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1.
Science ; 384(6701): eadj4301, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38870309

RESUMO

Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial ß-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.


Assuntos
Acetilcoenzima A , Hepatócitos , Regeneração Hepática , Mitocôndrias Hepáticas , Ácido Pirúvico , Animais , Hepatócitos/metabolismo , Acetilcoenzima A/metabolismo , Camundongos , Ácido Pirúvico/metabolismo , Mitocôndrias Hepáticas/metabolismo , Oxirredução , Proliferação de Células , Ácidos Graxos/metabolismo , Fígado/metabolismo , Transporte de Elétrons , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Masculino
2.
Cell ; 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38823389

RESUMO

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

3.
Int Rev Cell Mol Biol ; 365: 117-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34756242

RESUMO

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders with overproduction of mature myeloid blood cells, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). In 2005, several groups identified a single gain-of-function point mutation JAK2V617F in the majority of MPN patients. The JAK2V617F mutation confers cytokine independent proliferation to hematopoietic progenitor cells by constitutively activating canonical and non-canonical downstream pathways. In this chapter, we focus on (1) the regulation of JAK2, (2) the molecular mechanisms used by JAK2V617F to induce MPNs, (3) the factors that are involved in the phenotypic diversity in MPNs, and (4) the effects of JAK2V617F on hematopoietic stem cells (HSCs). The discovery of the JAK2V617F mutation led to a comprehensive understanding of MPN; however, the question still remains about how one mutation can give rise to three distinct disease entities. Various mechanisms have been proposed, including JAK2V617F allele burden, differential STAT signaling, and host genetic modifiers. In vivo modeling of JAK2V617F has dramatically enhanced the understanding of the pathophysiology of the disease and provided the pre-clinical platform. Interestingly, most of these models do not show an increased hematopoietic stem cell self-renewal and function compared to wildtype controls, raising the question of whether JAK2V617F alone is sufficient to give a clonal advantage in MPN patients. In addition, the advent of modern sequencing technologies has led to a broader understanding of the mutational landscape and detailed JAK2V617F clonal architecture in MPN patients.


Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , Células-Tronco Hematopoéticas , Humanos , Janus Quinase 2/genética , Mutação/genética
4.
Cell Stem Cell ; 28(11): 1982-1999.e8, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34450065

RESUMO

The electron transport chain promotes aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is limiting in normal stem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely on cell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors. Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase or treatment with 6-mercaptopurine attenuated the increased function of GLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration.


Assuntos
Ácido Aspártico , Células-Tronco Hematopoéticas , Animais , Proliferação de Células , Camundongos
5.
J Clin Invest ; 130(5): 2630-2643, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045382

RESUMO

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.


Assuntos
Eritrócitos/fisiologia , Mutação com Ganho de Função , Janus Quinase 2/genética , Janus Quinase 2/fisiologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/fisiopatologia , Animais , Antioxidantes/farmacologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Micropartículas Derivadas de Células/fisiologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiopatologia , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtornos Mieloproliferativos/complicações , Estresse Oxidativo , Sinvastatina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
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