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1.
Kidney Int ; 92(5): 1051-1057, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28893420

RESUMO

Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases because they serve as key regulatory hubs uniquely situated at crossroads between multiple cellular processes. This review provides an overview of the role of mitochondrial dysfunction in chronic kidney disease, with special emphasis on its role in the development of diabetic nephropathy. We examine the current understanding of the molecular mechanisms that cause mitochondrial dysfunction in the kidney and describe the impact of mitochondrial damage on kidney function. The new concept that mitochondrial shape and structure are closely linked with its function in the kidneys is discussed. Furthermore, the mechanisms that translate cellular cues and demands into mitochondrial remodeling and cellular damage, including the role of microRNAs and long noncoding RNAs, are examined with the final goal of identifying mitochondrial targets to improve treatment of patients with chronic kidney diseases.


Assuntos
Nefropatias Diabéticas/patologia , Rim/patologia , Mitocôndrias/patologia , Dinâmica Mitocondrial , Estresse Oxidativo , Insuficiência Renal Crônica/patologia , Animais , Humanos , Rim/metabolismo , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , RNA Longo não Codificante/metabolismo
2.
J Clin Invest ; 129(7): 2807-2823, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063459

RESUMO

Phosphorylation of Dynamin-related protein1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here we established the role of Drp1 Serine 600 (S600) phosphorylation on mitochondrial fission in vivo, and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus- but not cell type-dependent. Mechanistically, we showed that mitochondrial fission in high glucose conditions occurs through concomitant binding of phospho-Drp1S600 with mitochondrial fission factor (Mff) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo, and highlight the stimulus-specific consequences of Drp1S600 phosphorylation on mitochondrial dynamics.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Dinaminas/metabolismo , Mutação de Sentido Incorreto , Proteína 3 Relacionada a Actina/genética , Proteína 3 Relacionada a Actina/metabolismo , Substituição de Aminoácidos , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dinaminas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Fosforilação/genética
3.
Oncogene ; 38(34): 6211-6225, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31289360

RESUMO

One-carbon metabolism plays a central role in a broad array of metabolic processes required for the survival and growth of tumor cells. However, the molecular basis of how one-carbon metabolism may influence RNA methylation and tumorigenesis remains largely unknown. Here we show MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, contributes to the progression of renal cell carcinoma (RCC) via a novel epitranscriptomic mechanism that involves HIF-2α. We found that expression of MTHFD2 was significantly elevated in human RCC tissues, and MTHFD2 knockdown strongly reduced xenograft tumor growth. Mechanistically, using an unbiased methylated RNA immunoprecipitation sequencing (meRIP-Seq) approach, we found that MTHFD2 plays a critical role in controlling global N6-methyladenosine (m6A) methylation levels, including the m6A methylation of HIF-2α mRNA, which results in enhanced translation of HIF-2α. Enhanced HIF-2α translation, in turn, promotes the aerobic glycolysis, linking one-carbon metabolism to HIF-2α-dependent metabolic reprogramming through RNA methylation. Our findings also suggest that MTHFD2 and HIF-2α form a positive feedforward loop in RCC, promoting metabolic reprograming and tumor growth. Taken together, our results suggest that MTHFD2 links RNA methylation status to the metabolic state of tumor cells in RCC.


Assuntos
Aminoidrolases/fisiologia , Carcinoma de Células Renais/metabolismo , Glicólise/genética , Neoplasias Renais/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/fisiologia , Metiltransferases/metabolismo , Enzimas Multifuncionais/fisiologia , Processamento Pós-Transcricional do RNA/genética , Animais , Metabolismo dos Carboidratos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Reprogramação Celular/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Metilação , Camundongos , Camundongos Nus
4.
Org Lett ; 18(15): 3870-3, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27447361

RESUMO

By use of 1,3-dithian-2-yl-methoxycarbonyl (Dmoc) as a protecting group and linker for oligodeoxynucleotide (ODN) synthesis, deprotection and cleavage are achieved under non-nucleophilic oxidative conditions. The nucleophile-sensitive thioester and α-chloroacetyl groups are conveniently incorporated into ODN sequences. The technology could be universally useful for electrophilic ODN synthesis.


Assuntos
Oligodesoxirribonucleotídeos/síntese química , Conformação Molecular , Oligodesoxirribonucleotídeos/química
5.
J Clin Invest ; 126(11): 4205-4218, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760051

RESUMO

The regulatory roles of long noncoding RNAs (lncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator-activated receptor γ (PPARγ) coactivator α (PGC-1α, encoded by Ppargc1a) is functionally regulated by the lncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondrial function in podocytes. Using a murine model of diabetic nephropathy (DN), we performed an unbiased RNA-sequencing (RNA-seq) analysis of kidney glomeruli and identified Tug1 as a differentially expressed lncRNA in the diabetic milieu. Podocyte-specific overexpression (OE) of Tug1 in diabetic mice improved the biochemical and histological features associated with DN. Unexpectedly, we found that Tug1 OE rescued the expression of PGC-1α and its transcriptional targets. Tug1 OE was also associated with improvements in mitochondrial bioenergetics in the podocytes of diabetic mice. Mechanistically, we found that the interaction between Tug1 and PGC-1α promotes the binding of PGC-1α to its own promoter. We identified a Tug1-binding element (TBE) upstream of the Ppargc1a gene and showed that Tug1 binds with the TBE to enhance Ppargc1a promoter activity. These findings indicate that a direct interaction between PGC-1α and Tug1 modulates mitochondrial bioenergetics in podocytes in the diabetic milieu.


Assuntos
Nefropatias Diabéticas/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Mitocôndrias/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Podócitos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular Transformada , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Podócitos/patologia , RNA Longo não Codificante/genética
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