Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction

Furda, Amy M.; Marrangoni, Adele; Lokshin, Anna; Houten, Bennett Van

doi:10.1016/j.dnarep.2012.06.002

Cited by 88 publications

(90 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The model is consistent with the observations of Yakes and Van Houten (1997), who found that oxidative stress promoted a higher incidence of polymerase-blocking strand breaks and abasic sites in mtDNA than in nDNA. Recent studies using qPCR for the analysis of mtDNA provide further support for the notion of mtDNA degradation in response to oxidative stress (Rothfuss et al 2010;Furda et al 2012). Therefore, degradation of severely damaged mtDNA emerges as a unique, mitochondria-specific mechanism for the maintenance of DNA integrity.…”

Section: Mtdna Degradationmentioning

confidence: 91%

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Alexeyev

Shokolenko

Wilson

et al. 2013

Cold Spring Harbor Perspectives in Biology

374

342

View full text Add to dashboard Cite

DNA molecules in mitochondria, just like those in the nucleus of eukaryotic cells, are constantly damaged by noxious agents. Eukaryotic cells have developed efficient mechanisms to deal with this assault. The process of DNA repair in mitochondria, initially believed nonexistent, has now evolved into a mature area of research. In recent years, it has become increasingly appreciated that mitochondria possess many of the same DNA repair pathways that the nucleus does. Moreover, a unique pathway that is enabled by high redundancy of the mitochondrial DNA and allows for the disposal of damaged DNA molecules operates in this organelle. In this review, we attempt to present a unified view of our current understanding of the process of DNA repair in mitochondria with an emphasis on issues that appear controversial.

show abstract

Section: Mtdna Degradationmentioning

confidence: 91%

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Alexeyev

Shokolenko

Wilson

et al. 2013

Cold Spring Harbor Perspectives in Biology

374

342

View full text Add to dashboard Cite

show abstract

“…Damaged mtDNA molecules are degraded and replaced by newly synthesized DNA molecules using undamaged mtDNA copies as templates. Indeed, recently it has been shown that, in contrast to nDNA, degradation of unrepairable mtDNA, present in hundreds to thousands of copies per cell, represents a specific mitochondrial repair mechanism in response to OS [158,162,163]. Nevertheless, over the years, this view has changed and at present it is widely accepted that mammalian mitochondria possess almost all known nuclear DNA repair pathways, including base excision repair (BER), SSB repair, mismatch repair, and possibly homologous recombination (HR) and nonhomologous end joining (NHEJ) [23, [164][165][166][167].…”

Section: Mitochondrial Dna Repair Pathwaysmentioning

confidence: 99%

Mitochondrial DNA maintenance: an appraisal

Akhmedov

Marı́n-Garcı́a

2015

Mol Cell Biochem

View full text Add to dashboard Cite

Mitochondria play a crucial role in a variety of cellular processes ranging from energy metabolism, generation of reactive oxygen species (ROS), and Ca(2+) handling to stress responses, cell survival, and death. Malfunction of the organelle may contribute to the pathogenesis of neuromuscular disorders, cancer, premature aging, and cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Mitochondria are unique as they contain their own genome organized into DNA-protein complexes, so-called mitochondrial nucleoids, along with multiprotein machineries, which promote mitochondrial DNA (mtDNA) replication, transcription, and repair. Although the organelle possesses almost all known nuclear DNA repair pathways, including base excision repair, mismatch repair, and recombinational repair, the proximity of mtDNA to the main sites of ROS production and the lack of protective histones may result in increased susceptibility to oxidative stress and other types of mtDNA damage. Defects in the components of these highly organized machineries, which mediate mtDNA maintenance (replication and repair), may result in accumulation of point mutations and/or deletions in mtDNA and decreased mtDNA copy number impairing mitochondrial function. This review will focus on the mechanisms of mtDNA maintenance with emphasis on the proteins implicated in these processes and their functional role in various disease conditions and aging.

show abstract

“…Shimada et al [36] then found that mitochondrial dysfunction correlates with NLRP3 inflammasome activity, with binding of oxidized mtDNA a required step in NLRP3 inflammasome activation and IL-1β [36]. These results provide an unusual mechanism of inflammasome activation: while mtDNA damage is increasingly appearing as a common form of mitochondrial damage in a variety of cellular settings [37,38], it is unclear how a highly packaged, compacted circle of DNA [39,40] is released from a double membrane-bound organelle into the cytoplasm. Future research will undoubtedly shed new light on how mtDNA escapes the organelle to participate in inflammatory signaling.…”

Section: Mitochondria In Nlrp3 Inflammasome Signalingmentioning

confidence: 99%

Untitled

2014

CIIT

View full text Add to dashboard Cite

Inflammation is a crucial mechanism of innate immune response. Macrophages and neutrophils recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), undergoing a complex set of signaling interactions to release pro-inflammatory cytokines (most notably that prompt inflammatory response. To mediate innate immune response, pattern-recognition receptors (PRRs) recognize a broad range of markers of infection, stress, and damage. PRRs include membrane-bound receptors such as Toll-like receptors (TLRs), the interleukin receptors (ILRs), and the tumor necrosis factor receptors 1 (TNF-R1) and 2 (TNF-R2). Upon binding of extracellular ligands, these PRRs activate intracellular signaling events, such as activation of NFκB, a transcription factor that upregulates expression of a wide variety of stress-response genes, or through post-translational modification such as activation of c-Jun amino-terminal kinase (JNK) [2] to effect inflammatory response. Within the cytoplasm, inflammatory ligands bind and activate intracellular PRRs that combine with a variety of associated factors to form large cytoplasmic scaffolding assemblies that integrate inflammatory activation and activate secretion of the major cytokines IL-1β and IL-18 by binding and activating caspase-1 [3] (Figure 1). These cytoplasmic PRRs, classed as nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs), recognize a wide variety of intracellular inflammatory stimuli. Four classes of NLRs (NLRP1, NLRP3, NLRC4 and AIM2) share in common a nucleotide-binding oligomerization domain, and have demonstrated an ability to form large oligomeric inflammasome complexes in the cytoplasm [4]. While each of the four sense a variety of inflammatory signals to mediate caspase-dependent activation of inflammation, the NLRP3 inflammasome is the best characterized.Plasma membrane PRRs TLR, ILR, and TNF-R (red boxes) bind cytokines and extracellular ligands, activating NFκB and JNK, which activate nuclear transcription of cellular stress factors, particularly NLRP3. NLRP3 (blue), ASC (gold), and caspase-1 (purple) associate in the cytoplasm as the large, macromolecular NLRP3 inflammasome in macrophages. Mitochondria are impacted by membrane-bound PRR signals and aid in activating the NLRP3 inflammasome (via Gilkerson R and Materon L, J Clin Immunol Immunother 2014, 1: 004 DOI: 10.24966/CIIT-8844/100004 HSOA Journal of Clinical Immunology and Immunotherapy Review Article AbstractAs the complexity of cellular signaling in inflammatory response emerges, it is increasingly clear that mitochondria are directly involved in, and in some cases are even required for, activation of inflammatory response. As a bioenergetic organellar network, mitochondria dynamically modulate their organization and function in response to cellular signaling cues and metabolic demand. The NLRP3 inflammasome, a caspase-activating multifactor scaffolding assembly, is directly activated by mitochondrial factors and functional parameters. Mit...

show abstract

Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction

Cited by 88 publications

References 46 publications

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Mitochondrial DNA maintenance: an appraisal

Untitled

Contact Info

Product

Resources

About