Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells

Gilkerson, Robert; Margineantu, Daciana; Capaldi, Roderick A.; Selker, Jeanne M. L.

doi:10.1016/s0014-5793(00)01527-1

Cited by 104 publications

(98 citation statements)

References 26 publications

(30 reference statements)

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“…The mtDNA exclusively encodes RNA and proteins required for the formation of ETC complex; therefore, the defects in pseudo‐ρ0 cells are considered to be associated with ETC functions and limited to their relevant activities. This hypothesis has been supported by extensive studies of ρ0 cells,10, 12 thereby providing a valuable model for the evaluation of the significance of ETC functions in cells.…”

Section: Resultsmentioning

confidence: 82%

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Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA‐MB‐231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1‐mediated ETC‐dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC‐deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria‐targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

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Section: Resultsmentioning

confidence: 82%

“…In conclusion, our results suggest that mtROS production was reduced in the MDA/ρ0 cells similar to the other cell types. 6, 11, 12, 13 …”

Section: Resultsmentioning

confidence: 99%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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“…To investigate the mechanisms by which abnormalities in mitochondrial DNA may affect MHC I expression, we studied the expression of MHC I in osteosarcoma Rho 0 cells deficient in mitochondrial DNA compared with their parental line 143B with a normal mitochondrial genome (13). Lack of mitochondrial DNA in Rho 0 cells is associated with slightly higher surface expression of MHC I (2-fold) compared with 143B cells with a normal mitochondrial genome (Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Wang

Roifman

et al. 2003

The Journal of Immunology

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Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.

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“…In our search for specific proteases involved in HCC-1[9 -74] production, we screened an extended range of human tumoral cell lines for proteolytic activation of HCC-1. Subconfluent monolayer cultures of prostate carcinoma (PC-3, DU145) (30), osteosarcoma (143B) (31), melanoma (MeWo, Mel-Z2) (32), and breast adenocarcinoma (MCF-7) (33) cells were incubated for 48 h with full-length HCC-1 in culture medium. The medium was then recovered and tested for its ability to activate CCR5 in an aequorin-based bioassay (Fig.…”

Section: Resultsmentioning

confidence: 99%

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

Vakili

Ständker

Detheux

et al. 2001

The Journal of Immunology

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We have previously isolated from human hemofiltrate an N-terminally truncated form of the hemofiltrate CC chemokine 1 (HCC-1), and characterized HCC-1[9–74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3. In this study, we show that conditioned media from human tumor cell lines PC-3 and 143B contain proteolytic activities that convert HCC-1 into the [9–74] form. This activity was fully inhibited by inhibitors of urokinase-type plasminogen activator (uPA), including PA inhibitor-1, an anti-uPA mAb, and amiloride. Pure preparations of uPA processed HCC-1 with high efficiency, without further degrading HCC-1[9–74]. Plasmin could also generate HCC-1[9–74], but degraded the active product as well. The kinetics of HCC-1 cleavage by uPA and plasmin (Michaelis constant, Km, of 0.76 ± 0.4 μM for uPA, and 0.096 ± 0.05 μM for plasmin; catalytic rate constant, kcat: 3.36 ± 0.96 s−1 for uPA and 6 ± 3.6 s−1 for plasmin) are fully compatible with a role in vivo. The activation of an abundant inactive precursor into a broad-spectrum chemokine by uPA and plasmin directly links the production of uPA by numerous tumors and their ability to recruit mononuclear leukocytes, without the need for the transcriptional activation of chemokine genes.

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Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells

Cited by 104 publications

References 26 publications

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity

Urokinase Plasminogen Activator and Plasmin Efficiently Convert Hemofiltrate CC Chemokine 1 into Its Active [9–74] Processed Variant

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