Discovery of Mieap‐regulated mitochondrial quality control as a new function of tumor suppressor p53

Nakamura, Yasuyuki; Arakawa, Hirofumi

doi:10.1111/cas.13208

Cited by 32 publications

(30 citation statements)

References 75 publications

(181 reference statements)

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“…p53 is a transcription factor that activates the expression of various downstream genes in response to DNA damage . The central functions of this protein in tumor suppression are cell cycle arrest, apoptosis, DNA repair and anti‐angiogenesis . In particular, apoptosis is so important a function for p53‐related tumor suppression that p53 activates target genes, including Bax, Noxa, Puma, Apaf‐1 and p53AIP1, in response to DNA damage by radiation, UV and oxidative stress .…”

Section: Introductionmentioning

confidence: 99%

“…11 The central functions of this protein in tumor suppression are cell cycle arrest, apoptosis, DNA repair and anti-angiogenesis. [12][13][14][15][16] In particular, apoptosis is so important a function for p53-related tumor suppression that p53 activates target genes, including Bax, Noxa, Puma, Apaf-1 and p53AIP1, in response to DNA damage by radiation, UV and oxidative stress. 11,13,17 Although the mechanisms of apoptosis induced by DNA damage have been clarified, mitochondria are a pivotal organ for apoptosis, where these apoptosisrelated proteins localize and play an important role in mitochondria through caspase activation.…”

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confidence: 99%

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Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer

Gaowa

Futamura

Kamino³

et al. 2018

Cancer Science

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Mitochondria‐eating protein (Mieap), encoded by a p53‐target gene, plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal cancer. Here, we investigated its role as a tumor suppressor in breast cancer. The enforced expression of exogenous Mieap in breast cancer cells induced caspase‐dependent apoptosis, with activation of both caspase‐3/7 and caspase‐9. Immunohistochemistry revealed endogenous Mieap in the cytoplasm in 24/75 (32%) invasive ductal carcinomas (IDC), 15/27 (55.6%) cases of ductal carcinoma in situ (DCIS) and 16/18 (88.9%) fibroadenomas (FA) (IDC vs DCIS; P = 0.0389, DCIS vs FA; P = 0.0234, IDC vs FA; P < 0.0001). In IDC, the Mieap promoter was methylated in 6/46 (13%) cases, whereas p53 was mutated in 6/46 (13%) cases. Therefore, the p53/Mieap‐regulated MQC pathway was inactivated in 12/46 IDC (26.1%). Interestingly, all tumors derived from the 12 patients with Mieap promoter methylation or p53 mutations pathologically exhibited more aggressive and malignant breast cancer phenotypes. Impairment of p53/Mieap‐regulated MQC pathway resulted in significantly shorter disease‐free survival (DFS) (P = 0.021), although p53 status is more prognostic in DFS than Mieap promoter methylation. These results indicate that p53/Mieap‐regulated MQC has a critical role in tumor suppression in breast cancer, possibly in part through mitochondrial apoptotic pathway.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer

Gaowa

Futamura

Kamino³

et al. 2018

Cancer Science

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“…Beyond cell death induction, recent studies suggest that BNIP3 and Nix proteins are involved in another, highly important process of mitochondrial quality control by mediation in mitochondrial repair. Miyamoto et al (2011) described the process of intramitochondrial lysosomal degradation of oxidized proteins (MALM-Mieapinduced accumulation of lysosome-like organelles within mitochondria), in which the crucial roles are played by 3 proteins: Mieap, BNIP3 and Nix (Nakamura et al, 2017). Mieap/Nix/BNIP3 interaction at the outer mitochondrial membrane is essential for formation of pores through the double mitochondrial membrane in order to mediate the translocation of lysosomal-like structures from the cytoplasm to the mitochondrial matrix (Nakamura et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Those observations together with our results led us to the hypothesis that BNIP3 decrease in LHON cybrids could be a sign of a defective mitochondrial quality control system. MALM is a much longer process of protein degradation [around 24-72 h (Miyamoto et al, 2011;Nakamura et al, 2017;Nakamura et al, 2012)] than classical autophagy (a few hours). If this process is disturbed because of the low level of proteins involved in its activation it can be even extended to several days.…”

Section: Discussionmentioning

confidence: 99%

Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

et al. 2019

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Mitochondria are key players in cell death through the activation of the intrinsic apoptosis pathway. BNIP3 and BNIP3L/Nix are outer mitochondrial membrane bifunctional proteins which because of containing both BH3 and LIR domains play a role in cellular response to stress by regulation of apoptosis and selective autophagy. Leber’s Hereditary Optic Neuropathy (LHON) is the most common mitochondrial disease in adults, characterized by painless loss of vision caused by atrophy of the optic nerve. The disease in over 90% of cases is caused by one of three mutations in the mitochondrial genome: 11778G>A, 3460G>A or 14484T>C. The pathogenic processes leading to optic nerve degeneration are largely unknown, however, the most common explanation is that mtDNA mutations increase the apoptosis level in this tissue. Here we present the results of analysis of BNIP3 and BNIP3L/Nix proteins in cells harboring a combination of the 11778G>A and the 3460G>A LHON mutations. Experiments performed on cybrids revealed that BNIP3 protein level is decreased in LHON cells compared to controls. CCCP treatment resulted in apoptosis induction only in control cells. Moreover, we also noticed reduced level of autophagy in LHON cybrids. The presented results suggest that in cells carrying LHON mutations expression of proteins involved in regulation of apoptosis and autophagy is decreased what in turn may disturb cell death pathways in those cells and affect cellular response to stress.

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“…3), a key p53-inducible protein, which mediates the repair or degradation of unhealthy mitochondria, and phospholipid scramblase 3, which promotes translocation of cardiolipin from the inner to outer mitochondrial membrane and leads to mitophagy are other examples of mitochondrial QC. MIEAP also plays a pivotal role in mitochondrial QC by repairing or eliminating unhealthy mitochondria via MALM (MIEAP-induced accumulation of lysosome-like 14 organelles within mitochondria) or MIV (MIEAP-induced vacuole) generation, respectively (Kitamura et al, 2011;Nakamura & Arakawa 2017). Damaged mitochondria can be discarded by an organelle specific form of autophagy known as mitophagy or mitochondrial autophagy.…”

Section: Discussionmentioning

confidence: 99%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies. SynopsisEnergy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin. ACKNOWLEDGMENTSWe thank Nancy Busija, MA, for editing the manuscript. We thank Dana Liu for technical help.

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Discovery of Mieap‐regulated mitochondrial quality control as a new function of tumor suppressor p53

Cited by 32 publications

References 75 publications

Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer

Possible role of p53/Mieap‐regulated mitochondrial quality control as a tumor suppressor in human breast cancer

Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

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