Nuclear encoded mitochondrial ribosomal proteins are required to initiate gastrulation

Abstract

Mitochondria are essential for energy production and although they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear-encoded mitochondrial proteins and in-depth characterization of mouse embryos mutant for the Mrp genes Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22. Loss of each MRP results in successful implantation and egg-cylinder formation, followed by severe developmental delay and failure to initiate gastrulation by embryonic day 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pregastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are crucial at specific time points during mammalian development. This article has an associated 'The people behind the papers' interview.

Role of Mitochondria in Viral Infections

“…The mitochondrial genome is comprised of 37 genes that encode 13 polypeptides (ETC essential genes), 2 rRNA genes (12S and 16S rRNA), and 22 tRNA genes required for mitochondrial protein synthesis [ 22 ]. The remaining mitochondrial proteins are encoded by nuclear genes and approximately 1500 nuclear encoded proteins are involved in regulating mitochondrial functions in humans [ 23 , 24 ].…”

The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development

“…Heart development involves complex morphological changes that are tightly and accurately regulated (Bruneau and Srivastava, 2014;Kathiriya et al, 2015). It is increasingly appreciated that mitochondrial function and metabolism play a crucial role in the maturation of cardiomyocytes and heart development (Cheong et al, 2020;Hom et al, 2011;Larsson et al, 1998). However, compared with postnatal cardiomyocytes, the understanding of mitochondrial metabolism and regulation in prenatal cardiomyocytes is largely lacking, and is derived from very limited studies and literature.…”

CLPX regulates erythroid heme synthesis by control of mitochondrial heme synthesis enzymes and iron utilization

“…Although this structure is conserved in vertebrates, there are several reports that CLPX has roles that are distinct from its function in CLPXP mediated proteolysis (Cheong et al, 2020;Kardon et al, 2015;Seo et al, 2016;Wang et al, 2018). This is most strikingly illustrated by the fact that Clpx -/-mouse embryos die by E8.5 with severe gastrulation defects (Cheong et al, 2020), while Clpp -/-mice survive to adulthood (Wang et al, 2018). Our data adds to studies that demonstrate that CLPX has roles that are independent of its function within the CLPXP proteolytic complex.…”

“…The CLPXP proteolytic complex, which has been extensively studied in bacteria, consists of an ATP-dependent CLPX subunit which unfolds and translocates protein substrates into a CLPP proteolytic barrel, which then degrades unfolded protein substrates (Olivares et al, 2016). Although this structure is conserved in vertebrates, there are several reports that CLPX has roles that are distinct from its function in CLPXP mediated proteolysis (Cheong et al, 2020;Kardon et al, 2015;Seo et al, 2016;Wang et al, 2018). This is most strikingly illustrated by the fact that Clpx -/-mouse embryos die by E8.5 with severe gastrulation defects (Cheong et al, 2020), while Clpp -/-mice survive to adulthood (Wang et al, 2018).…”