Browsing by Author "Moreno, Armando"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Examining Sporadic Cancer Mutations Uncovers a Set of Genes Involved in Mitochondrial Maintenance
    (MDPI, 2023) Moreno, Armando; Taffet, Allison; Tjahjono, Elissa; Anderson, Quinton L.; Kirienko, Natalia V.
    Mitochondria are key organelles for cellular health and metabolism and the activation of programmed cell death processes. Although pathways for regulating and re-establishing mitochondrial homeostasis have been identified over the past twenty years, the consequences of disrupting genes that regulate other cellular processes, such as division and proliferation, on affecting mitochondrial function remain unclear. In this study, we leveraged insights about increased sensitivity to mitochondrial damage in certain cancers, or genes that are frequently mutated in multiple cancer types, to compile a list of candidates for study. RNAi was used to disrupt orthologous genes in the model organism Caenorhabditis elegans, and a series of assays were used to evaluate these genes’ importance for mitochondrial health. Iterative screening of ~1000 genes yielded a set of 139 genes predicted to play roles in mitochondrial maintenance or function. Bioinformatic analyses indicated that these genes are statistically interrelated. Functional validation of a sample of genes from this set indicated that disruption of each gene caused at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of NADH or ROS, or altered oxygen consumption. Interestingly, RNAi-mediated knockdown of these genes often also exacerbated α-synuclein aggregation in a C. elegans model of Parkinson’s disease. Additionally, human orthologs of the gene set showed enrichment for roles in human disorders. This gene set provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.
  • Thumbnail Image
    Item
    Uncovering Genes Responsible for Mitochondrial Maintenance and Surveillance
    (2023-07-27) Moreno, Armando; Kirienko, Natasha
    Mitochondria are key organelles for cellular health and metabolism and the activation of programmed cell death processes. Although pathways for regulating and re-establishing mitochondrial homeostasis have been identified over the past twenty years, the consequences of disrupting genes that regulate other cellular processes, such as division and proliferation on affecting mitochondrial function remain unclear. Using a cancer cell line mutation database, I developed a set of 139 genes in Caenorhabditis elegans predicted to play roles in mitochondrial maintenance or function. Disruption of a sample of genes from this set caused phenotypes consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of NADH, or ROS, or altered oxygen consumption. RNAi-mediated knockdown of these genes often also exacerbated α-synuclein aggregation in a C. elegans model of Parkinson’s disease. This gene set provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis and can be potentially used in targeted therapeutics of diseases such as cancer and neurodegenerative disease. In addition to the genes mentioned above, mitochondrial surveillance mechanisms are also essential for healthy mitochondrial function. These mechanisms are in place to ameliorate the deleterious effects of faulty protein import, increase in oxidative stress, and bioenergetic disruption. While some regulators for the ESRE (Ethanol and Stress Response Element) mitochondrial surveillance network have been identified in the past, a transcription factor specific to ESRE regulation has not been identified. Through a high-throughput screen, I discovered F23B12.7, a bZIP transcription factor, as an ESRE regulator. F23B12.7 is necessary for proper ESRE activation in C. elegans and is necessary for survival during Pseudomonas aeruginosa infection. This transcription factor is also necessary for protection against mitochondrial damaging agents such 1,10-Phenanthroline. F23B12.7 also shows regulation of both box C/D and box H/ACA snoRNP complexes (known for their role in ribosome biogenesis). This discovery opens a new avenue of research of the interplay between ribosomal biogenesis and mitochondrial health. Further understanding of these mitochondrial surveillance networks will also provide insight into how these mechanisms react to stress or infection and can be potential targets of treatment for mitochondrial related diseases.