Investigating the response of mitochondrial transcriptional regulation to environmental cues: potential insights for the soldier in routine security missions and in the battlefield
Abstract
The mitochondria are the major energy providers of our cells. Hence, it is not surprising that during the ~2 billion years that passed since the event of endosymbiosis these organelles have adapted to allow response to diverse environmental conditions encountered by different tissues, different human populations, and different species. With this in mind, field troops in the US army, in contrast to most national armies, are posted worldwide in different environmental conditions, that in some cases are extreme. Such exposure to challenging combat zones in extreme conditions for variable periods, will most likely leave its signature on the physiological and regulatory levels of soldiers. Although mitochondria are pivotal in the ability of cells to cope with different environmental stresses, the regulatory basis of their response to such stresses is frequently overlooked. We have recently been funded by the Life Sciences division of the US army to explore the regulatory cross talk of the unique bi-genomic (mito-nuclear) mitochondrial genetic system in response to stressful conditions, such as those encountered in the battlefield. In the frame of the funded study, we identified the coordination between mitochondrial and nuclear DNA gene expression across human tissues; we found in vivo quantitative and qualitative variation in mitochondrial DNA (mtDNA) transcription (using PRO-seq) among human tissues and multicellular organisms, and discovered conserved mtDNA higher order organization, which is formed during mammalian embryogenesis. These results, in addition to our previous discovery of in vivo mtDNA binding by known transcription regulators of nuclear genes (such as c-Jun, JunD and C/EBPB) that are also imported into the mitochondria, suggest that mtDNA transcriptional regulation is more complex than once thought. Hence, we challenge a 50 years old notion, and argue that (A) mtDNA transcription is not governed solely by dedicated factors, and (B) regulatory elements could be throughout the mtDNA, even within coding region. In support of these challenges, our preliminary results show that the above-mentioned transcription regulators (such as c-Jun, JunD and C/EBPB), not only bind the mtDNA within genes, but also modulate its transcription either as potential repressors (c-Jun and C/EBPB) or as positive modulator (JunD). Second, while assessing in vivo impact of mitochondria-related environmental stresses on mtDNA regulation in human cells, we found partial premature termination of mtDNA light strand transcription in response to hypoxia around mtDNA position 9000, which does not correspond to any known regulatory element. We therefore hypothesize, that mtDNA transcription regulation as a whole, and its response to environmental cues, require additional factors to the known core regulatory factors. To address this hypothesis, we designed the following objectives: (A) investigate the mechanism by which c-Jun and JunD modulate mtDNA transcription including initiation, elongation and termination, (B) investigate the impact of these factors on modulating mtDNA gene expression in response to environmental cues, and (C) assess mito-nuclear gene expression coordination in hypoxia and normal conditions during evolution. To achieve these goals, we will employ a combination of functional genomics techniques (such as PRO-seq, RNA-seq and ATAC-seq), gene manipulation in cell culture, molecular biology and computational biology approaches We believe that our study design will not only shed light on the mechanism underlying the regulation of mitochondrial gene expression and coordination with the nucleus but will also set the basis to better understanding its response to environmental cues (such as hypoxia, sharp changes in temperatures) encountered by field soldiers. Our results will potentially enable future design of treatments to soldiers which are differentially sensitive to such conditions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 20, 2022
- Source ID
- W911NF2210242
Entities
People
- Dan Mishmar
Organizations
- Army Contracting Command
- Ben-Gurion University of the Negev
- United States Army