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

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.

Indispensable role of microbes in anticancer drugs and discovery trends.

Recent years have seen an increased focus on the advancement of naturally derived products for the treatment of cancer. Since the beginning of recorded history, nature has provided a variety of medicinal agents, and an overwhelming number of drugs that we have today are derived from natural sources. Such natural agents are prominently used to treat several diseases such as diabetes, malaria, Alzheimer's, pulmonary disorders, etc. with cancer being the highlight of this review. Due to the rapid development of resistance to chemotherapeutic drugs, the hunt for effective novel drugs is still a paramount concern in cancer treatment. Moreover, many chemotherapy drugs typically have high toxicity and adverse side effects, which necessitates the need to develop anti-tumor drugs that can be employed to treat deadly tumors with fewer negative effects on health and better efficacy. Isolation of several chemotherapeutic drugs has been conducted from a wide range of natural sources which include plants, microbes, fungi, and marine microorganisms. Considering the trends of previous decades, microbial diversity has grown to play a significant role in the formulation of pharmaceuticals and drugs, especially antibiotics and anti-cancer medications. Microbe-derived antitumor antibiotics such as anthracycline, epothilones, bleomycin, actinomycin, and staurosporine are amongst the widely used cancer chemotherapeutic agents. This review deals majorly with microbe-derived anticancer drugs taking into account their derivatives, mechanism of action, isolation procedures, limitations, and tumors targeted by them. This article also reports the phase of clinical study these drugs are undergoing. Moreover, it intends to portray the indispensable part that these microbes have been playing since time immemorial in the odyssey of chemotherapeutic agents. KEY POINTS: • Microbial diversity contributes heavily towards the formulation of anticancer drugs. • Polypeptides, carbohydrates, and alkaloids are prevalent microbe-based drug classes. • Microbe-derived anticancer agents target various sarcomas, carcinomas, and lymphomas.