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Scientific Reports Jan 2021Earlier we have reported mercury-induced alterations in functional dynamics of buck spermatozoa through free radicals-mediated oxidative stress and spontaneous acrosome...
Earlier we have reported mercury-induced alterations in functional dynamics of buck spermatozoa through free radicals-mediated oxidative stress and spontaneous acrosome reaction. Based on our earlier findings, we aimed to investigate the effect of mercury exposure on motility, kinematic patterns, DNA damage, apoptosis and ultra-structural alterations in goat spermatozoa following in vitro exposure to different concentrations (0.031-1.25 µg/ml) of mercuric chloride for 15 min and 3 h. Following exposure of sperm cells to 0.031 µg/ml of mercuric chloride for 3 h, livability and motility of sperms was significantly reduced along with altered kinematic patterns, significant increase in per cent necrotic sperm cells and number of cells showing DNA damage; and this effect was dose- and time-dependent. Contrary to up-regulation of Bax gene after 3 h in control group, there was significant increase in expression of Bcl-2 in mercury-treated groups. Transmission electron microscopy studies revealed rifts and nicks in plasma and acrosomal membrane, mitochondrial sheath, and collapsed mitochondria with loss of helical organization of mitochondria in the middle piece of spermatozoa. Our findings evidently suggest that mercury induces necrosis instead of apoptosis and targets the membrane, acrosome, mid piece of sperms; and the damage to mitochondria seems to be responsible for alterations in functional and kinematic attributes of spermatozoa.
Topics: Animals; Biomechanical Phenomena; Goats; Male; Mercury; Mitochondria; Mitochondrial Membranes; Sperm Capacitation; Sperm Motility; Spermatozoa
PubMed: 33436823
DOI: 10.1038/s41598-020-80235-y -
Current Biology : CB Jun 2022Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients...
Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients into the energy-rich compound ATP. Mitochondrial ATP biosynthesis is a marvel of thermodynamic efficiency. Via the tricarboxylic acid cycle (TCA) and fatty acid β-oxidation, mitochondria extract electrons from dietary carbon compounds and pass them to nucleotides that ultimately deliver them to the respiratory chain complexes located in invaginations in the inner mitochondrial membrane (IMM) known as cristae. The respiratory chain complexes donate electrons in stepwise redox reactions to molecular oxygen and, with the exception of complex II, use the liberated energy to pump protons across the proton-impermeable IMM, generating a proton electrochemical gradient. This gradient is then utilized by the ATP synthase, which, in a rotary mechanism, catalyzes the formation of the high-energy γ-phosphate chemical bond between ADP and inorganic phosphate. The conversion of the chemical energy of carbon compounds into a physical, vectorial form of energy (the electrochemical gradient) maximizes the yield of the ATP biosynthetic process and is perhaps one of the foundations of life as we know it.
Topics: Adenosine Triphosphate; Carbon; Mitochondria; Mitochondrial Membranes; Protons
PubMed: 35728541
DOI: 10.1016/j.cub.2022.05.006 -
Trends in Cancer Dec 2017Until recently, the dual roles of mitochondria in ATP production (bioenergetics) and apoptosis (cell life/death decision) were thought to be separate. New evidence... (Review)
Review
Until recently, the dual roles of mitochondria in ATP production (bioenergetics) and apoptosis (cell life/death decision) were thought to be separate. New evidence points to a more intimate link between these two functions, mediated by the remodeling of the mitochondrial ultrastructure during apoptosis. While most of the key molecular players that regulate this process have been identified (primarily membrane proteins), the exact mechanisms by which they function are not yet understood. Because resistance to apoptosis is a hallmark of cancer, and because ultimately all chemotherapies are believed to result directly or indirectly in induction of apoptosis, a better understanding of the biophysical processes involved may lead to new avenues for therapy.
Topics: Adenosine Triphosphate; Apoptosis; Energy Metabolism; Humans; Mitochondria; Mitochondrial Membranes; Neoplasms
PubMed: 29198441
DOI: 10.1016/j.trecan.2017.10.006 -
PLoS Biology Aug 2023The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell...
The convolution of membranes called cristae is a critical structural and functional feature of mitochondria. Crista structure is highly diverse between different cell types, reflecting their role in metabolic adaptation. However, their precise three-dimensional (3D) arrangement requires volumetric analysis of serial electron microscopy and has therefore been limiting for unbiased quantitative assessment. Here, we developed a novel, publicly available, deep learning (DL)-based image analysis platform called Python-based human-in-the-loop workflow (PHILOW) implemented with a human-in-the-loop (HITL) algorithm. Analysis of dense, large, and isotropic volumes of focused ion beam-scanning electron microscopy (FIB-SEM) using PHILOW reveals the complex 3D nanostructure of both inner and outer mitochondrial membranes and provides deep, quantitative, structural features of cristae in a large number of individual mitochondria. This nanometer-scale analysis in micrometer-scale cellular contexts uncovers fundamental parameters of cristae, such as total surface area, orientation, tubular/lamellar cristae ratio, and crista junction density in individual mitochondria. Unbiased clustering analysis of our structural data unraveled a new function for the dynamin-related GTPase Optic Atrophy 1 (OPA1) in regulating the balance between lamellar versus tubular cristae subdomains.
Topics: Humans; Mitochondrial Membranes; Deep Learning; Mitochondria; Acclimatization; Algorithms
PubMed: 37651352
DOI: 10.1371/journal.pbio.3002246 -
Current Biology : CB Mar 2023Striated intracytoplasmic membranes in alphaproteobacteria are often reminiscent of millefoglie pastries. A new study reveals a protein complex homologous to that...
Striated intracytoplasmic membranes in alphaproteobacteria are often reminiscent of millefoglie pastries. A new study reveals a protein complex homologous to that responsible for mitochondrial cristae formation drives intracytoplasmic membrane formation, thereby establishing bacterial ancestry for the biogenesis of mitochondrial cristae.
Topics: Mitochondria; Mitochondrial Proteins; Mitochondrial Membranes
PubMed: 36977381
DOI: 10.1016/j.cub.2023.02.037 -
Advanced Biology Jan 2024Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The...
Mitochondria are required for energy production and even give brown adipose tissue (BAT) its characteristic color due to their high iron content and abundance. The physiological function and bioenergetic capacity of mitochondria are connected to the structure, folding, and organization of its inner-membrane cristae. During the aging process, mitochondrial dysfunction is observed, and the regulatory balance of mitochondrial dynamics is often disrupted, leading to increased mitochondrial fragmentation in aging cells. Therefore, it is hypothesized that significant morphological changes in BAT mitochondria and cristae will be present with aging. A quantitative 3D electron microscopy approach is developed to map cristae network organization in mouse BAT to test this hypothesis. Using this methodology, the 3D morphology of mitochondrial cristae is investigated in adult (3-month) and aged (2-year) murine BAT tissue via serial block face-scanning electron microscopy (SBF-SEM) and 3D reconstruction software for manual segmentation, analysis, and quantification. Upon investigation, an increase is found in mitochondrial volume, surface area, and complexity and decreased sphericity in aged BAT, alongside significant decreases in cristae volume, area, perimeter, and score. Overall, these data define the nature of the mitochondrial structure in murine BAT across aging.
Topics: Animals; Mice; Adipose Tissue, Brown; Mitochondrial Membranes; Mitochondria; Energy Metabolism; Aging
PubMed: 37607124
DOI: 10.1002/adbi.202300186 -
Journal of Biological Inorganic... Jun 2018The majority of established model organisms belong to the supergroup Opisthokonta, which includes yeasts and animals. While enlightening, this focus has... (Review)
Review
The majority of established model organisms belong to the supergroup Opisthokonta, which includes yeasts and animals. While enlightening, this focus has neglected protists, organisms that represent the bulk of eukaryotic diversity and are often regarded as primitive eukaryotes. One of these is the "supergroup" Excavata, which comprises unicellular flagellates of diverse lifestyles and contains species of medical importance, such as Trichomonas, Giardia, Naegleria, Trypanosoma and Leishmania. Excavata exhibits a continuum in mitochondrial forms, ranging from classical aerobic, cristae-bearing mitochondria to mitochondria-related organelles, such as hydrogenosomes and mitosomes, to the extreme case of a complete absence of the organelle. All forms of mitochondria house a machinery for the assembly of Fe-S clusters, ancient cofactors required in various biochemical activities needed to sustain every extant cell. In this review, we survey what is known about the Fe-S cluster assembly in the supergroup Excavata. We aim to bring attention to the diversity found in this group, reflected in gene losses and gains that have shaped the Fe-S cluster biogenesis pathways.
Topics: Eukaryota; Iron; Iron-Sulfur Proteins; Mitochondria
PubMed: 29623424
DOI: 10.1007/s00775-018-1556-6 -
Cell Metabolism Jun 2015Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is...
Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo.
Topics: Animals; Cytochromes c; GTP Phosphohydrolases; Mice; Mice, Transgenic; Mitochondria; Muscular Atrophy; Oxygen Consumption; Reactive Oxygen Species
PubMed: 26039448
DOI: 10.1016/j.cmet.2015.05.007 -
The Journal of Biological Chemistry Oct 2023Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the question of whether their...
Respiratory complexes and cardiolipins have exceptionally long lifetimes. The fact that they co-localize in mitochondrial cristae raises the question of whether their longevities have a common cause and whether the longevity of OXPHOS proteins is dependent on cardiolipin. To address these questions, we developed a method to measure side-by-side the half-lives of proteins and lipids in wild-type Drosophila and cardiolipin-deficient mutants. We fed adult flies with stable isotope-labeled precursors (CN-lysine or C-glucose) and determined the relative abundance of heavy isotopomers in protein and lipid species by mass spectrometry. To minimize the confounding effects of tissue regeneration, we restricted our analysis to the thorax, the bulk of which consists of post-mitotic flight muscles. Analysis of 680 protein and 45 lipid species showed that the subunits of respiratory complexes I-V and the carriers for phosphate and ADP/ATP were among the longest-lived proteins (average half-life of 48 ± 16 days) while the molecular species of cardiolipin were the longest-lived lipids (average half-life of 27 ± 6 days). The remarkable longevity of these crista residents was not shared by all mitochondrial proteins, especially not by those residing in the matrix and the inner boundary membrane. Ablation of cardiolipin synthase, which causes replacement of cardiolipin by phosphatidylglycerol, and ablation of tafazzin, which causes partial replacement of cardiolipin by monolyso-cardiolipin, decreased the lifetimes of the respiratory complexes. Ablation of tafazzin also decreased the lifetimes of the remaining cardiolipin species. These data suggest that an important function of cardiolipin in mitochondria is to protect respiratory complexes from degradation.
Topics: Animals; Cardiolipins; Mitochondria; Mitochondrial Membranes; Muscles; Drosophila melanogaster
PubMed: 37690688
DOI: 10.1016/j.jbc.2023.105241 -
Molecular Genetics and Metabolism 2020Mitochondrial respiratory chain integrity depends on a number of proteins encoded by nuclear and mitochondrial genomes. Mutations of such factors can result in isolated...
Mitochondrial respiratory chain integrity depends on a number of proteins encoded by nuclear and mitochondrial genomes. Mutations of such factors can result in isolated or combined respiratory chain deficits, some of which can induce abnormal morphology of the mitochondrial network or accumulation of intermediary metabolites. Consequently, affected patients are clinically heterogeneous, presenting with central nervous system, muscular, or neurodegenerative disorders. ATAD3A is a nuclear-encoded ATPase protein of the AAA+ family and has been localized to the inner mitochondrial membrane. Recently reported mutations or large deletions in the ATDA3A gene in patients have been shown to induce altered mitochondrial structure and function and abnormal cholesterol metabolism in a recessive or dominant manner. Here, we report two siblings presenting axonal sensory-motor neuropathy associated with neonatal cataract. Genetic analyses identified two novel mutations in ATAD3A; a point mutation and an intronic 15 bp deletion affecting splicing and leading to exon skipping. Biochemical analysis in patient cells and tissues showed abnormal function of the mitochondrial respiratory chain in muscle and abnormal mitochondrial cristae structure. These new cases underline the large spectrum of biochemical and clinical presentations of ATAD3A deficiency and the different modes of inheritance, making it an atypical mitochondrial disorder.
Topics: ATPases Associated with Diverse Cellular Activities; Adolescent; Adult; Child; Child, Preschool; Electron Transport; Female; Humans; Male; Membrane Proteins; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Sensorimotor Cortex; Siblings
PubMed: 32933822
DOI: 10.1016/j.ymgme.2020.09.002