Fanconi Anemia Proteins Function in Mitophagy and Immunity

Sumpter, Rhea; Sirasanagandla, Shyam; Fernández, Álvaro F.; Wei, Yongjie; Dong, Xiaonan; Franco, Luis H.; Zou, Zhongju; Marchal, Christophe; Lee, Ming Yeh; Clapp, D. Wade; Hanenberg, Helmut; Levine, Beth

doi:10.1016/j.cell.2016.04.006

Cited by 211 publications

(230 citation statements)

References 52 publications

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“…17,28,29 In DBA, hyper-activation of mTOR is congruent with the increment in OXPHOS over glycolytic metabolism, while in FA and SDS, hyper-activation of mTOR might suggest the cells' attempt to overcome the energy defect through glutaminolysis, a pathway used in particular by cancer cells to support their energy requirements. Moreover, hyper-activation of mTOR inhibits autophagy and these data fit with its reduction in FA, 30 even though in SDS and DBA, autophagy increases. 15 Finally, Ca 2C is a crucial signaling molecule in energy metabolism that regulates many cellular ATP-consuming reactions.…”

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confidence: 51%

Why is an energy metabolic defect the common outcome in BMFS?

2016

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Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases. KEYWORDSBone marrow failures, oxidative stress, energy metabolism, cancer prone diseases, hematopoietic stem cellsThe bone marrow failure syndromes (BMFS) include a group of disorders than can be either inherited or acquired, and share phenotypic hallmarks of age-related diseases. The aging process in particular affects haematopoietic stem cells, inducing reduced regenerative potential with a possible increase in genetically unstable cells and malignancy. Although the genetic origin of these pathologies involves genes with different functions 1,2 (e.g., DNA repair, ribosome biogenesis, and telomere maintenance) there is a common final pathway, yet still largely elusive, by which HSC are unable to support the production of blood cells. 3Telomere maintenance, DNA repair and oxidative stress are biochemically interrelated processes responsible for cellular aging. Even though the aging mechanism has not yet been clarified and several theories are proposed, 4 mitochondrial metabolism, reactive oxygen species (ROS) and cellular antioxidant systems maintain a central role in the aging process. 5,6 In fact, oxidative stress and ROS increment are a common factor in BMFS. 7Fanconi's Anaemia (FA), Shwachman-Diamond Syndrome (SDS), Dyskeratosis Congenital (DC) and the Diamond-Blackfan Syndrome (DBA) are the most frequent inherited BMFS disorders. FA cells show chromosomal instability, hypersensitivity to crosslinking agents and defects of DNA repair mechanisms. These characteristics seem strikingly linked to defects in the oxidative stress response. In fact, chromosomal aberrations in FA lymphocytes are positively related to oxygen tension and spontaneous chromosomal instability is reduced by superoxide dismutase and catalase activity. Recently, it has been shown that antioxidant (AO) molecules improve haematopoiesis and reduce spontaneous and induced chromosomal instability in FA. Moreover, oxidative stress is a critical factor in the pathogenesis of bone marrow failure and leukemia progression in FA cells. 8,9 SDS cells have a defect in ribosome biogenesis, chemotaxis, mitotic spindle formation and cellular stress...

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confidence: 51%

Why is an energy metabolic defect the common outcome in BMFS?

2016

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“…SIN is a single‐stranded RNA virus in the alphavirus family, and numerous previous studies have shown that SIN viral nucleocapsids are degraded by selective autophagy 16, 17, 18. In HeLa cells stably expressing GFP‐LC3 (HeLa/GFP‐LC3 cells) and infected with SIN, four siRNA oligos that target PEX13 (and decrease PEX13 expression [Fig 1A]) resulted in a decrease in colocalization between mCherry‐capsid and GFP‐LC3 puncta (Fig 1B and C).…”

Section: Resultsmentioning

confidence: 99%

“…Like MEFs, primary human fibroblasts do not express endogenous Parkin and CCCP or OA treatment results in Parkin‐independent partial mitochondrial clearance and compaction around the perinuclear region 18. Similar to our findings in CCCP‐treated Pex13 − / − vs. Pex13 + / + MEFs, OA treatment resulted in partial mitochondrial clearance and compaction of remaining mitochondria in the perinuclear region, whereas fragments of damaged mitochondria accumulated throughout the cytoplasm in a higher percentage of PEX13 W313G mutant than PEX13 wild‐type cells (Fig 3E and F).…”

Section: Resultsmentioning

confidence: 99%

Peroxisomal protein PEX 13 functions in selective autophagy

et al. 2016

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PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease‐associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13‐mediated mitophagy may contribute to ZSS pathogenesis.

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“…Furthermore, novel functions of BRCA2 have been reported and could influence our model of its role in genome stability. Although BRCA2 functions have so far taken place in the nucleus, a recent study raises the intriguing possibility that BRCA2, along with BRCA1 and multiple proteins of the FA pathway (FANCA, FANCF, FANCL, FANCD2), facilitates mitophagy, a cytoplasmic process that targets damaged mitochondria to selective autophagy (Sumpter et al 2016). Mitophagy is critical to maintain low level of mitochondrial reactive oxygen species (mtROS), and recent evidence suggests that the accumulation of mtROS impacts transformation and tumors progression (Chourasia et al 2015).…”

Section: Discussionmentioning

confidence: 99%

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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Fanconi Anemia Proteins Function in Mitophagy and Immunity

Cited by 211 publications

References 52 publications

Why is an energy metabolic defect the common outcome in BMFS?

Why is an energy metabolic defect the common outcome in BMFS?

Peroxisomal protein PEX 13 functions in selective autophagy

BRCA2 functions: from DNA repair to replication fork stabilization

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