Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction
| Autor: | Patricia L. Opresko, Simon C. Watkins, Namrata Kumar, Dmytro Kolodieznyi, Vera Roginskaya, Marcel P. Bruchez, Elise Fouquerel, Bennett Van Houten, Wei Qian, Sruti Shiva |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Mitochondrial ROS
Mitochondrial DNA Mitochondrial Diseases DNA Repair Apoptosis Oxidative phosphorylation Mitochondrion medicine.disease_cause DNA damage response DNA Mitochondrial singlet oxygen Membrane Potentials 03 medical and health sciences 0302 clinical medicine ATM signaling Superoxides medicine Humans DNA Breaks Double-Stranded 030304 developmental biology Cell Proliferation chemistry.chemical_classification 0303 health sciences Reactive oxygen species telomere Multidisciplinary Chemistry Cell Cycle Cell Biology Hydrogen Peroxide Biological Sciences Telomere Nuclear DNA Cell biology Mitochondria Oxygen Oxidative Stress HEK293 Cells PNAS Plus Reactive Oxygen Species Tumor Suppressor p53-Binding Protein 1 030217 neurology & neurosurgery Oxidative stress DNA Damage Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance It is highly controversial whether secondary reactive oxygen species generated by dysfunctional mitochondria are able to diffuse across the cytoplasm to the nucleus and cause subsequent nuclear changes. We have developed a targeted chemoptogenetic technology to induce mitochondrial dysfunction by generating short-lived highly reactive singlet oxygen exclusively in the mitochondria, with precise spatiotemporal control by light stimulation. Through careful analysis of the events involving mitochondrial dysfunction and subsequent nuclear oxidative stress that resulted in specific telomere damage, we delineated the mechanism of mitochondria–telomere axis of cellular damage. Our findings revealed a fundamental mechanism underlying the pathophysiological role of mitochondrial singlet oxygen, with important ramifications for understanding the role of mitochondrial signaling in aging and cancer among other human diseases. Reactive oxygen species (ROS) play important roles in aging, inflammation, and cancer. Mitochondria are an important source of ROS; however, the spatiotemporal ROS events underlying oxidative cellular damage from dysfunctional mitochondria remain unresolved. To this end, we have developed and validated a chemoptogenetic approach that uses a mitochondrially targeted fluorogen-activating peptide (Mito-FAP) to deliver a photosensitizer MG-2I dye exclusively to this organelle. Light-mediated activation (660 nm) of the Mito-FAP–MG-2I complex led to a rapid loss of mitochondrial respiration, decreased electron transport chain complex activity, and mitochondrial fragmentation. Importantly, one round of singlet oxygen produced a persistent secondary wave of mitochondrial superoxide and hydrogen peroxide lasting for over 48 h after the initial insult. By following ROS intermediates, we were able to detect hydrogen peroxide in the nucleus through ratiometric analysis of the oxidation of nuclear cysteine residues. Despite mitochondrial DNA (mtDNA) damage and nuclear oxidative stress induced by dysfunctional mitochondria, there was a lack of gross nuclear DNA strand breaks and apoptosis. Targeted telomere analysis revealed fragile telomeres and telomere loss as well as 53BP1-positive telomere dysfunction-induced foci (TIFs), indicating that DNA double-strand breaks occurred exclusively in telomeres as a direct consequence of mitochondrial dysfunction. These telomere defects activated ataxia-telangiectasia mutated (ATM)-mediated DNA damage repair signaling. Furthermore, ATM inhibition exacerbated the Mito-FAP–induced mitochondrial dysfunction and sensitized cells to apoptotic cell death. This profound sensitivity of telomeres through hydrogen peroxide induced by dysregulated mitochondria reveals a crucial mechanism of telomere–mitochondria communication underlying the pathophysiological role of mitochondrial ROS in human diseases. |
| Databáze: | OpenAIRE |
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