Modeling human mitochondrial diseases in flies

Sánchez-Martínez, Álvaro; Luo, Ningguang; Clemente, Paula; Adán, Cristina; Hernández-Sierra, Rosana; Ochoa, Pilar; Fernández-Moreno, Miguel Ángel; Kaguni, Laurie S.; Garesse, Rafael

doi:10.1016/j.bbabio.2006.05.008

Cited by 30 publications

(26 citation statements)

References 66 publications

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“…In humans, mutations in ANT1 (the heart and skeletal muscle isoform) demonstrate a range of symptoms from myopathy (1) to autosomal dominant progressive external ophthalmoplegia (20). Drosophila is a useful model system for study of mitochondrial defects (43), usually in the context of neural function (50). In Drosophila, sesB mutants were first obtained in a screen for mechanical stress sensitivity (52), and mutants have been shown to have an impact on synaptic transmission (40).…”

Section: Resultsmentioning

confidence: 99%

Mislocalization of mitochondria and compromised renal function and oxidative stress resistance inDrosophila SesBmutants

Terhzaz

Cabrero

Chintapalli

et al. 2010

Physiological Genomics

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Terhzaz S, Cabrero P, Chintapalli VR, Davies S, Dow JAT. Mislocalization of mitochondria and compromised renal function and oxidative stress resistance in Drosophila SesB mutants. Physiol Genomics 41: 33-41, 2010. First published December 15, 2009 doi:10.1152/physiolgenomics.00147.2009.-Mitochondria accumulate at sites of intense metabolic activity within cells, but the adaptive value of this placement is not clear. In Drosophila, sesB encodes the ubiquitous isoform of adenine nucleotide translocase (ANT, the mitochondrial inner membrane ATP/ADP exchanger); null alleles are lethal, whereas hypomorphic alleles display sensitivity to a range of stressors. In the adult renal tubule, which is densely packed with mitochondria and hence enriched for sesB, both hypomorphic alleles and RNA interference knockdowns cause the mitochondria to lose their highly polarized distribution in the tissue and to become rounded. Basal cytoplasmic and mitochondrial calcium levels are both increased, and neuropeptide calcium response compromised, with concomitant defects in fluid secretion. The remaining mitochondria in sesB mutants are overactive and maintain depleted cellular ATP levels while generating higher levels of hydrogen peroxide than normal. When sesB expression is knocked down in just tubule principal cells, the survival of the whole organism upon oxidative stress is reduced, implying a limiting role for the tubule in homeostatic response to stressors. The physiological impacts of defective ANT expression are thus widespread and diverse. Drosophila melanogaster; Malpighian tubule; adenine nucleotide translocase; mitochondria MITOCHONDRIA ARE ESSENTIAL organelles for the function of all aerobic cells, as they produce ATP, buffer cytosolic calcium, and sequester apoptotic factors. Impairment of mitochondrial function, resulting in excitotoxic metabolic insufficiency, cell death, and oxidative damage, can contribute to severe tissue pathologies and diseases (36,44). Mitochondria are also highly dynamic, and accumulate at sites with particularly high ATP consumption (3,13,17,31,37).The mitochondrial adenine nucleotide translocase (ANT) is the most abundant protein of the inner mitochondrial membrane and a crucial component in the maintenance of cellular energy homeostasis, as well as in the formation of the mitochondrial permeability transition pore (2, 15). It catalyzes ADP/ATP exchange across the mitochondrial inner membrane (24) and thus has the potential to allow mitochondrial sensing of subcellular ATP:ADP poise. ANT is a target of oxidative damage, and functional inactivation has been associated with chronological age as well as physiological age (51). In mammals, the majority of species, including humans, possess three distinct genes for ANT (9,25,26,28). Drosophila harbors two overlapping ANT genes, ANT1 (sesB), and ANT2, with 72% nucleotide identity with 78% amino acid sequence identity (52). Mutations affecting ANT1 in Drosophila were originally identified as a stress-sensitive strain of animals (sesB) that are condi...

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Section: Resultsmentioning

confidence: 99%

Mislocalization of mitochondria and compromised renal function and oxidative stress resistance inDrosophila SesBmutants

Terhzaz

Cabrero

Chintapalli

et al. 2010

Physiological Genomics

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“…Recently, Drosophila melanogaster has proven a powerful tool in uncovering the molecular mechanisms involved in several human metabolic diseases – in fact an average of 75% of the known human disease-related genes are conserved in the fly (Reiter et al , 2001; Sanchez-Martinez et al , 2006; Baker and Thummel, 2007; Fernández-Moreno et al , 2007; Birse et al , 2010; Musselman et al , 2011; Na et al , 2013). Methods exist in the fly for the analysis of metabolic profiles including measurement of circulating and stored lipids and carbohydrates and ATP levels as well as tools for metabolomics (Tennessen et al , 2014).…”

Section: Benefits Of the Drosophila Model In Metabolic Studiesmentioning

confidence: 99%

Modeling dietary influences on offspring metabolic programming in Drosophila melanogaster

Brookheart¹,

Duncan²

2016

Reproduction

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The influence of nutrition on offspring metabolism has become a hot topic in recent years owing to the growing prevalence of maternal and childhood obesity. Studies in mammals have identified several factors correlating with parental and early offspring dietary influences on progeny health; however, the molecular mechanisms that underlie these factors remain undiscovered. Mammalian metabolic tissues and pathways are heavily conserved in Drosophila melanogaster, making the fly an invaluable genetic model organism for studying metabolism. In this review, we discuss the metabolic similarities between mammals and Drosophila and present evidence supporting its use as an emerging model of metabolic programming.Reproduction (2016) 152 R79-R90

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“…Mitochondria are assembled by proteins encoded by either the mitochondrial genome or the nuclear genome. The entire mitochondrial DNA as well as nuclear genes encoding mitochondrial proteins are highly conserved between the mammalian and Drosophila system (Sanchez-Martinez et al 2006). Thus, Drosophila has been successfully utilized as a model system to study various mitochondrial diseases (SanchezMartinez et al 2006).…”

mentioning

confidence: 99%

Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster

Chen¹,

Shi²,

Padmanabhan³

et al. 2007

Genome Res.

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Mitochondrial dysfunction is associated with many human diseases. There has not been a systematic genetic approach for identifying regulators of basal mitochondrial biogenesis and function in higher eukaryotes. We performed a genome-wide RNA interference (RNAi) screen in Drosophila cells using mitochondrial Citrate synthase (CS) activity as the primary readout. We screened 13,071 dsRNAs and identified 152 genes that modulate CS activity. These modulators are involved in a wide range of biological processes and pathways including mitochondrial-related functions, transcriptional and translational regulation, and signaling pathways. Selected hits among the 152 genes were further analyzed for their effect on mitochondrial CS activity in transgenic flies or fly mutants. We confirmed a number of gene hits including HDAC6, Rpd3(HDAC1), CG3249, vimar, Src42A, klumpfuss, barren, and smt3 which exert effects on mitochondrial CS activities in vivo, demonstrating the value of Drosophila genome-wide RNAi screens for identifying genes and pathways that modulate mitochondrial function.

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Modeling human mitochondrial diseases in flies

Cited by 30 publications

References 66 publications

Mislocalization of mitochondria and compromised renal function and oxidative stress resistance inDrosophila SesBmutants

Mislocalization of mitochondria and compromised renal function and oxidative stress resistance inDrosophila SesBmutants

Modeling dietary influences on offspring metabolic programming in Drosophila melanogaster

Identification of novel modulators of mitochondrial function by a genome-wide RNAi screen in Drosophila melanogaster

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