Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

Igoillo-Esteve, Mariana; Oliveira, Andrea Luiza de; Cristina, Carolina; Fantuzzi, Federica; Demarez, Céline; Toivonen, Sanna; Hu, Amélie; Chintawar, Satyan; Lopes, Miguel; Pachera, Nathalie; Cai, Ying; Abdulkarim, Baroj; Rai, Myriam; Marselli, Lorella; Marchetti, Piero; Mohammad, Tariq; Jonas, Jean‐Christophe; Boscolo, Marina; Pandolfo, Massimo; Eizirik, Décio L.; Cnop, Miriam

doi:10.1172/jci.insight.134221

Cited by 45 publications

(43 citation statements)

References 80 publications

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“…Extracellular flux analyses have so far been reported only recently in FRDA cellular models, namely in sensory neurons differentiated from induced pluripotent stem cells derived from patients harboring homozygous repeat expansions (i.e. chronically low FXN WT expression) ( Igoillo-Esteve et al, 2020 ) and an inducible FXN overexpression HEK293 cell line (i.e. short-term high FXN WT expression) ( Vannocci et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…short-term high FXN WT expression) ( Vannocci et al, 2018 ). Basal and maximal respiration and ATP production were significantly reduced in FXN WT -deficient sensory neurons ( Igoillo-Esteve et al, 2020 ), and no beneficial effects were observed for these parameters upon FXN WT overexpression ( Vannocci et al, 2018 ). Expression of only Fxn G127V protein was sufficient to maintain basal respiration at levels observed for WT MEFs at early and late passages.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia

Fil

Chacko

Conley

et al. 2020

Disease Models &Amp; Mechanisms

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Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, whereas a fraction of patients are compound heterozygotes, with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring an Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure-to-thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA lesions and fragmentation are accompanied by marked amplification of mitochondrial DNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life, and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia

Fil

Chacko

Conley

et al. 2020

Disease Models &Amp; Mechanisms

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“…iPSC culturing and differentiation into β cells. iPSCs were cultured in Matrigel-coated plates (Corning) in E8 medium as previously described (61,62). Four YIPF5 mutant cell lines (2 clones from each Human pancreata not suitable for clinical purposes were collected from nondiabetic, brain-dead organ donors after written informed consent from next of kin, and handled as described (64) with the approval of the Ethical Committee, University of Pisa.…”

Section: Methodsmentioning

confidence: 99%

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Franco

Lytrivi

Ibrahim

et al. 2020

Journal of Clinical Investigation

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Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models ( YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

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“…Moreover, mutations in the mitochondrial gene encoding frataxin, known for its iron–sulphur cluster activation and respiratory function in mitochondria, are associated with Friedreich’s ataxia (FRDA) [ 39 ], which involves mitochondrial iron overload, respiratory chain dysfunction, impaired OXPHOS and ATP production. Importantly, frataxin expression is upregulated by glucagon-like peptide (GLP-1) receptor agonists [ 40 ], an effect that may contribute to the glucose-lowering actions of these drugs.…”

Section: Mitochondria and Insulin Secretionmentioning

confidence: 99%

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

et al. 2020

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All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed (‘disallowed’) in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1–7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell–beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion.

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Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia

Cited by 45 publications

References 80 publications

Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia

Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

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