PhD defense - Nhu Dinh (eq. BONNEFOY - Biocell dpt)

Title: Role of Proteins from the LYRM Superfamily in Mitochondrial Biogenesis of the Fission Yeast Schizosaccharomyces pombe

Keywords: fission yeast, mitochondria, OXPHOS complex biogenesis, LYRM superfamily, physical partners, genetic and chemical compensation

Abstract: For a vast number of eukaryotes, mitochondria perform vital cellular functions, one of which is energy production via the oxidative phosphorylation (OXPHOS) complexes I-V. The biogenesis of these complexes is dually controlled by the mitochondrial and nuclear genomes. Specifically in humans, the mitochondrial DNA (mtDNA) encodes 13 subunits of the OXPHOS complexes, two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Meanwhile, the nuclear genome encodes hundreds of proteins necessary for mitochondrial functions. These include the remaining OXPHOS complex subunits, and numerous factors essential to mitochondrial gene expression, complex assembly and supercomplex organisation. Schizosaccharomyces pombe (fission yeast) exhibits mitochondrial physiology and mtDNA structure closely resembling those of human cells, hence is suitable as a model.

On the one hand, a majority of respiratory complexes require nuclear-encoded, mitochondrial-localised leucine-tyrosine-arginine motif (mtLYRM) proteins for subunit integration and performance. Mutations in human mtLYRM members are associated with severe pathophysiological conditions, emphasising the importance of further research. The doctoral thesis demonstrates that (i) three novel S. pombe mtLYRM factors constitute the mitochondrial ribonuclease P (mtRNase P), responsible for the 5’ endonucleolytic cleavage of mitochondrial tRNAs; (ii) the S. pombe mtRNase P cooperates with the mitochondrial ribonuclease Z, the mitochondrial translation machinery and the mitochondrial fatty acid synthesis via unknown mechanisms; and (iii) both the ribozyme and protein subunit of canonical bacterial RNase P are carried over to yeast mitochondria. Prior to this work, the mtLYRM superfamily had never been implicated in mitochondrial RNA maturation.

On the other hand, the spatial arrangement of OXPHOS complexes is governed by the mitochondrial contact site and cristae organising system (MICOS). The doctoral project provides evidence on (i) the in vivo architecture of the S. pombe MICOS, and (ii) the effect of nifuroxazide, a drug that could be repurposed for MICOS-related amyotrophic lateral sclerosis.