Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma

Gopal, Raj K.; Calvo, Sarah E.; Shih, Angela R.; Cháves, Frances; McGuone, Declan; Mick, Eran; Pierce, Kerry A.; Li, Yang; Garofalo, Andrea; Allen, Eliezer M. Van; Clish, Clary B.; Oliva, Esther; Mootha, Vamsi K.

doi:10.1073/pnas.1711888115

Cited by 77 publications

(73 citation statements)

References 49 publications

(70 reference statements)

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“…This result is similar to that reported by Ishikawa and colleagues, who demonstrated complex I deficiencies caused by a MT-ND6 frameshift mutation contributed to tumor progression and metastasis (42). Recently, Gopal and colleagues reported that LoF mutations in the complex I genes lead to rewiring of glutathione metabolism in renal oncocytoma and are early genetic events that contribute to tumor formation (43). Notably, 13 and 8 of these 45 LoF mutations that we found were above 15% and 40% heteroplasmy, respectively, with the highest observed at 73% in a neuroblastoma tumor ( Supplementary Table S1).…”

Section: Clustering Of Loss-of-function and Pathogenic Trna Tumor-onlsupporting

confidence: 88%

Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

et al. 2019

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Little is known about the spectrum of mitochondrial DNA (mtDNA) mutations across pediatric malignancies. In this study, we analyzed matched tumor and normal whole genome sequencing data from 616 pediatric patients with hematopoietic malignancies, solid tumors, and brain tumors. We identified 391 mtDNA mutations in 284 tumors including 45 loss-of-function mutations, which clustered at four statistically significant hotspots in MT-COX3, MT-ND4, and MT-ND5, and at a mutation hotspot in MT-tRNA-MET. A skewed ratio (4.83) of nonsynonymous versus synonymous (dN/dS) mtDNA mutations with high statistical significance was identified on the basis of Monte Carlo simula-tions in the tumors. In comparison, opposite ratios of 0.44 and 0.93 were observed in 616 matched normal tissues and in 249 blood samples from children without cancer, respectively. mtDNA mutations varied by cancer type and mtDNA haplogroup. Collectively, these results suggest that deleterious mtDNA mutations play a role in the development and progression of pediatric cancers.Significance: This pan-cancer mtDNA study establishes the landscape of germline and tumor mtDNA mutations and identifies hotspots of tumor mtDNA mutations to pinpoint key mitochondrial functions in pediatric malignancies.

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Section: Clustering Of Loss-of-function and Pathogenic Trna Tumor-onlsupporting

confidence: 88%

Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

et al. 2019

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“…5b). This outcome was confirmed by quantitative real-time PCR analysis of MT-CO1 and Letm1, the mitochondrial homeostasis gene [9,12] (upper panels in Fig. 5c).…”

Section: Accumulation Of Oxidative-damaged Mitochondria In Diabetic Ksupporting

confidence: 53%

“…4). Next, to examine the histological aspect of mitochondria in the diabetic kidney, immunohistological analysis was carried out with the use of a mitochondrial marker antibody against MT-CO1 (one of the mitochondrially encoded cytochrome c oxidases [12]). MT-CO1 immunoreactivity was clearly observed in the cytoplasm of renal tubules (Fig.…”

Section: Accumulation Of Oxidative-damaged Mitochondria In Diabetic Kmentioning

confidence: 99%

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

Haraguchi

Kohara

Matsubayashi

et al. 2020

Acta Histochem. Cytochem

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Diabetic nephropathy is a major source of end-stage renal failure, affecting about one-third cases of diabetes mellitus. It has long been accepted that diabetic nephropathy is mainly characterized by glomerular defects, while clinical observations have implied that renal tubular damage is closely linked to kidney dysfunction at the early stages of diabetic nephropathy. In this study, we conducted pathohistological analyses focusing on renal tubular lesions in the early-stage diabetic kidney with the use of a streptozotocin (STZ)induced diabetes mellitus mouse model. The results revealed that histological alterations in renal tubules, shown by a vacuolar nucleic structure, accumulations of PAS-positive substance, and accelerated restoration stress, occur initially without the presence of glomerular lesions in the early-stage diabetic kidney, and that these tubular defects are localized mainly in proximal renal tubules. Moreover, enhanced expression of RAGE, suggesting an aberrant activation of AGEs-RAGE signaling pathway, and accumulation of oxidative modified mitochondria through the impaired autophagy/lysosome system, were also seen in the damaged diabetic proximal renal tubules. Our findings indicate that proximal tubular defects are the initial pathological events increasingly linked to the progression of diabetic nephropathy, and that controlling renal tubular damage could be an effective therapeutic strategy for the clinical treatment of diabetic nephropathy.

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“…The most strikingly increased set of metabolites in pRCC were those involved in glutathione metabolism (GSH, GSSG, cysteine-glutathione disulfide, ophthalmic acid). This is similar to those previously identified in renal oncocytomas (17,55) and chRCC (27,56). GSH is an important ROS scavenger (57) and frequently produced by several tumor types to withstand unusual levels of oxidative stress (22).…”

Section: Discussionsupporting

confidence: 86%

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

Alahmad

Paffrath

Clima

et al. 2019

Preprint

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Papillary renal cell carcinoma (pRCC) is a malignant kidney cancer with a prevalence of 7-20% of all renal tumors. Proteome and metabolome profiles of 19 pRCC and patient-matched healthy kidney controls were used to elucidate the regulation of metabolic pathways and the underlying molecular mechanisms. Glutathione (GSH), a main reactive oxygen species (ROS) scavenger, was highly increased and can be regarded as a new hallmark in this malignancy. Isotope tracing of pRCC derived cell lines revealed an increased de novo synthesis rate of GSH, based on glutamine consumption. Furthermore, rewiring of the main pathways involved in ATP and glucose synthesis was observed at the protein level. In contrast, transcripts encoding for the respiratory chain were not regulated, which prompts for non-genetic profiling. The molecular characteristics of pRCC are increased GSH synthesis to cope with ROS stress, deficient anabolic glucose synthesis, and compromised oxidative phosphorylation, which could potentially be exploited in innovative anti-cancer strategies.

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Early loss of mitochondrial complex I and rewiring of glutathione metabolism in renal oncocytoma

Cited by 77 publications

References 49 publications

Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

Landscape of Germline and Somatic Mitochondrial DNA Mutations in Pediatric Malignancies

New Insights into the Pathogenesis of Diabetic Nephropathy: Proximal Renal Tubules Are Primary Target of Oxidative Stress in Diabetic Kidney

Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis

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