DNA damage related crosstalk between the nucleus and mitochondria

Saki, Mohammad; Prakash, Aishwarya

doi:10.1016/j.freeradbiomed.2016.11.050

Cited by 125 publications

(111 citation statements)

References 251 publications

(265 reference statements)

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“…In addition, it is intuitive that mitochondria sense energy sources and communicate to nuclei to assess and respond to energetic needs. Although numerous molecules have been implicated in this bidirectional communication (32, 49–51), the relative importance of each and context dependency have not yet been defined. Although topics of compelling interest, we have not yet defined parameters associated with mitochondrial localization, mitochondrial shape, or fission/fusion in the MNX models.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

et al. 2017

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Using a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P < 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

et al. 2017

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“…As a coenzyme, NAD regulates electron transport and the TCA cycle in the mitochondria. It also regulates glycolysis [53, 318, 406]. NAD+ serves as a substrate for two families of proteins involved in response to the DNA damage.…”

Section: Disparity At the Level Of Mitochondria-to-nucleus Cross Tmentioning

confidence: 99%

“…NAD+ serves as a substrate for two families of proteins involved in response to the DNA damage. These proteins include the PARP family and the sirtuin family of NAD+-dependent deacetylases (SIRTs) [278, 318]. …”

Section: Disparity At the Level Of Mitochondria-to-nucleus Cross Tmentioning

confidence: 99%

“…PARPs utilize NAD+ as a substrate and transfer the ADP-ribose moiety of NAD+ to acceptor proteins. PARP1 and PARP2 are then auto-PARylated, and further recruit and PARylate other repair enzymes [34, 47, 315, 318]. PARP1, which localize to the mitochondria [311], PARylate POLG and EXOG and, in contrast to its function in the nucleus, inhibit BER [355].…”

Section: Disparity At the Level Of Mitochondria-to-nucleus Cross Tmentioning

confidence: 99%

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Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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“…As such, damage to some genomes can be compensated by others; thus, the full complement of repair pathways in mitochondria might not be necessary. Furthermore, it would appear that some forms of damaged mitochondrial genomes can be removed by mitophagy [5]. Evidence from many studies indicates that the primary DNA repair activity in mammalian mitochondria is base excision repair (BER), which removes oxidative DNA lesions, single strand breaks and alkylated bases.…”

Section: Introductionmentioning

confidence: 99%

POLB: A new role of DNA polymerase beta in mitochondrial base excision repair

Kaufman

Houten

2017

DNA Repair

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The mitochondrial genome is a matrilineally inherited DNA that encodes numerous essential subunits of the respiratory chain in all metazoans. As such mitochondrial DNA (mtDNA) sequence integrity is vital to organismal survival, but it has a limited cadre of DNA repair activities, primarily base excision repair (BER). We have known that the mtDNA is significantly oxidized by both endogenous and exogenous sources, but this does not lead to the expected preferential formation of transversion mutations, which suggest a robust base excision repair (BER) system. This year, two different groups reported compelling evidence that what was believed to be exclusively nuclear DNA repair polymerase, POLB, is located in the mitochondria and plays a significant role in mitochondrial BER, mtDNA integrity and mitochondrial function. In this commentary, we review the findings and highlight remaining questions for the field.

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DNA damage related crosstalk between the nucleus and mitochondria

Cited by 125 publications

References 251 publications

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner

Mitochondrial determinants of cancer health disparities

POLB: A new role of DNA polymerase beta in mitochondrial base excision repair

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