scholarly journals Maintenance of Complex I and respiratory super-complexes by NDUF-11 is essential for respiratory function, mitochondrial structure and health in C. elegans

2021 ◽  
Author(s):  
Amber Knapp-Wilson ◽  
Gonçalo C. Pereira ◽  
Emma Buzzard ◽  
Andrew Richardson ◽  
Robin A. Corey ◽  
...  
Keyword(s):  
Respiratory Function ◽  
Complex I ◽  
Metabolic Stress ◽  
Development Stage ◽  
Complex Iii ◽  
Mitochondrial Morphology ◽  
C Elegans ◽  
Monomeric Complex ◽  
L2 Development ◽  
Conserved Core

ABSTRACTMitochondrial super-complexes form around a conserved core of monomeric complex I and dimeric complex III; wherein subunit NDUFA11, of the former, is conspicuously situated at the interface. We identified B0491.5 (NDUF-11) as the C. elegans homologue, of which animals homozygous for a CRISPR-Cas9 generated knockout allele arrested at the L2 development stage. Reducing expression by RNAi allowed development to the adult stage, enabling characterisation of the consequences: destabilisation of complex I and its super-complexes, and perturbation of respiratory function. The loss of NADH-dehydrogenase activity is compensated by enhanced complex II activity, resulting in excessive detrimental ROS production. Meanwhile, electron cryo-tomography highlight aberrant cristae morphology and widening of the inter-membrane space and cristae junctions. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development highlights the importance of complex I/ super-complex maintenance. Their perturbation by this, or other means, is likely to be the cause of metabolic stress and disease.

scholarly journals Maintenance of complex I and its super-complexes by NDUF-11 is essential for mitochondrial structure, function and health

2021 ◽  
Author(s):  
Amber Knapp-Wilson ◽  
Gonçalo C. Pereira ◽  
Emma Buzzard ◽  
Holly C. Ford ◽  
Andrew Richardson ◽  
...  
Keyword(s):  
Complex I ◽  
Nadh Dehydrogenase ◽  
Development Stage ◽  
Complex Iii ◽  
Mitochondrial Morphology ◽  
C Elegans ◽  
Monomeric Complex ◽  
L2 Development ◽  
Conserved Core ◽  
Knockout Allele

Mitochondrial super-complexes form around a conserved core of monomeric complex I and dimeric complex III; wherein subunit NDUFA11, of the former, is conspicuously situated at the interface. We identified B0491.5 (NDUF-11) as the C. elegans homologue, of which animals homozygous for a CRISPR-Cas9 generated knockout allele arrested at the L2 development stage. Reducing (but not eliminating) expression by RNAi allowed development to adulthood, enabling characterisation of the consequences: destabilisation of complex I and its super-complexes, and perturbation of respiratory function. The loss of NADH-dehydrogenase activity is compensated by enhanced complex II activity, with the potential for detrimental ROS-production. Electron cryo-tomography highlight aberrant cristae morphology and inter-membrane-space widening and cristae-junctions. The requirement of NDUF-11 for balanced respiration, mitochondrial morphology and development presumably arises due to its involvement in complex I/ super-complex maintenance. This highlights the importance of respiratory complex integrity for health and the potential of its perturbation for mitochondrial disease.

scholarly journals Beta-carotene Oxygenase 2 (BCO2) Regulates the Mitochondrial Dynamics in Mice (FS06-06-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Dingbo Lin ◽  
Lei Wu ◽  
Xin Guo ◽  
Siau Yen Wong ◽  
Peiran Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Complex I ◽  
Respiratory Activity ◽  
Mitochondrial Dynamics ◽  
Beta Carotene ◽  
Complex Iii ◽  
Mitochondrial Morphology ◽  
Chow Diet ◽  
Wild Type ◽  
Mitochondrial Respiratory

Abstract Objectives Beta-carotene oxygenase 2 (BCO2) is a carotenoid metabolic enzyme located to the inner membrane of mitochondria. Decreased expression of and mutations in BCO2 are associated with obesity and metabolic disorders in humans and mice. We recently reported that depletion of BCO2 alters mitochondrial respiratory activity. Here, we further present that BCO2 is important for mitochondrial dynamics and respiratory supercomplex formation in mice. Methods Six-week-old male and female 129S6 (wild type, WT) and BCO2 knockout (KO) mice fed a chow diet were used in the current study. Hypothalamic tissues were collected for mitochondrial morphology by transmission electron microscopy, mitochondrial proteomics, and mitochondrial respiratory supercomplex formation and respiratory activity assays. Key proteins in mitochondrial dynamics, including OPA1, Mfn2, DRP1, p62, ULK1 were assessed by Western blot. Cardiolipin was measured by ELISA. Results The results showed that mitochondrial complex I subunit NDUFA11 was more abundant, assembly of complex I into the I-III-IV-containing supercomplexes was greatly enhanced, yet complex III homodimer was diminished in the hypothalamus of the BCO2 knockout mouse, compared to the wild type. Decreases in mitochondrial respiration activities, disruption of mitochondrial elongation (e.g., increased DRP1 and pS757-ULK1), suppression of mitochondrial biogenesis (e.g., decreased PPARgamma and PGC-1alpha), promotion of mitochondrial oxidative stress, and elevation of the cardiolipin level occurred in depletion of BCO2. Conclusions BCO2 is critical for the hypothalamic mitochondrial homeostasis through regulation of respiratory supercomplex formation, mitochondrial dynamics, and consequent oxidative stress. Funding Sources N/A.

scholarly journals Heterochronic Parabiosis: Old Blood Induces Changes in Mitochondrial Structure and Function of Young Mice

2020 ◽  
Author(s):  
Jenny L Gonzalez-Armenta ◽  
Ning Li ◽  
Rae-Ling Lee ◽  
Baisong Lu ◽  
Anthony J A Molina
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Structure And Function ◽  
Muscle Performance ◽  
Mitochondrial Morphology ◽  
Positive Effects ◽  
Mitochondrial Structure ◽  
And Function ◽  
Old Mice ◽  
Young Mice

Abstract Heterochronic parabiosis models have been utilized to demonstrate the role of blood-borne circulating factors in systemic effects of aging. In previous studies, heterochronic parabiosis has shown positive effects across multiple tissues in old mice. More recently, a study demonstrated old blood had a more profound negative effect on muscle performance and neurogenesis of young mice. In this study, we used heterochronic parabiosis to test the hypothesis that circulating factors mediate mitochondrial bioenergetic decline, a well-established biological hallmark of aging. We examined mitochondrial morphology, expression of mitochondrial complexes, and mitochondrial respiration from skeletal muscle of mice connected as heterochronic pairs, as well as young and old isochronic controls. Our results indicate that young heterochronic mice had significantly lower total mitochondrial content and on average had significantly smaller mitochondria compared to young isochronic controls. Expression of complex IV followed a similar pattern: young heterochronic mice had a trend for lower expression compared to young isochronic controls. Additionally, respirometric analyses indicate that young heterochronic mice had significantly lower complex I, complex I + II, and maximal mitochondrial respiration and a trend for lower complex II-driven respiration compared to young isochronic controls. Interestingly, we did not observe significant improvements in old heterochronic mice compared to old isochronic controls, demonstrating the profound deleterious effects of circulating factors from old mice on mitochondrial structure and function. We also found no significant differences between the young and old heterochronic mice, demonstrating that circulating factors can be a driver of age-related differences in mitochondrial structure and function.

scholarly journals Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Zou ◽  
Qixin Chen ◽  
Jesse Slone ◽  
Li Yang ◽  
Xiaoting Lou ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Optic Atrophy ◽  
Respiratory Function ◽  
Clinical Symptoms ◽  
Mitochondrial Dynamics ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Living Cells ◽  
Mitochondrial Morphology ◽  
Mitochondrial Oxidative Phosphorylation

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.

scholarly journals The idebenone metabolite QS10 is an electron donor to complex III and rescues respiration in complex I-deficient cells and rotenone-treated zebrafish

2016 ◽  
Vol 1857 ◽  
pp. e50-e51
Author(s):  
Marco Schiavone ◽  
Valentina Giorgio ◽  
Valeria Petronilli ◽  
Francesco Argenton ◽  
Tatiana Da Ros ◽  
...  
Keyword(s):  
Electron Donor ◽  
Complex I ◽  
Complex Iii

Abstract 296: Early Mitochondrial Gene Regulation in Pediatric Cardiac Arrest

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Marco M Hefti ◽  
Kumaran Senthil ◽  
Michael Karlsson ◽  
Johannes Ehinger ◽  
Constantine D Mavroudis ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Differential Expression ◽  
Respiratory Chain ◽  
Complex I ◽  
Mitochondrial Fission ◽  
Differential Expression Analysis ◽  
Complex Iii ◽  
Swine Model ◽  
Multiple Components ◽  
Dynamin 2

Introduction: Cerebral mitochondrial dysfunction is thought to play a role in the post-cardiac arrest syndrome, propagating secondary morbidity and mortality after return of spontaneous circulation (ROSC). Hypothesis: Based on our previous studies showing a persistent decrease in oxidative phosphorylation (particularly Complex I) and increased mitochondrial fission in a swine model of in-hospital cardiac arrest, we hypothesized that nuclear and mitochondrial genes related to respiratory function would be downregulated and genes promoting mitochondrial fission would be upregulated four hours post-ROSC. Methods: One-month old piglets were subjected to sham anesthesia (n=5) or asphyxial cardiac arrest (n=6; 7 minutes of asphyxia followed by induction of ventricular fibrillation) and treated with 10-20 minutes of AHA guideline-based CPR followed by four hours of standardized post-arrest management and humane euthanasia. RNA was extracted from flash-frozen sections of cerebral cortex using a QIAsymphony robot and sequenced on an Illumina HiSeq. Reads were aligned to the reference (SusScrofa11.1 and NC_012095) using STAR and quantified using subreads. Normalization and differential expression analysis were performed using DESeq2 with RNA quality, intra-arrest and post-ROSC physiologic variables as covariates. All p values were adjusted for multiple comparisons (Benjamini-Hochberg) with a significance cutoff of 0.05. Results: Compared to sham, cardiac arrest animals demonstrated reduced expression of multiple components of the respiratory chain, including NDUFA5 (2.4-fold, p<0.001) and NDUFC1 (2.0-fold, p=0.02), key components of Complex I. Components of Complex III (UQCRB, UQCRH) and Complex IV (COX1, COX7C, COX7A2, COX7B) were also downregulated. Dynamin-2 (DNM2), which increases mitochondrial fission, was upregulated (2.3-fold, p=0.005). There was also differential expression of inner membrane solute channel expression (SLC44A1, SLC25A48 and SLC25A16). Conclusions: Multiple components of the mitochondrial respiratory chain are downregulated 4 hours post-ROSC in the brain, including key components of Complex I with concurrent upregulation of the mitochondrial fission protein dynamin-2.

Corrigendum to: IQ motif containing D (IQCD), a new acrosomal protein involved in the acrosome reaction and fertilisation

2019 ◽  
Vol 31 (5) ◽  
pp. 1033
Author(s):  
Peng Zhang ◽  
Wanjun Jiang ◽  
Na Luo ◽  
Wenbing Zhu ◽  
Liqing Fan
Keyword(s):  
Acrosome Reaction ◽  
Development Stage ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Dependent Manner ◽  
Iq Motif ◽  
C Elegans ◽  
Fertilisation Rate ◽  
Age Dependent ◽  
Mammalian Spermatozoa

The acrosome is single, large, dense-core secretory granule overlying the nucleus of most mammalian spermatozoa. Its exocytosis, the acrosome reaction, is a crucial event during fertilisation. In this study we identified a new acrosome-associated gene, namely IQ motif containing D (IQCD), expressed nearly in multiple tissues with highest expression levels in the testis. In mouse testis, Iqcd transcript accumulated from Postnatal Day (PND) 1 to adulthood. However, expression of IQCD protein at the testicular development stage started primarily from PND 18 and increased in an age-dependent manner until plateauing in adulthood. IQCD was primarily accumulated in the acrosome area of round and elongating spermatids within seminiferous tubules of the testes during the late stage of spermiogenesis; this immunolocalisation pattern is similar in mice and humans. IQCD levels in spermatozoa were significantly lower in IVF patients with total fertilisation failure or a low fertilisation rate than in healthy men. Anti-IQCD antibody significantly inhibited the acrosome reaction and slightly reduced protein tyrosine phosphorylation levels in human spermatozoa, but specifically blocked murine IVF. IQCD interacted with mammalian homolog of C. elegans uncoordinated gene 13 (Munc13) in spermatozoa and may participate in acrosome exocytosis. In conclusion, this study identified a new acrosomal protein, namely IQCD, which is involved in fertilisation and the acrosome reaction.

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