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1.
Mol Cell ; 84(16): 3098-3114.e6, 2024 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-39142278

RESUMEN

Ferroptosis, an iron-dependent form of nonapoptotic cell death mediated by lipid peroxidation, has been implicated in the pathogenesis of multiple diseases. Subcellular organelles play pivotal roles in the regulation of ferroptosis, but the mechanisms underlying the contributions of the mitochondria remain poorly defined. Optic atrophy 1 (OPA1) is a mitochondrial dynamin-like GTPase that controls mitochondrial morphogenesis, fusion, and energetics. Here, we report that human and mouse cells lacking OPA1 are markedly resistant to ferroptosis. Reconstitution with OPA1 mutants demonstrates that ferroptosis sensitization requires the GTPase activity but is independent of OPA1-mediated mitochondrial fusion. Mechanistically, OPA1 confers susceptibility to ferroptosis by maintaining mitochondrial homeostasis and function, which contributes both to the generation of mitochondrial lipid reactive oxygen species (ROS) and suppression of an ATF4-mediated integrated stress response. Together, these results identify an OPA1-controlled mitochondrial axis of ferroptosis regulation and provide mechanistic insights for therapeutically manipulating this form of cell death in diseases.


Asunto(s)
Factor de Transcripción Activador 4 , Ferroptosis , GTP Fosfohidrolasas , Mitocondrias , Especies Reactivas de Oxígeno , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Ferroptosis/genética , Animales , Especies Reactivas de Oxígeno/metabolismo , Humanos , Mitocondrias/metabolismo , Mitocondrias/genética , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Dinámicas Mitocondriales , Ratones , Ratones Noqueados , Estrés Oxidativo , Transducción de Señal , Peroxidación de Lípido , Mutación
2.
Proc Natl Acad Sci U S A ; 120(51): e2303713120, 2023 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-38091291

RESUMEN

The mitochondrial permeability transition pore (mPTP) is a channel in the inner mitochondrial membrane whose sustained opening in response to elevated mitochondrial matrix Ca2+ concentrations triggers necrotic cell death. The molecular identity of mPTP is unknown. One proposed candidate is the mitochondrial ATP synthase, whose canonical function is to generate most ATP in multicellular organisms. Here, we present mitochondrial, cellular, and in vivo evidence that, rather than serving as mPTP, the mitochondrial ATP synthase inhibits this pore. Our studies confirm previous work showing persistence of mPTP in HAP1 cell lines lacking an assembled mitochondrial ATP synthase. Unexpectedly, however, we observe that Ca2+-induced pore opening is markedly sensitized by loss of the mitochondrial ATP synthase. Further, mPTP opening in cells lacking the mitochondrial ATP synthase is desensitized by pharmacological inhibition and genetic depletion of the mitochondrial cis-trans prolyl isomerase cyclophilin D as in wild-type cells, indicating that cyclophilin D can modulate mPTP through substrates other than subunits in the assembled mitochondrial ATP synthase. Mitoplast patch clamping studies showed that mPTP channel conductance was unaffected by loss of the mitochondrial ATP synthase but still blocked by cyclophilin D inhibition. Cardiac mitochondria from mice whose heart muscle cells we engineered deficient in the mitochondrial ATP synthase also demonstrate sensitization of Ca2+-induced mPTP opening and desensitization by cyclophilin D inhibition. Further, these mice exhibit strikingly larger myocardial infarctions when challenged with ischemia/reperfusion in vivo. We conclude that the mitochondrial ATP synthase does not function as mPTP and instead negatively regulates this pore.


Asunto(s)
Poro de Transición de la Permeabilidad Mitocondrial , ATPasas de Translocación de Protón Mitocondriales , Ratones , Animales , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Ciclofilinas/genética , Ciclofilinas/metabolismo , Peptidil-Prolil Isomerasa F , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/metabolismo , Calcio/metabolismo
3.
PLoS Genet ; 16(1): e1008558, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31923184

RESUMEN

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.


Asunto(s)
Beclina-1/genética , Inestabilidad Cromosómica , Haploinsuficiencia , Proteínas Asociadas a Microtúbulos/genética , Neoplasias Ováricas/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular , Femenino , Metaboloma , Ratones , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología
4.
Proc Natl Acad Sci U S A ; 116(37): 18423-18428, 2019 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-31444302

RESUMEN

During prophase I of meiosis, chromosomes become organized as loop arrays around the proteinaceous chromosome axis. As homologous chromosomes physically pair and recombine, the chromosome axis is integrated into the tripartite synaptonemal complex (SC) as this structure's lateral elements (LEs). While the components of the mammalian chromosome axis/LE-including meiosis-specific cohesin complexes, the axial element proteins SYCP3 and SYCP2, and the HORMA domain proteins HORMAD1 and HORMAD2-are known, the molecular organization of these components within the axis is poorly understood. Here, using expansion microscopy coupled with 2-color stochastic optical reconstruction microscopy (STORM) imaging (ExSTORM), we address these issues in mouse spermatocytes at a resolution of 10 to 20 nm. Our data show that SYCP3 and the SYCP2 C terminus, which are known to form filaments in vitro, form a compact core around which cohesin complexes, HORMADs, and the N terminus of SYCP2 are arrayed. Overall, our study provides a detailed structural view of the meiotic chromosome axis, a key organizational and regulatory component of meiotic chromosomes.


Asunto(s)
Cromosomas de los Mamíferos/química , Cromosomas de los Mamíferos/metabolismo , Microscopía/métodos , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Unión al ADN/metabolismo , Masculino , Mamíferos/genética , Meiosis , Ratones , Espermatocitos/metabolismo , Coloración y Etiquetado , Complejo Sinaptonémico/metabolismo
6.
Org Biomol Chem ; 14(35): 8241-5, 2016 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-27530345

RESUMEN

Understanding trafficking in cells and tissues is one of the most critical steps in exploring the mechanisms and modes of action (MOAs) of a small molecule. Typically, deciphering the role of concentration presents one of the most difficult challenges associated with this task. Herein, we present a practical solution to this problem by developing concentration gradients within single dishes of cells. We demonstrate the method by evaluating fluorescently-labelled probes developed from two classes of natural products that have been identified as potential anti-cancer leads by STORM super-resolution microscopy.

7.
J Nat Sci ; 3(7)2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28815209

RESUMEN

Genome sequencing technologies and corresponding oncology publications have generated enormous publicly available datasets for many cancer types. While this has enabled new treatments, and in some limited cases lifetime management of the disease, the treatment options for serous ovarian cancer remain dismal. This review summarizes recent advances in our understanding of ovarian cancer, with a focus on heterogeneity, functional genomics, and actionable data.

8.
Nat Commun ; 8: 14423, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28198375

RESUMEN

Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions. Compared with 20 other cancer types, OV is most severely disrupted in autophagy and in compensatory proteostasis pathways. Network analysis prioritizes MAP1LC3B (LC3) and BECN1 as most impactful. Knockdown of LC3 and BECN1 expression confers sensitivity to cells undergoing autophagic stress independent of platinum resistance status. The results support the use of pathway network tools to evaluate how the copy-number landscape of a tumour may guide therapy.


Asunto(s)
Alelos , Haploinsuficiencia/genética , Mutación/genética , Neoplasias Ováricas/genética , Autofagia/genética , Línea Celular Tumoral , Proliferación Celular/genética , Variaciones en el Número de Copia de ADN/genética , Sistemas de Liberación de Medicamentos , Femenino , Genes Relacionados con las Neoplasias , Humanos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteostasis/genética
9.
PLoS One ; 8(12): e82859, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24349380

RESUMEN

The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2 × 10(-10)). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.


Asunto(s)
Metaboloma , Metabolómica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Microambiente Tumoral , Adolescente , Médula Ósea/metabolismo , Médula Ósea/patología , Niño , Preescolar , Humanos , Quimioterapia de Inducción , Lactante , Redes y Vías Metabólicas/efectos de los fármacos , Metabolómica/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico
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