Do mitochondrial DNA fragments promote cancer and aging?

Richter, Christoph

doi:10.1016/0014-5793(88)81018-4

Cited by 211 publications

(79 citation statements)

References 81 publications

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“…8-OHdG is present in hepatic mtDNA at 16-fold higher levels than in corresponding nuclear DNA (Richter, 1988;Richter et al, 1988). In human hearts, similar observations were made (Hayakawa et al, 1992).…”

Section: Mutations Of Mtdna: the Third Stepsupporting

confidence: 64%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

156

111

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Section: Mutations Of Mtdna: the Third Stepsupporting

confidence: 64%

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Lewis

Copeland

Day

2001

Laboratory Investigation

156

111

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“…Historically, aberrant mitochondrial activity has been recognized as a consistent occurrence associated with the process of carcinogenesis and metastatic progression [34][35][36][37][38][39][40][41][42]. Additionally, mitochondria display abnormal genotypic and phenotypic characteristics within the context of multiple non-cancer diseases and aging [43].…”

Section: Discussionmentioning

confidence: 99%

Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function

Dement

Maloney

Reeves

2007

Experimental Cell Research

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We have previously demonstrated that HMGA1 proteins translocate from the nucleus to mitochondria and bind to mitochondrial DNA (mtDNA) at the D-loop control region [11]. To elucidate possible physiological roles for such binding, we employed methods to analyze mtDNA transcription, mitochondrial maintenance and other organelle functions in transgenic human MCF-7 cells (HA7C) induced to over-express an HA-tagged HMGA1 protein and control (parental) MCF-7 cells. Quantitative real-time (RT) PCR analyses demonstrated that mtDNA levels were reduced approximately 2-fold in HMGA1 over-expressing HA7C cells and flow cytometric analyses further revealed that mitochondrial mass was significantly reduced in these cells. Cellular ATP levels were also reduced in HA7C cells and survival studies showed an increased sensitivity to killing by 2-deoxy-D-glucose, a glycolysis-specific inhibitor. Flow cytometric analyses revealed additional mitochondrial abnormalities in HA7C cells that are consistent with a cancerous phenotype: namely, increased reactive oxygen species (ROS) and increased mitochondrial membrane potential (Δψ m ). Additional RT-PCR analyses demonstrated that gene transcripts from both the heavy (ND2, COXI, ATP6) and light (ND6) strands of mtDNA were up-regulated approximately 3-fold in HA7C cells. Together, these mitochondrial changes are consistent with many previous reports and reveal several possible mechanisms by which HMGA1 over-expression, a common feature of naturally occurring cancers, may affect tumor progression.

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“…The mitochondrial genome appears to be a vulnerable target of adriamycin because it lacks protective histones and is continuously exposed to ROS produced within the mitochondria (Richter, 1988;Singh, 1998). ROS produced by adriamycin may make mitDNA even more vulnerable to damage.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA determines the cellular response to cancer therapeutic agents

Singh¹,

Russell²,

Sigala³

et al. 1999

Oncogene

166

102

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Mutations in the mitochondrial genome leading to mitochondrial dysfunction have been reported in a variety of cancers. However, the potential implication of these ®ndings in the cellular response to cancer therapeutic agents is unclear. To examine the importance of mitochondrial DNA (mitDNA) encoded functions in cancer therapeutic response, we determined the clonogenic survival of HSL2 (Rho + , HeLa subline), and its derivative cell line lacking mitDNA (Rho 0 ) after exposure to di erent anticancer agents. We found that isogenic Rho 0 cells lacking mitDNA were extremely resistant to adriamycin and photodynamic therapy (PDT) induced cell death, whereas the Rho + cell line was sensitive. However, there was no measurable di erence in the responses of these cell lines to either alkylating agent or g-radiation. We show that the development of resistance to adriamycin was not due to changes in apoptotic cell death, cell cycle response or to the uptake of adriamycin in isogenic Rho 0 cells. We also demonstrate that exposure of HeLa cells to adriamycin leads to mutations in mitDNA. These studies provide direct evidence that mitDNA plays an important role in cellular sensitivity to cancer therapeutic agents.

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Do mitochondrial DNA fragments promote cancer and aging?

Cited by 211 publications

References 81 publications

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

Nuclear HMGA1 nonhistone chromatin proteins directly influence mitochondrial transcription, maintenance, and function

Mitochondrial DNA determines the cellular response to cancer therapeutic agents

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