Hypoxamirs and Mitochondrial Metabolism

Cottrill, Katherine A.; Chan, Stephen Y.; Loscalzo, Joseph

doi:10.1089/ars.2013.5641

Cited by 20 publications

(12 citation statements)

References 101 publications

(122 reference statements)

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“…Hypoxamirs have been identified as miRNAs contributing to mitochondrial respiration arrest in a low oxygen environment. 43 In our study, CNTR fibroblasts upregulated six hypoxamirs (let-7b*, miR-192, miR-26a, miR-98, miR-23a and miR-7) 44 in response to RL, whereas MDD fibroblasts downregulated them. This particular difference in the MDD response compared with CNTR further supports the notion of mitochondrial dysfunction in MDD.…”

Section: Discussionsupporting

confidence: 47%

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

et al. 2015

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Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tissues. We examined the effects of two metabolic stressors, galactose (GAL) or reduced lipids (RL), on the transcriptome and miRNome of human fibroblasts from 16 pairs of patients with MDD and matched healthy controls (CNTR). Our results demonstrate that both MDD and CNTR fibroblasts had a robust molecular response to GAL and RL challenges. Most importantly, a significant part (messenger RNAs (mRNAs): 26–33% microRNAs (miRNAs): 81–90%) of the molecular response was only observed in MDD, but not in CNTR fibroblasts. The applied metabolic challenges uncovered mRNA and miRNA signatures, identifying responses to each stressor characteristic for the MDD fibroblasts. The distinct responses of MDD fibroblasts to GAL and RL revealed an aberrant engagement of molecular pathways, such as apoptosis, regulation of cell cycle, cell migration, metabolic control and energy production. In conclusion, the metabolic challenges evoked by GAL or RL in dermal fibroblasts exposed adaptive dysfunctions on mRNA and miRNA levels that are characteristic for MDD. This finding underscores the need to challenge biological systems to bring out disease-specific deficits, which otherwise might remain hidden under resting conditions.

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Section: Discussionsupporting

confidence: 47%

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

et al. 2015

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“…Micro-RNAs regulate tumor cell migration, angiogenesis, and metastasis (16). Hypoxia is known to induce changes in a number of micro-RNAs (17). Hypoxia down-regulates Dicer and thereby alters microRNA biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi¹,

Subramanian²,

Schnettler³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominantnegative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3′-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR199a, and HIF, with implications in cancer metastasis.microRNA | iron regulation E pithelial ovarian cancer (EOC) is the leading cause of death among the gynecological malignancies (1). Ascites development and peritoneal metastasis are unique features of ovarian cancer progression. Gas analyses of ovarian cancer ascites show about 2.5% dissolved oxygen content, whereas the blood oxygen content ranges between 15% and 23% (2). Hypoxic areas are common in tumor microenvironment as increased metabolic demands of rapidly proliferating cells outpace oxygen availability. Sustained exposure to hypoxia spurs cells to reorganize cellular processes, and energy-consuming functions, such as endocytosis, are suppressed (3, 4). Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (HIF-1α/HIF-2α) are principal coordinators of these responses. HIF-1α/HIF-2α are stabilized in hypoxia and associate with hypoxia-inducible factor-1β (HIF-1β) to form heterodimeric transcription factors and induce the expression of target genes (5, 6). HIF-1-mediated expression of lysyloxidase (LOX) cross-links collagens and induces cell migration (7). Epithelial ovarian cancer cells (EOCCs) that have adapted to hypoxia by activating HIF-1 disseminate from primary ovarian tumors and exfoliate into the peritoneal cavity. HIF-1 significantly enhances gene signatures associated with tissue remodeling, the morbidity and mortality associated with EOC (8, 9).Regulation of HIF-1 is a key step in the hypoxic response with profound implications for EOC metastasis. Under normoxia, HIF-1α is hydroxylated within its oxygen-dependent degradation domain (ODDD) by prolylhydroxylases (PHDs). This reaction is an oxygen-, iron-, 2-oxoglutarate and ascorbate-dependent process. Hydroxylated HIF-1α is recognized and bound by a complex that...

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“…Other miRNAs also appear to modulate mitochondrial function, especially two classes, hypoxamirs and mitomirs. Hypoxamirs are, as the name suggests, induced by hypoxic response (32). This is relevant to both asthma and COPD.…”

Section: L108mentioning

confidence: 99%

Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria

Agrawal

Mabalirajan

2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model--repair, reprogramming, and replacement--for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases.

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Hypoxamirs and Mitochondrial Metabolism

Cited by 20 publications

References 101 publications

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria

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