Biology subjects

Owusu-Ansah, E.

Publications and source records attributed to Owusu-Ansah, E..

5 recordsLinked to original sources

bioRxiv2022

A Ferroptosis-mediated regulation of the biogenesis of the oxidative phosphorylation system

Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI; but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that when the mitochondrial NADPH-generating enzyme - Isocitrate Dehydrogenase 2 - is genetically disrupted, ROS levels are elevated and assembly of the oxidative phosphorylation system (OXPHOS) is impaired. Mechanistically, this begins with a ROS-mediated inhibition of biosynthesis of the matrix domain of CI, which progresses to a point where ferroptotic signals are induced, the mitochondrial unfolded protein response is activated and multiple OXPHOS complexes are impaired. Disruption of other enzymes that eliminate hydrogen peroxide, but not those that eliminate the superoxide radical, recapitulates the phenotype; implicating hydrogen peroxide as the signaling molecule involved. Thus, the redox status of the mitochondrion modulates the assembly of the matrix domain of CI and ultimately that of the entire OXPHOS.

cell biology↗

bioRxiv2021

Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimers disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.

cell biology↗

bioRxiv2021

Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors

Tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (-3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

cancer biology↗

bioRxiv2021

The Mitochondrial Calcium Uniporter of Pulmonary Type 2 Cells Determines Severity of ARDS

Acute lung immunity to inhaled pathogens elicits defensive pneumonitis that may convert to the Acute Respiratory Distress Syndrome (ARDS), causing high mortality. Mechanisms underlying the conversion are not understood, but are of intense interest because of the ARDS-induced mortality in the ongoing Covid-19 pandemic. Here, by optical imaging of live lungs we show that key to the lethality is the functional status of mitochondrial Ca2+ buffering across the mitochondrial Ca2+ uniporter (MCU) in the lungs alveolar type 2 cells (AT2), which protect alveolar stability. In mice subjected to ARDS by airway exposure to lipopolysaccharide (LPS), or to Pseudomonas aeruginosa, there was marked loss of MCU expression in AT2. The ability of mice to survive ARDS depended on the extent to which the MCU expression recovered, indicating that the viability of Ca2+ buffering by AT2 mitochondria critically determines ARDS severity. Mitochondrial transfer to enhance AT2 MCU expression might protect against ARDS.

physiology↗

bioRxiv2019

Cyb5r3 links FoxO1-dependent mitochondrial dysfunction with β-cell failure

ObjectiveDiabetes is characterized by pancreatic {beta}-cell dedifferentiation. Dedifferentiating {beta}-cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the {beta}-cells response to an adverse metabolic environment with impaired mitochondrial function remains unclear.\n\nMethodsHere we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to {beta}-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and NAD/NADH ratios.\n\nResultsExpression of Cyb5r3 is decreased in FoxO1-deficient {beta}-cells. Mice with {beta}-cell-specific deletion of Cyb5r3 have impaired insulin secretion resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient {beta}-cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient {beta}-cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability.\n\nConclusionsThe findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate {beta}-cell failure.

molecular biology↗