mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations

Abstract

<jats:title>Abstract</jats:title> <jats:p>Mitochondria participate in metabolism and signaling. They adapt to the requirements of various cell types. Publicly available expression data permit to study expression dynamics of genes with mitochondrial function (mito-genes) in various cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for mito-genes. Here, we introduce the visual data mining platform mitoXplorer, which integrates expression and mutation data of mito-genes with a manually curated mitochondrial interactome containing ∼1200 genes grouped in 38 mitochondrial processes. User-friendly analysis and visualization tools allow to mine mitochondrial expression dynamics and mutations across various datasets from four model species including human. To test the predictive power of mitoXplorer, we quantify mito-gene expression dynamics in trisomy 21 cells, as mitochondrial defects are frequent in trisomy 21. We uncover remarkable differences in the regulation of the mitochondrial transcriptome and proteome in one of the trisomy 21 cell lines, caused by dysregulation of the mitochondrial ribosome and resulting in severe defects in oxidative phosphorylation. With the newly developed Fiji plugin mitoMorph, we identify mild changes in mitochondrial morphology in trisomy 21. Taken together, mitoXplorer (http://mitoxplorer.ibdm.univ-mrs.fr) is a user-friendly, web-based and freely accessible software, aiding experimental scientists to quantify mitochondrial expression dynamics.</jats:p>

Genotoxic stress in constitutive trisomies induces autophagy and the innate immune response via the cGAS-STING pathway

“…Gain of a chromosome was shown to cause genotoxic stress due to abnormal replication 3,19,20 , and we propose that this may be the reason for the accumulation of dsDNA in the cytosol of trisomic cells. The DNA may also originate from damaged mitochondria that are often found in trisomic cells 50 ; however, our data suggest rather a nuclear origin of the cytosolic DNA. Micronuclei arising from missegregation of chromosomes were previously reported to activate the cGAS-STING pathway and, subsequently, the NF-κB-mediated transcription [51][52][53] ; however, the used model trisomic cell lines do not missegregate chromosomes at a significantly higher rate than the parental diploids 20 .…”

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation and Cellular Bioenergetics in Human Down Syndrome Fibroblasts

“…We hypothesize that Down syndrome cells upregulate the 3-MST protein through the regulation of mRNA stability, and/or through various transcriptional mechanisms that may become activated in response to the presence of the additional 21 st chromosome in the cells, and/or through post-translational mechanisms (i.e., inhibition of 3-MST protein degradation), and/or through an increased transport of 3-MST into the mitochondria. Indeed, prior studies have shown that Down syndrome cells have significant disturbances in transcriptional and protein degradation and processing mechanisms, as well as in mitochondrial protein accumulation [32][33][34][35]. The above hypotheses describe conceivable potential mechanisms.…”

Pressure-Driven Mitochondrial Transfer Pipeline Generates Mammalian Cells of Desired Genetic Combinations and Fates

“…We then used the MitoXplorer pipeline ( Yim et al, 2020 ) to quantify the representation of 38 distinct mitochondrial processes within the identified DEGs. As anticipated from abolished respiration, BJ ρ0 fibroblasts showed DEGs for 29 mitochondrial processes compared to native BJ fibroblasts, especially within oxidative phosphorylation, mitochondrial genome translation, and amino acid metabolism processes ( Figure 5D ).…”