bims-cytox1 2017-03-26 papers

World J Microbiol Biotechnol. 2017 Apr;33(4): 75

Mechanisms of iron sensing and regulation in the yeast Saccharomyces cerevisiae.

María Teresa Martínez-Pastor, Ana Perea-García, Sergi Puig.

Iron is a redox active element that functions as an essential cofactor in multiple metabolic pathways, including respiration, DNA synthesis and translation. While indispensable for eukaryotic life, excess iron can lead to oxidative damage of macromolecules. Therefore, living organisms have developed sophisticated strategies to optimally regulate iron acquisition, storage and utilization in response to fluctuations in environmental iron bioavailability. In the yeast Saccharomyces cerevisiae, transcription factors Aft1/Aft2 and Yap5 regulate iron metabolism in response to low and high iron levels, respectively. In addition to producing and assembling iron cofactors, mitochondrial iron-sulfur (Fe/S) cluster biogenesis has emerged as a central player in iron sensing. A mitochondrial signal derived from Fe/S synthesis is exported and converted into an Fe/S cluster that interacts directly with Aft1/Aft2 and Yap5 proteins to regulate their transcriptional function. Various conserved proteins, such as ABC mitochondrial transporter Atm1 and, for Aft1/Aft2, monothiol glutaredoxins Grx3 and Grx4 are implicated in this iron-signaling pathway. The analysis of a wide range of S. cerevisiae strains of different geographical origins and sources has shown that yeast strains adapted to high iron display growth defects under iron-deficient conditions, and highlighted connections that exist in the response to both opposite conditions. Changes in iron accumulation and gene expression profiles suggest differences in the regulation of iron homeostasis genes.

Keywords: Aft1; Fe-S cluster synthesis; Iron deficiency; Iron homeostasis; Saccharomyces cerevisiae; Yap5; Yeast

DOI: https://doi.org/10.1007/s11274-017-2215-8

J Mol Biol. 2017 Mar 14. pii: S0022-2836(17)30110-9. [Epub ahead of print]

Mic10, a Core Subunit of the Mitochondrial Contact Site and Cristae Organizing System, Interacts with the Dimeric F1Fo-ATP Synthase.

Heike Rampelt, Maria Bohnert, Ralf M Zerbes, Susanne E Horvath, Bettina Warscheid, Nikolaus Pfanner, Martin van der Laan.

The mitochondrial contact site and cristae organizing system (MICOS) is crucial for maintaining the architecture of the mitochondrial inner membrane. MICOS is enriched at crista junctions that connect the two inner membrane domains: inner boundary membrane and cristae membrane. MICOS promotes the formation of crista junctions, whereas the oligomeric F1Fo-ATP synthase is crucial for shaping cristae rims, indicating antagonistic functions of these machineries in organizing inner membrane architecture. We report that the MICOS core subunit Mic10, but not Mic60, binds to the F1Fo-ATP synthase. Mic10 selectively associates with the dimeric form of the ATP synthase and supports the formation of ATP synthase oligomers. Our results suggest that Mic10 plays a dual role in mitochondrial inner membrane architecture. In addition to its central function in sculpting crista junctions, a fraction of Mic10 molecules interact with the cristae rim-forming F1Fo-ATP synthase.

Keywords: MICOS; cell organelles; inner membrane; membrane architecture; mitochondria

DOI: https://doi.org/10.1016/j.jmb.2017.03.006

J Neurosci. 2017 Mar 17. pii: 0756-16. [Epub ahead of print]

Respiration-deficient astrocytes survive as glycolytic cells in vivo.

Lotti M Supplie, Tim Düking, Graham Campbell, Francisca Diaz, Carlos T Moraes, Magdalena Götz, Bernd Hamprecht, Susann Boretius, Don Mahad, Klaus-Armin Nave.

Neurons and glial cells exchange energy-rich metabolites and it has been suggested, originally based on in vitro data, that astrocytes provide lactate to glutamatergic synapses ("lactate shuttle"). Here, we have studied astrocytes that lack mitochondrial respiration in vitro and in vivo A novel mouse mutant (GLASTCreERT2:Cox10flox/flox ) was generated, in which the administration of tamoxifen causes mutant astrocytes to fail in the assembly of mitochondrial cytochrome c oxidase (COX). Focussing on cerebellar Bergmann glial cells that exhibit the highest rate of Cre-mediated recombination, we find a normal density of viable astrocytes even one year after tamoxifen-induced Cox10 gene targeting. Our data show that Bergmann glial cells, and presumably all astrocytes, can survive by aerobic glycolysis for an extended period of time, in the absence of glial pathology or unspecific signs of neurodegeneration.SIGNIFICANCE STATEMENTWhen astrocytes are placed into culture they import glucose and release lactate, an energy-rich metabolite readily metabolized by neurons. This observation led to the "glia-to-neuron lactate shuttle hypothesis", but in vivo evidence for this hypothesis is weak. To study astroglial energy metabolism and the directionality of lactate flux, we generated conditional Cox10 mouse mutants lacking mitochondrial respiration in astrocytes thus forcing these cells to survive by aerobic glycolysis. Here, we report that these mice are fully viable in the absence of any signs of glial or neuronal loss, suggesting that astrocytes are naturally glycolytic cells.

DOI: https://doi.org/10.1523/JNEUROSCI.0756-16.2017

EMBO J. 2017 Mar 17. pii: e201695546. [Epub ahead of print]

Non-coding RNAs: the dark side of nuclear-mitochondrial communication.

Roberto Vendramin, Jean-Christophe Marine, Eleonora Leucci.

Mitochondria are critical hubs for the integration of several key metabolic processes implicated in cell growth and survival. They originated from bacterial ancestors through endosymbiosis, following the transfer of more than 90% of their endosymbiont genome to the host cell nucleus. Over time, a mutually beneficial symbiotic relationship has been established, which relies on continuous and elaborate signaling mechanisms between this life-essential organelle and its host. The ability of mitochondria to signal their functional state and trigger compensatory and adaptive cellular responses has long been recognized, but the underlying molecular mechanisms involved have remained poorly understood. Recent evidence indicates that non-coding RNAs (ncRNAs) may contribute to the synchronization of a series of essential cellular and mitochondrial biological processes, acting as "messengers" between the nucleus and the mitochondria. Here, we discuss the emerging putative roles of ncRNAs in various bidirectional signaling pathways established between the host cell and its mitochondria, and how the dysregulation of these pathways may lead to aging-related diseases, including cancer, and offer new promising therapeutic avenues.

Keywords: miRNA; mitochondria; non‐coding RNA; retrograde signaling

DOI: https://doi.org/10.15252/embj.201695546

Br J Ophthalmol. 2017 Mar 17. pii: bjophthalmol-2016-310072. [Epub ahead of print]

Childhood-onset Leber hereditary optic neuropathy.

Anna Majander, Richard Bowman, Joanna Poulton, Richard J Antcliff, M Ashwin Reddy, Michel Michaelides, Andrew R Webster, Patrick F Chinnery, Marcela Votruba, Anthony T Moore, Patrick Yu-Wai-Man.

BACKGROUND: The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup.
METHODS: Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic review of the literature. Patients were included if visual loss occurred at the age of 12 years or younger with a confirmed pathogenic mitochondrial DNA mutation: m.3460G>A, m.11778G>A or m.14484T>C.
RESULTS: In the UK paediatric LHON cohort, three patterns of visual loss and progression were observed: (1) classical acute (17/27, 63%); (2) slowly progressive (4/27, 15%); and (3) insidious or subclinical (6/27, 22%). Diagnostic delays of 3-15 years occurred in children with an insidious mode of onset. Spontaneous visual recovery was more common in patients carrying the m.3460G>A and m.14484T>C mutations compared with the m.11778G>A mutation. Based a meta-analysis of 67 patients with available visual acuity data, 26 (39%) patients achieved a final best-corrected visual acuity (BCVA) ≥0.5 Snellen decimal in at least one eye, whereas 13 (19%) patients had a final BCVA <0.05 in their better seeing eye.
CONCLUSIONS: Although childhood-onset LHON carries a relatively better visual prognosis, approximately 1 in 5 patients will remain within the visual acuity criteria for legal blindness in the UK. The clinical presentation can be insidious and LHON should be considered in the differential diagnosis when faced with a child with unexplained subnormal vision and optic disc pallor.

Keywords: Child health (paediatrics); Diagnostic tests/Investigation; Genetics; Optic Nerve; Vision

DOI: https://doi.org/10.1136/bjophthalmol-2016-310072

Cell Chem Biol. 2017 Mar 16. pii: S2451-9456(17)30069-7. [Epub ahead of print]24(3): 250-251

Mapping New Residents of the Mitochondrial Nucleoid.

Laura Trinkle-Mulcahy.

In this issue of Cell Chemical Biology, Han et al. (2017) used a powerful combination of quantitative ratiometric mass spectrometry with APEX peroxidase-catalyzed proximity biotinylation to selectively highlight proteins associated with mitochondrial DNA above the background of contaminants and matrix proteins. In addition to identifying novel nucleoid factors, this study extends the APEX strategy to the proteomic mapping of non-membrane-bound multiprotein complexes.

DOI: https://doi.org/10.1016/j.chembiol.2017.03.006