scholarly journals Adenine nucleotide translocase 4 deficiency leads to early meiotic arrest of murine male germ cells

Reproduction ◽  
2009 ◽  
Vol 138 (3) ◽  
pp. 463-470 ◽  
Author(s):  
Jeffrey V Brower ◽  
Chae Ho Lim ◽  
Marda Jorgensen ◽  
S Paul Oh ◽  
Naohiro Terada
Keyword(s):  
Adenine Nucleotide ◽  
Strand Break ◽  
Pachytene Spermatocyte ◽  
Inner Mitochondrial Membrane ◽  
Meiotic Arrest ◽  
Atp Production ◽  
Dna Double Strand Break ◽  
Complex Protein ◽  
Synaptonemal Complex Protein ◽  
Pachytene Spermatocytes

Male fertility relies on the highly specialized process of spermatogenesis to continually renew the supply of spermatozoa necessary for reproduction. Central to this unique process is meiosis that is responsible for the production of haploid spermatozoa as well as for generating genetic diversity. During meiosis I, there is a dramatic increase in the number of mitochondria present within the developing spermatocytes, suggesting an increased necessity for ATP production and utilization. Essential for the utilization of ATP is the translocation of ADP and ATP across the inner mitochondrial membrane, which is mediated by the adenine nucleotide translocases (Ant). We recently identified and characterized a novel testis specific Ant, ANT4 (also known as SLC25A31 and Aac4). The generation ofAnt4-deficient animals resulted in the severe disruption of the seminiferous epithelium with an apparent spermatocytic arrest of the germ cell population. In the present study utilizing a chromosomal spread technique, we determined thatAnt4-deficiency results in an accumulation of leptotene spermatocytes, a decrease in pachytene spermatocytes, and an absence of diplotene spermatocytes, indicating early meiotic arrest. Furthermore, the chromosomes ofAnt4-deficient pachytene spermatocyte occasionally demonstrated sustained γH2AX association as well as synaptonemal complex protein 1 (SYCP1)/SYCP3 dissociation beyond the sex body. Large ATP supplies from mitochondria may be critical for normal progression of spermatogenesis during early stages of meiotic prophase I, including DNA double-strand break repair and chromosomal synapsis.

scholarly journals Structural Basis of Substrate Recognition by the Mitochondrial ADP/ATP Transporter

2021 ◽  
Author(s):  
Shihao Yao ◽  
Qiuzi Yi ◽  
Boyuan Ma ◽  
Xiaoting Mao ◽  
Ye Chen ◽  
...  
Keyword(s):  
Binding Site ◽  
Transport Process ◽  
Conformational Transition ◽  
Adenine Nucleotide ◽  
Substrate Recognition ◽  
Md Simulations ◽  
Structural Basis ◽  
Specific Substrate ◽  
Inner Mitochondrial Membrane ◽  
Atp Production

AbstractSpecific import of ADP and export of ATP by ADP/ATP carrier (AAC) across the inner mitochondrial membrane are crucial for sustainable energy supply in all eukaryotes. However, mechanism for highly specific substrate recognition in the dynamic transport process remains largely elusive. Here, unguided MD simulations of 22 microseconds in total reveal that AAC in ground c-state uses the second basic patch (K91K95R187), tyrosine ladder (Y186Y190Y194), F191 and N115 in the upper region of the cavity to specifically recognize ADP and confer selectivity for ADP over ATP. Mutations of these residues in yeast AAC2 reduce ADP transport across the L. lactis membrane and induce defects in OXPHOS and ATP production in yeast. Sequence analyses also suggest that AAC and other adenine nucleotide transporters use the upper region of the cavity, rather than the central binding site to discriminate their substrates. Identification of the new site unveils the unusually high substrate specificity of AAC, and together with central binding site support early biochemical findings about existence of two substrate binding sites. Our results imply that using different sites for substrate recognition and conformational transition could be a smart strategy for transporters to cope with substrate recognition problem in the highly dynamic transport process.

scholarly journals Polo-like kinase-dependent phosphorylation of the synaptonemal complex protein SYP-4 regulates double-strand break formation through a negative feedback loop.

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Saravanapriah Nadarajan ◽  
Talley J Lambert ◽  
Elisabeth Altendorfer ◽  
Jinmin Gao ◽  
Michael D Blower ◽  
...  
Keyword(s):  
Synaptonemal Complex ◽  
Central Region ◽  
Feedback Loop ◽  
Strand Break ◽  
Dynamic State ◽  
Strand Breaks ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Complex Protein ◽  
Synaptonemal Complex Protein

The synaptonemal complex (SC) is an ultrastructurally conserved proteinaceous structure that holds homologous chromosomes together and is required for the stabilization of pairing interactions and the completion of crossover (CO) formation between homologs during meiosis I. Here, we identify a novel role for a central region component of the SC, SYP-4, in negatively regulating formation of recombination-initiating double-strand breaks (DSBs) via a feedback loop triggered by crossover designation in C. elegans. We found that SYP-4 is phosphorylated dependent on Polo-like kinases PLK-1/2. SYP-4 phosphorylation depends on DSB formation and crossover designation, is required for stabilizing the SC in pachytene by switching the central region of the SC from a more dynamic to a less dynamic state, and negatively regulates DSB formation. We propose a model in which Polo-like kinases recognize crossover designation and phosphorylate SYP-4 thereby stabilizing the SC and making chromosomes less permissive for further DSB formation.

Top-down control analysis of the cadmium effects on molluscan mitochondria and the mechanisms of cadmium-induced mitochondrial dysfunction

2011 ◽  
Vol 300 (1) ◽  
pp. R21-R31 ◽  
Author(s):  
Ilya O. Kurochkin ◽  
Markus Etzkorn ◽  
David Buchwalter ◽  
Larry Leamy ◽  
Inna M. Sokolova
Keyword(s):  
Mitochondrial Function ◽  
Adenine Nucleotide ◽  
Eastern Oyster ◽  
Substrate Oxidation ◽  
Proton Leak ◽  
Control Analysis ◽  
Proton Conductance ◽  
Inner Mitochondrial Membrane ◽  
Top Down ◽  
Atp Production

Cadmium (Cd) is a toxic metal and an important environmental pollutant that can strongly affect mitochondrial function and bioenergetics in animals. We investigated the mechanisms of Cd action on mitochondrial function of a marine mollusk (the eastern oyster Crassostrea virginica ) by performing a top-down control analysis of the three major mitochondrial subsystems (substrate oxidation, proton leak, and phosphorylation). Our results showed that the substrate oxidation and proton leak subsystems are the main targets for Cd toxicity in oyster mitochondria. Exposure to 12.5 μM Cd strongly inhibited the substrate oxidation subsystem and stimulated the proton conductance across the inner mitochondrial membrane. Proton conductance was also elevated and substrate oxidation inhibited by Cd in the presence of a mitochondrially targeted antioxidant, MitoVitE, indicating that Cd effects on these subsystems were to a large extent ROS independent. Cd did not affect the kinetics of the phosphorylation system, indicating that it has negligible effects on F1, FO ATP synthase and/or the adenine nucleotide transporter in oyster mitochondria. Cd exposure altered the patterns of control over mitochondrial respiration, increasing the degree of control conferred by the substrate oxidation subsystem, especially in resting (state 4) mitochondria. Taken together, these data suggest that Cd-induced decrease of mitochondrial efficiency and ATP production are predominantly driven by the high sensitivity of substrate oxidation and proton leak subsystems to this metal.

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