Aconitase Couples Metabolic Regulation to Mitochondrial DNA Maintenance

Chen, Xin Jie; Wang, Xiaowen; Kaufman, Brett A.; Butow, Ronald A.

doi:10.1126/science.1106391

Cited by 285 publications

(258 citation statements)

References 29 publications

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“…ACO1 and IDH have both been described to have bifunctional roles in yeast mitochondria. In addition to TCA cycle functions, ACO1 is involved in mitochondrial DNA maintenance [39], and IDH has been shown to be a mitochondrial mRNA-binding protein [40]. The latter observation led to a hypothesis that IDH might be a regulator of mitochondrial translation [41].…”

Section: Discussionmentioning

confidence: 99%

“…Since, in the current study, we saw similar relative effects on COX2 and COX3 levels in aco1 Δ and in aco1 Δ cit1 Δ strains, it is possible that elevated cellular levels of citrate in the idhΔ and aco1 Δ strains may detrimentally affect mitochondrial translation or stability of the translation products, and that this effect is reduced by co-disruption of the CIT1 gene. For ACO1, a distinction between its dual functions was recently demonstrated using mutants expressing catalytically inactive forms of ACO1 [39]. These mutant strains were found to be glutamate auxotrophs (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Suppression of metabolic defects of yeast isocitrate dehydrogenase and aconitase mutants by loss of citrate synthase

Hakala

Weintraub

et al. 2008

Archives of Biochemistry and Biophysics

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Yeast mutants lacking mitochondrial NAD + -specific isocitrate dehydrogenase (idhΔ) or aconitase (aco1 Δ) were found to share several growth phenotypes as well as patterns of specific protein expression that differed from the parental strain. These shared properties of idhΔ and aco1 Δ strains were eliminated or moderated by co-disruption of the CIT1 gene encoding mitochondrial citrate synthase. Gas chromatography/mass spectrometry analyses indicated a particularly dramatic increase in cellular citrate levels in idhΔ and aco1 Δ strains, whereas citrate levels were substantially lower in idhΔcit1 Δ and aco1 Δcit1 Δ strains. Exogenous addition of citrate to parental strain cultures partially recapitulated effects of high endogenous levels of citrate in idh Δ and aco1 Δ strains. Finally, effects of elevated cellular citrate in idhΔ and aco1 Δ mutant strains were partially alleviated by addition of iron or by an increase in pH of the growth medium, suggesting that detrimental effects of citrate are due to elevated levels of the ionized form of this metabolite.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Suppression of metabolic defects of yeast isocitrate dehydrogenase and aconitase mutants by loss of citrate synthase

Hakala

Weintraub

et al. 2008

Archives of Biochemistry and Biophysics

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“…A number of mt (cp) nucleoid proteins have been identified in yeast (39)(40)(41)(42), algae (43), and plants (44,45). An intriguing example of a mt nucleoid protein is Glom, which is a structural nucleoid protein that also maintains the replication and transcriptional activity of mtDNA in slime mold (46).…”

Section: Discussionmentioning

confidence: 99%

Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Nishimura

Yoshinari

Naruse

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

104

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In almost all eukaryotes, mitochondrial (mt) genes are transmitted to progeny mainly from the maternal parent. The most popular explanation for this phenomenon is simple dilution of paternal mtDNA, because the paternal gametes (sperm) are much smaller than maternal gametes (egg) and contribute a limited amount of mitochondria to the progeny. Recently, this simple explanation has been challenged in several reports that describe the active digestion of sperm mtDNA, down-regulation of mtDNA replication in sperm, and proteolysis of mitochondria triggered by ubiquitination. In this investigation, we visualized mt nucleoids in living sperm by using highly sensitive SYBR green I vital staining. The ability to visualize mt nucleoids allowed us to clarify that the elimination of sperm mtDNA upon fertilization is achieved through two steps: (i) gradual decrease of mt nucleoid numbers during spermatogenesis and (ii) rapid digestion of sperm mtDNA just after fertilization. One notable point is that the digestion of mtDNA is achieved before the complete destruction of mitochondrial structures, which may be necessary to avoid the diffusion and transmission of potentially deleterious sperm mtDNA to the progeny. maternal inheritance ͉ medaka ͉ mtDNA M itochondria and chloroplasts contain their own genomes, which are believed to be vestiges of their bacterial ancestors (1). Mitochondrial (mt) and chloroplast (cp) genes are inherited in non-Mendelian fashion. A variety of patterns and mechanisms have been observed for the transmission of these genes, but in almost all eukaryotes, they are inherited mainly from the maternal parent (2-4).Generally, the maternal inheritance of mt (cp) DNA is thought to be a result of the dilution of the paternal contribution, because the paternal gametes (sperm) are much smaller than maternal gametes (egg) and contribute only a limited amount of cytoplasm to the progeny. In animals, a mature sperm carries Ϸ100 copies of mtDNA, which might be necessary to maintain the integrity of mitochondrial activity (5). In contrast, the animal oocyte contains Ϸ10 5 to 10 8 copies of mtDNA, exceeding that of sperm by a factor of at least 10 3 (3, 6). Therefore, the paternal contribution of mtDNA or cpDNA would be diluted beyond the limits of detection by using conventional restriction enzyme analysis (7).This simple explanation, however, has been challenged by many findings (8). For example, there have been several fairly unsuccessful attempts to detect leaky transmission of paternal mtDNA by repetitive backcross experiments using lepidopteran insects (9). On the contrary, in mussels (Mtylus), paternal mtDNA can be transmitted to male progeny at a remarkably high frequency, even though paternal mtDNAs are transmitted by sperm (10-12). A more striking example was found in the unicellular alga Chlamydomonas reinhardtii. In C. reinhardtii, despite the fact that mtϩ (female) and mtϪ (male) gametes contribute equal amounts of cytoplasm to the progeny, cpDNA is transmitted only from the mtϩ parent. One biochemical stud...

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“…The ancestral protein that gave rise to the IRP/IRE system is likely an aconitase, which is broadly distributed in all phyla (12) and has binding affinity to nucleic acids (13). Saccharomyces cerevisiae contains only a single aconitase gene, encoding a mitochondrial enzyme, though low amounts of aconitase can be detected in the cytosol (14).…”

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confidence: 99%

Of Two Cytosolic Aconitases Expressed in Drosophila, Only One Functions as an Iron-regulatory Protein

Lind

Missirlis

Melefors

et al. 2006

Journal of Biological Chemistry

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In mammalian cells, iron homeostasis is largely regulated by post-transcriptional control of gene expression through the binding of iron-regulatory proteins (IRP1 and IRP2) to iron-responsive elements (IREs) contained in the untranslated regions of target mRNAs. IRP2 is the dominant iron sensor in mammalian cells under normoxia, but IRP1 is the more ancient protein in evolutionary terms and has an additional function as a cytosolic aconitase. The Caenorhabditis elegans genome does not contain an IRP2 homolog or identifiable IREs; its IRP1 homolog has aconitase activity but does not bind to mammalian IREs. The Drosophila genome offers an evolutionary intermediate containing two IRP1-like proteins (IRP-1A and IRP-1B) and target genes with IREs. Here, we used purified recombinant IRP-1A and IRP-1B from Drosophila melanogaster and showed that only IRP-1A can bind to IREs, although both proteins possess aconitase activity. These results were also corroborated in whole-fly homogenates from transgenic flies that overexpress IRP-1A and IRP-1B in their fat bodies. Ubiquitous and muscle-specific overexpression of IRP-1A, but not of IRP-1B, resulted in pre-adult lethality, underscoring the importance of the biochemical difference between the two proteins. Domain-swap experiments showed that multiple amino acid substitutions scattered throughout the IRP1 domains are synergistically required for conferring IRE binding activity. Our data suggest that as a first step during the evolution of the IRP/IRE system, the ancient cytosolic aconitase was duplicated in insects with one variant acquiring IRE-specific binding.Iron is required for aerobic metabolism and is actively sensed, sequestered, and regulated by organisms, including hosts and pathogens, that often compete for metal acquisition (1). In multicellular organisms, signals exist for systemic control of iron metabolism (2). One of the central regulators of cellular iron metabolism is the IRP/IRE system (3). In brief, absence of iron is sensed by IRP1 and IRP2, which then bind to ironresponsive elements (IREs) 4 in the 5Ј-untranslated regions of mRNAs encoding several storage or consumer iron proteins, inhibiting their translation. IRP1 and IRP2 also bind to IREs in the 3Ј-untranslated regions of mRNAs encoding proteins that function in cellular iron import, stabilizing the transcripts and enhancing iron sequestration. There is much interest in defining how IRP1 and IRP2 sense iron levels. IRP1 interconverts between an iron-sulfur protein with aconitase activity and the apoprotein that binds to the IRE (4). IRP2 has an additional 73-amino acid domain inserted in the protein and has no aconitase activity (5, 6). Extensive analysis of knock-out mice has led to the conclusion that IRP2 dominates mammalian cellular iron metabolism (7). IRP1 also contributes to the regulation of cellular iron metabolism, albeit to a lesser extent, because its iron-sulfur cluster is efficiently repaired and the protein functions mostly as an aconitase (8 -10). It is also well established that b...

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Aconitase Couples Metabolic Regulation to Mitochondrial DNA Maintenance

Cited by 285 publications

References 29 publications

Suppression of metabolic defects of yeast isocitrate dehydrogenase and aconitase mutants by loss of citrate synthase

Suppression of metabolic defects of yeast isocitrate dehydrogenase and aconitase mutants by loss of citrate synthase

Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers

Of Two Cytosolic Aconitases Expressed in Drosophila, Only One Functions as an Iron-regulatory Protein

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