Mitochondrial DNA Breaks Activate an Integrated Stress Response to Reestablish Homeostasis

Fu, Yi; Kanshin, Evgeny; Ueberheide, Beatrix; Sfeir, Agnel

doi:10.1101/2022.10.01.510431

Cited by 3 publications

(2 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the involvement of such responses in mtDNA damage is not known. Koczor et al, did observe CHK2 activation in response to increased ROS production in HeLa cells [162] . This response was deactivated when mtDNA-associated BER proteins were overexpressed, suggesting a link between mtDNA integrity and DNA damage checkpoint activation.…”

Section: Future Perspectivesmentioning

confidence: 95%

Mechanisms regulating mitochondrial DNA quality control

Dua¹,

Badrinarayanan²

2023

J Transl Genet Genom

View full text Add to dashboard Cite

Maintenance of genome integrity is essential for cellular survival. There are mechanisms utilized by the cells to sense and respond to assaults on genomic DNA. These mechanisms are conserved across all domains of life and are collectively called the DNA damage response pathways. However, eukaryotic cells also have extrachromosomal DNA in mitochondria (mtDNA), which is indispensable for mitochondrial function, and hence cell survival. Indeed, impaired mitochondrial activity arising due to mutations in mtDNA has been found to be associated with many human pathologies. Despite its importance, our understanding of how cells ensure mtDNA genome integrity is limited. Since mitochondria do not encode for machinery required for the maintenance of their own genomes, they depend on the nucleus for replication, transcription, and repair processes. This adds a layer of complexity with the requirement for organelle crosstalk and coordination in response to mtDNA damage. This review summarizes recent findings that provide new insights into mechanisms involved in mtDNA quality control, acting at the level of mtDNA or organelle and also discusses a few new avenues of research towards a comprehensive understanding of the “mtDNA damage response”.

show abstract

Section: Future Perspectivesmentioning

confidence: 95%

Mechanisms regulating mitochondrial DNA quality control

Dua¹,

Badrinarayanan²

2023

J Transl Genet Genom

View full text Add to dashboard Cite

show abstract

“…We then asked whether the accumulation of mitochondrial precursors in CCCP/valinomycin-treated cells is controlled at the translational level. The ISR is induced by various mitochondrial stressors in mammalian cells, including CCCP 16,[34][35][36][37][38] . ISR activation leads to enhanced phosphorylation of eIF2α and subsequent attenuation of global translation 15,35 .…”

Section: Activation Of the Integrated Stress Response Prevents Accumu...mentioning

confidence: 99%

ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

Kim,

Goldstein,

Zecchel

et al. 2023

Preprint

View full text Add to dashboard Cite

Mitochondria require the constant import of nuclear-encoded proteins for proper functioning. Impaired protein import not only depletes mitochondria of essential factors but also leads to toxic accumulation of un-imported proteins outside the organelle. Defects in mitochondrial protein import are associated with neurodegenerative and bioenergetic diseases. Here, we investigated the consequences of mitochondrial protein import stress in human cells. We demonstrated that un-imported proteins can clog the mitochondria by stalling inside the translocase of the outer membrane (TOM). We found that the integrated stress response (ISR) acted as the first line of defense to mitochondrial clogging by attenuating global protein translation and preventing excessive accumulation of un-imported proteins. A second mechanism, mediated by a mitochondrial ATPase, ATAD1, acted specifically to remove proteins from TOM and clear the entry gate into the mitochondria. ATAD1 interacted with both TOM and stalled proteins, and its knockout resulted in extensive accumulation of mitochondrial precursors as well as decreased protein import. Increased ATAD1 expression improved tolerance of cells to defective mitochondrial protein import, demonstrating the importance of this quality control pathway in surveilling protein import and its contribution to cellular health.

show abstract

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

Lopez-Nieto,

Sun,

Relton

et al. 2023

Preprint

View full text Add to dashboard Cite

To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that SGs and UPRmt pathways are intertwined and communicate with each other. UPRmt induction results in eIF2α phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. We show that the induction of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial respiration is enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that may contribute to restoring mitochondrial functions under stressful conditions.

show abstract

Mitochondrial DNA Breaks Activate an Integrated Stress Response to Reestablish Homeostasis

Cited by 3 publications

References 75 publications

Mechanisms regulating mitochondrial DNA quality control

Mechanisms regulating mitochondrial DNA quality control

ATAD1 and the integrated stress response prevent clogging of TOM and damage caused by un-imported mitochondrial proteins

Activation of the mitochondrial unfolded protein response regulates the formation of stress granules

Contact Info

Product

Resources

About