Primary Coenzyme Q Deficiency in Pdss2 Mutant Mice Causes Isolated Renal Disease

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2kd/kd genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2kd/kd mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2loxP/loxP knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2loxP/loxP knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment

Human Placental Transcriptome Reveals Critical Alterations in Inflammation and Energy Metabolism with Fetal Sex Differences in Spontaneous Preterm Birth

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB

A mitochondrial DNA variant of the COX-1 subunit of C. elegnas’ complex IV significantly alters mitochondrial energy metabolism of geographically divergent wild isolates.

Mitochondrial DNA (mtDNA) sequence variation is increasingly recognized to influence the penetrance of complex diseases and climatic adaptation in mammals, although little is known about its influence on invertebrate species’ adaptation to unique geographic niches. We investigated whether natural variation in mtDNA-encoded respiratory chain subunits alters the inherent mitochondrial energy capacity of wild C. elegans isolates to match local environmental energy demands. We found that relative to the classic N2 Bristol (England) wild-type strain, CB4856 wild isolates from a warmer and more equatorial native climate (Hawaii) had a unique A12S amino acid substitution in the N-terminal string of the COX-1 core catalytic subunit of complex IV. In silico modeling predicted that the A12S substitution increased MAPK-1 kinase binding affinity, which would increase COX-1 subunit phosphorylation in CB4856. Indeed, the CB4856 worms had significantly increased mitochondrial complex IV enzyme activity relative to N2 Bristol. While CB4856 had equivalent amounts of complex IV, mitochondria, and respiratory chain supercomplexes, its integrated mitochondrial respiratory capacity and membrane potential was significantly reduced when grown at 20°C. CB4856 also had significantly reduced lifespan and increased oxidative stress when grown at 20°C. Interestingly, the mitochondrial membrane potential of CB4856 was significantly increased relative to that of N2 Bristol when grown at its native temperature of 25°C degrees. To determine the effects of only the COX-1 sequence variant without possible contribution from the CB4856 nuclear genome background, we generated a transmitochondrial cybrid worm strain, chpIR(M,N2\u3eCB4856), containing the CB4856 mtDNA in the N2 Bristol wild-type nuclear background. This strain also had increased CIV activity, which supports that the A12S mtDNA variant is causative of the increased CIV activity of CB4856 relative to N2 Bristol. Differences in comparative functional analyses among the three strains further suggest their nuclear background also modulates mitochondrial function. The cybrid C. elegans strain also had reduced lifespan relative to CB4856, highlighting the importance of precise co-evolution of mitochondrial and nuclear genomes. Overall, these data show that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA-encoded sequence alterations that modulate critical aspects of mitochondrial energy metabolism

Primary coenzyme Q deficiency in Pdss2 mutant mice causes isolated renal disease.

Coenzyme Q (CoQ) is an essential electron carrier in the respiratory chain whose deficiency has been implicated in a wide variety of human mitochondrial disease manifestations. Its multi-step biosynthesis involves production of polyisoprenoid diphosphate in a reaction that requires the enzymes be encoded by PDSS1 and PDSS2. Homozygous mutations in either of these genes, in humans, lead to severe neuromuscular disease, with nephrotic syndrome seen in PDSS2 deficiency. We now show that a presumed autoimmune kidney disease in mice with the missense Pdss2(kd/kd) genotype can be attributed to a mitochondrial CoQ biosynthetic defect. Levels of CoQ9 and CoQ10 in kidney homogenates from B6.Pdss2(kd/kd) mutants were significantly lower than those in B6 control mice. Disease manifestations originate specifically in glomerular podocytes, as renal disease is seen in Podocin/cre,Pdss2(loxP/loxP) knockout mice but not in conditional knockouts targeted to renal tubular epithelium, monocytes, or hepatocytes. Liver-conditional B6.Alb/cre,Pdss2(loxP/loxP) knockout mice have no overt disease despite demonstration that their livers have undetectable CoQ9 levels, impaired respiratory capacity, and significantly altered intermediary metabolism as evidenced by transcriptional profiling and amino acid quantitation. These data suggest that disease manifestations of CoQ deficiency relate to tissue-specific respiratory capacity thresholds, with glomerular podocytes displaying the greatest sensitivity to Pdss2 impairment

Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease

Corner of Marguerite Street and A Z Berman Drive, Lentegeur, Mitchell's Plain, Cape Town. In an area developed in the 1970s as a coloured area, to provide housing to those removed from their homes by the Group Areas Act. Many families from District Six relocated here when their community was razed.distant view, southwest elevation of mosque under construction, with school at right, 198

Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring

BACKGROUND: Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE: We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS: Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10 mu g/kg/d-LowerB and 10 mg/kg/d-UpperB). RESULTS: Both doses of BM significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and-UpperB induced islet inflammation in male 1 offspring that persisted into the next generation. We also observed close-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced beta-cell mass and increased beta-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important beta-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION: These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications