Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency

Abstract

Premature ovarian insufficiency (POI) is a common cause of infertility in women, characterised by amenorrhea and elevated FSH under the age of 40 years. In some cases, POI is syndromic in association with other features such as sensorineural hearing loss in Perrault syndrome. POI is a heterogeneous disease with over 80 causative genes known so far; however, these explain only a minority of cases. Using whole-exome sequencing (WES), we identified a MRPL50 homozygous missense variant (c.335T > A; p.Val112Asp) shared by twin sisters presenting with POI, bilateral high-frequency sensorineural hearing loss, kidney and heart dysfunction. MRPL50 encodes a component of the large subunit of the mitochondrial ribosome. Using quantitative proteomics and western blot analysis on patient fibroblasts, we demonstrated a loss of MRPL50 protein and an associated destabilisation of the large subunit of the mitochondrial ribosome whilst the small subunit was preserved. The mitochondrial ribosome is responsible for the translation of subunits of the mitochondrial oxidative phosphorylation machinery, and we found patient fibroblasts have a mild but significant decrease in the abundance of mitochondrial complex I. These data support a biochemical phenotype associated with MRPL50 variants. We validated the association of MRPL50 with the clinical phenotype by knockdown/knockout of mRpL50 in Drosophila, which resulted abnormal ovarian development. In conclusion, we have shown that a MRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function.

Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis

“…To gain insights into the mechanisms responsible for the increased specific activities, we assessed the relative complex abundance (RCA) 25 by grouping mitochondrial proteins quantified by proteomics in the liver of NCD-fed LMKO mice according to the macromolecular complexes to which they belong (Fig. 2H , Supplementary Dataset 2 ).…”

Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation

“…Indeed, mutations in mitoribosomal proteins lead to variable disease phenotypes ( Table S1 ). 16 , 21 , 22 , 23 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 To date, snMRP proteins associated with human disease are mS22, mS23, mS25, mS34, and mS39. 22 , 32 , 36 , 37 , 39 All reported patients have mitoribosome instability.…”

Premature ovarian insufficiency: a review on the role of oxidative stress and the application of antioxidants

“…Miao C et al (46) found that granulosa cell insufficiency in POI was associated with elevated ROS levels and reduced mitochondrial membrane potential (MMP) and adenosine triphosphate(ATP), suggesting considerable mitochondrial dysfunction. Moreover, Bakhshalizadeh S et al found that mitochondrial ribosomal protein L50 (MRPL50) error variants destabilize mitochondrial ribosomes, leading to oxidative phosphorylation deficiency and syndrome POI (47), highlighting the importance of mitochondrial support in ovarian development and function. Mitochondria are extremely abundant in the oocyte, not only providing energy but also acting as signal transduction hubs to regulate physiological activities such as intracellular signaling, calcium homeostasis, apoptosis and autophagy, which are essential for oocyte quality (48,49).…”