochondria: mitochondrial RNA metabolism and human disease. Int J Biochem Cell Biol 45, 845-9
  3. Haack TB, Kopajtich R, Freisinger P, Wieland T, Rorbach J, Nicholls TJ, Baruffini E, Walther A, Danhauser K, Zimmermann FA, Husain RA, Schum J, Mundy H, Ferrero I, Strom TM, Meitinger T, Taylor RW, Minczuk MA, Mayr JA & Prokisch H (2013) ELAC2 mutations cause a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Am J Hum Genet 93, 211-23
  4. Kopajtich R, Nicholls TJ, Rorbach J, Metodiev MD, Freisinger P, Mandel H, Vanlander A, Ghezzi D, Carrozzo R, Taylor RW, Marquard K, Murayama K, Wieland T, Schwarzmayr T, Mayr JA, Pearce SF, Powell CA, Saada A, Ohtake A, Invernizzi F, Lamantea E, Sommerville EW, Pyle A, Chinnery PF, Crushell E, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Assouline Z, Rio M, Feillet F, de Camaret BMousson, Chretien D, Munnich A, Menten B, Sante T, Smet J, Régal L, Lorber A, Khoury A, Zeviani M, Strom TM, Meitinger T, Bertini ES, Van Coster R, Klopstock T, Rötig A, Haack TB, Minczuk MA & Prokisch H (2014) Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am J Hum Genet 95, 708-20
  5. Powell CA, Kopajtich R, D'Souza AR, Rorbach J, Kremer LS, Husain RA, Dallabona C, Donnini C, Alston CL, Griffin H, Pyle A, Chinnery PF, Strom TM, Meitinger T, Rodenburg RJ, Schottmann G, Schuelke M, Romain N, Haller RG, Ferrero I, Haack TB, Taylor RW, Prokisch H & Minczuk MA (2015) TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies. Am J Hum Genet 97, 319-28
  6. Van Haute L, Dietmann S, Kremer L, Hussain S, Pearce SF, Powell CA, Rorbach J, Lantaff R, Blanco S, Sauer S, Kotzaeridou U, Hoffmann GF, Memari Y, Kolb-Kokocinski A, Durbin R, Mayr JA, Frye M, Prokisch H & Minczuk MA (2016) Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nature Communications 7, 12039
  7. Powell CA, Nicholls TJ & Minczuk MA (2015) Nuclear-encoded factors involved in post-transcriptional processing and modification of mitochondrial tRNAs in human disease. Front Genet 6, 79
  8. Kornblum C, Nicholls TJ, Haack TB, Schöler S, Peeva V, Danhauser K, Hallmann K, Zsurka G, Rorbach J, Iuso A, Wieland T, Sciacco M, Ronchi D, Comi GP, Moggio M, Quinzii CM, DiMauro S, Calvo SE, Mootha VK, Klopstock T, Strom TM, Meitinger T, Minczuk MA, Kunz WS & Prokisch H (2013) Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease. Nat Genet 45, 214-9
  9. Nicholls TJ, Zsurka G, Peeva V, Schöler S, Szczesny RJ, Cysewski D, Reyes A, Kornblum C, Sciacco M, Moggio M, Dziembowski A, Kunz WS & Minczuk MA (2014) Linear mtDNA fragments and unusual mtDNA rearrangements associated with pathological deficiency of MGME1 exonuclease. Hum Mol Genet 23, 6147-62