Dominant membrane uncoupling by mutant adenine nucleotide translocase in mitochondrial diseases

Wang, Xiaowen; Salinas, Kelly; Zuo, Xiaoming; Kucejová, Blanka; Chen, Xin Jie

doi:10.1093/hmg/ddn306

Cited by 31 publications

(47 citation statements)

References 37 publications

(36 reference statements)

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“…Consequently, the flow of protons back to the matrix is blocked and the ⌬m increases until it reaches a level that prohibits oxidative phosphorylation, resulting in increased ROS production and mt DNA damage (76). Furthermore, mutations in the human ANT1 gene cause autosomal dominant progressive external ophthalmoplegia (adPEO), an mt disorder characterized by reduced respiration, lowered mt cytochrome content, and mt DNA deletions (54,77). Moreover, this loss of mt DNA can further exacerbate the adPEO disorder by compromising the synthesis of specific respiratory subunits (75).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, the lack of AAC activity triggers mt DNA rearrangements and deletions followed by a complete loss of mt DNA (53,54). To ascertain if a loss of mt DNA also occurs in T. brucei with downregulated TbAAC, the nuclear and mt DNA (termed kinetoplast DNA in these protists) were stained with DAPI and visualized by fluorescence microscopy (Fig.…”

Section: -D Page Reveals That a Minor Proportion Of Tbaac Migrates Amentioning

confidence: 99%

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The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

et al. 2015

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The highly conserved ADP/ATP carrier (AAC) is a key energetic link between the mitochondrial (mt) and cytosolic compartments of all aerobic eukaryotic cells, as it exchanges the ATP generated inside the organelle for the cytosolic ADP. Trypanosoma brucei, a parasitic protist of medical and veterinary importance, possesses a single functional AAC protein (TbAAC) that is related to the human and yeast ADP/ATP carriers. However, unlike previous studies performed with these model organisms, this study showed that TbAAC is most likely not a stable component of either the respiratory supercomplex III؉IV or the ATP synthasome but rather functions as a physically separate entity in this highly diverged eukaryote. Therefore, TbAAC RNA interference (RNAi) ablation in the insect stage of T. brucei does not impair the activity or arrangement of the respiratory chain complexes. Nevertheless, RNAi silencing of TbAAC caused a severe growth defect that coincides with a significant reduction of mt ATP synthesis by both substrate and oxidative phosphorylation. Furthermore, TbAAC downregulation resulted in a decreased level of cytosolic ATP, a higher mt membrane potential, an elevated amount of reactive oxygen species, and a reduced consumption of oxygen in the mitochondria. Interestingly, while TbAAC has previously been demonstrated to serve as the sole ADP/ATP carrier for ADP influx into the mitochondria, our data suggest that a second carrier for ATP influx may be present and active in the T. brucei mitochondrion. Overall, this study provides more insight into the delicate balance of the functional relationship between TbAAC and the oxidative phosphorylation (OXPHOS) pathway in an early diverged eukaryote. The origination event of an ADP/ATP carrier (AAC) was crucial in the evolution of the present-day mitochondrion that enabled it to become the powerhouse of the eukaryotic cell. Due to the activity of AAC, the energy-producing mitochondria can supply the cytosol with ATP molecules, which fuel most cellular reactions. AAC belongs to the well-defined family of mitochondrial (mt) carrier proteins that are located in the inner mt membrane and are involved in the transport of a wide range of metabolites (1). Under physiological aerobic conditions, AAC is responsible for the 1:1 counterexchange of mt ATP for cytosolic ADP (2). mt ATP is produced mainly by the evolutionarily conserved biochemical pathway of oxidative phosphorylation (OXPHOS), which employs respiratory complexes I through IV to convert the redox energy of various mt substrates into an electrochemical proton gradient (⌬m) across the mt inner membrane. Respiratory complexes I (NADH-ubiquinone oxidoreductase) and II (succinate-ubiquinone oxidoreductase) are responsible for the oxidation of reduced NADH and FADH 2 , respectively. The electrons derived from these biochemical processes continue along the electron transport chain as they are sequentially passed to coenzyme Q, complex III (ubiquinol-cytochrome c oxidoreductase), cytochrome c, complex IV (cytochrome c-O 2 oxid...

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Section: Discussionmentioning

confidence: 99%

Section: -D Page Reveals That a Minor Proportion Of Tbaac Migrates Amentioning

confidence: 99%

The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

et al. 2015

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“…DC is critical for the normal maintenance of mtDNA (Chen 2002;Wang et al 2008). This gradient is required for import of nuclear-encoded mitochondrial proteins, including those involved in mitochondrial genome replication and maintenance (Mokranjac and Neupert 2008).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in Multiple Genes Contribute to the Spontaneous Mitochondrial Genome Instability ofSaccharomyces cerevisiaeS288C Strains

et al. 2009

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The mitochondrial genome (mtDNA) is required for normal cellular function; inherited and somatic mutations in mtDNA lead to a variety of diseases. Saccharomyces cerevisiae has served as a model to study mtDNA integrity, in part because it can survive without mtDNA. A measure of defective mtDNA in S. cerevisiae is the formation of petite colonies. The frequency at which spontaneous petite colonies arise varies by $100-fold between laboratory and natural isolate strains. To determine the genetic basis of this difference, we applied quantitative trait locus (QTL) mapping to two strains at the opposite extremes of the phenotypic spectrum: the widely studied laboratory strain S288C and the vineyard isolate RM11-1a. Four main genetic determinants explained the phenotypic difference. Alleles of SAL1, CAT5, and MIP1 contributed to the high petite frequency of S288C and its derivatives by increasing the formation of petite colonies. By contrast, the S288C allele of MKT1 reduced the formation of petite colonies and compromised the growth of petite cells. The former three alleles were found in the EM93 strain, the founder that contributed $88% of the S288C genome. Nearly all of the phenotypic difference between S288C and RM11-1a was reconstituted by introducing the common alleles of these four genes into the S288C background. In addition to the nuclear gene contribution, the source of the mtDNA influenced its stability. These results demonstrate that a few rare genetic variants with individually small effects can have a profound phenotypic effect in combination. Moreover, the polymorphisms identified in this study open new lines of investigation into mtDNA maintenance.

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“…The mitochondrial ATP/ ADP translocator AAC is a key enzyme in the inner membrane of mitochondria, and the ADP/ATP catalyzing function of AAC2 is conserved between yeast and plants (22). In yeast, a dominant mutation is described which impairs the electron transport chain, resulting in membrane uncoupling (23). We introduced an analogous mutation into Arabidopsis AAC2 (Fig.…”

Section: Mitochondrial Dysfunction In the Central Cell Extends Antipodalmentioning

confidence: 99%

The gametic central cell of Arabidopsis determines the lifespan of adjacent accessory cells

Kägi

Baumann

Nielsen

et al. 2010

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

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Plant germ cells develop in specialized haploid structures, termed gametophytes. The female gametophyte patterns of flowering plants are diverse, with often unknown adaptive value. Here we present the Arabidopsis fiona mutant, which forms a female gametophyte that is structurally and functionally reminiscent of a phylogenetic distant female gametophyte. The respective changes include a modified reproductive behavior of one of the female germ cells (central cell) and an extended lifespan of three adjacent accessory cells (antipodals). FIONA encodes the cysteinyl t-RNA synthetase SYCO ARATH (SYCO), which is expressed and required in the central cell but not in the antipodals, suggesting that antipodal lifespan is controlled by the adjacent gamete. SYCO localizes to the mitochondria, and ultrastructural analysis of mutant central cells revealed that the protein is necessary for mitochondrial cristae integrity. Furthermore, a dominant ATP/ADP translocator caused mitochondrial cristae degeneration and extended antipodal lifespan when expressed in the central cell of wild-type plants. Notably, this construct did not affect antipodal lifespan when expressed in antipodals. Our results thus identify an unexpected noncell autonomous role for mitochondria in the regulation of cellular lifespan and provide a basis for the coordinated development of gametic and nongametic cells.cell-cell communication | gametes | programmed cell death I n angiosperms, gametes form in few-celled haploid structures, termed gametophytes. The female gametophyte of most flowering plants originates from a single haploid spore through three syncytial division cycles. Subsequent cellularization generates two synergids, three antipodal cells, and two types of female gametes, an egg and a central cell. The different cell types have distinct functions in the reproductive process. Synergids mediate short-range pollen tube attraction and direct the subsequent release of the two sperm cells (1). The fertilized egg gives rise to an embryo, and the fusion of the second sperm cell with the central cell initiates the formation of endosperm, which nurtures the developing embryo. The central cell initially comprises two haploid polar nuclei, which, in many flowering plant species, fuse before fertilization, generating a diploid secondary nucleus (2). The diploid status of the central cell translates into triploid endosperm with a maternal/paternal ratio of 2:1. This ratio has been shown to critically impact on seed size as, for example, a relative decrease in the maternal contribution results in bigger seeds (3). Antipodals, the accessory cells that lie adjacent to the central cell, might also play a nutritive role by transferring nutrients from the maternal sporophyte to the female gametophyte (4). In several grass species, like wheat and maize, antipodal cells proliferate (5). By contrast, in most higher eudicots antipodal cells do not persist but undergo programmed cell death (PCD) (4) (Fig. 1 A-C). The adaptive value of this derived developmental program (...

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Dominant membrane uncoupling by mutant adenine nucleotide translocase in mitochondrial diseases

Cited by 31 publications

References 37 publications

The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

The ADP/ATP Carrier and Its Relationship to Oxidative Phosphorylation in Ancestral Protist Trypanosoma brucei

Polymorphisms in Multiple Genes Contribute to the Spontaneous Mitochondrial Genome Instability ofSaccharomyces cerevisiaeS288C Strains

The gametic central cell of Arabidopsis determines the lifespan of adjacent accessory cells

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