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SUMMARY:PhD Defense - Molecular insights into the LRPPRC/SLIRP complex and
  its role in mitochondrial disease
DTSTART:20260424T110000Z
DTEND:20260424T130000Z
DTSTAMP:20260410T082300Z
UID:indico-event-39554@indico.in2p3.fr
DESCRIPTION:Speakers: Louise LAMBERT\n\n(The PhD defense will be in French
 )\nThe LRPPRC/SLIRP complex is a key post-transcriptional regulator of mit
 ochondrial DNA (mtDNA) expression. Acting as an mRNA chaperone\, this comp
 lex promotes the stability and translation of mitochondrial mRNAs by facil
 itating their polyadenylation and delivery to the mitoribosome. Mutations 
 in LRPPRC are associated with several mitochondrial diseases\, primarily a
 ffecting the oxidative phosphorylation (OXPHOS) system.In this thesis\, we
  analyzed in vitro the RNA-binding affinity of wild-type (WT) LRPPRC and t
 hree pathogenic variants: A354V\, the most frequent mutation responsible f
 or the French-Canadian form of Leigh syndrome\, K909del\, and R1276_K1300d
 el. Electrophoretic mobility shift assays (EMSAs) were performed using pro
 bes corresponding to the ATP6 mRNA and a poly(A) RNA\, used to mimic the p
 oly(A) tails of mitochondrial mRNAs. In the absence of SLIRP\, all mutants
  displayed reduced RNA binding\, particularly with the poly(A) RNA probe\,
  with the R1276_K1300del mutant showing no detectable binding. In contrast
 \, in the presence of SLIRP\, RNA binding of the R1276_K1300del mutant was
  largely restored on the mATP6 probe. Titration experiments revealed that 
 this mutant required between two and three SLIRP molecules per LRPPRC to r
 each ~50% of the binding level observed for the WT protein. Single-molecul
 e measurements by acoustic force spectroscopy further demonstrated that th
 e RNA-binding modes of WT and R1276_K1300del LRPPRC/SLIRP complexes were c
 omparable. Additionally\, in silico structural predictions indicate that S
 LIRP binding induces a conformational rearrangement of the mutant protein\
 , bringing it closer to the WT structure.Taken together\, these results de
 monstrate that all three mutations severely impair the intrinsic RNA-bindi
 ng capacity of LRPPRC. However\, SLIRP can partially restore the function 
 of the R1276_K1300del mutant\, suggesting a SLIRP-mediated stabilization o
 f the mutant protein. These findings highlight the essential role of SLIRP
  in modulating LRPPRC function and open perspectives for potential therape
 utic approaches in LRPPRC-related mitochondrial diseases.\n\nhttps://indic
 o.in2p3.fr/event/39554/
LOCATION:Amphi Recherche
URL:https://indico.in2p3.fr/event/39554/
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