Mito-TIPTP Increases Mitochondrial Function by Repressing the Rubicon-p22phox Interaction in Colitis-Induced Mice

The run/cysteine-rich-domain-containing Beclin1-interacting autophagy protein (Rubicon) is essential for the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase by interacting with p22phox to trigger the production of reactive oxygen species (ROS) in immune cells. In a previous study, we demonstrated that the interaction of Rubicon with p22phox increases cellular ROS levels. The correlation between Rubicon and mitochondrial ROS (mtROS) is poorly understood. Here, we report that Rubicon interacts with p22phox in the outer mitochondrial membrane in macrophages and patients with human ulcerative colitis. Upon lipopolysaccharide (LPS) activation, the binding of Rubicon to p22phox was elevated, and increased not only cellular ROS levels but also mtROS, with an impairment of mitochondrial complex III and mitochondrial biogenesis in macrophages. Furthermore, increased Rubicon decreases mitochondrial metabolic flux in macrophages. Mito-TIPTP, which is a p22phox inhibitor containing a mitochondrial translocation signal, enhances mitochondrial function by inhibiting the association between Rubicon and p22phox in LPS-primed bone-marrow-derived macrophages (BMDMs) treated with adenosine triphosphate (ATP) or dextran sulfate sodium (DSS). Remarkably, Mito-TIPTP exhibited a therapeutic effect by decreasing mtROS in DSS-induced acute or chronic colitis mouse models. Thus, our findings suggest that Mito-TIPTP is a potential therapeutic agent for colitis by inhibiting the interaction between Rubicon and p22phox to recover mitochondrial function.

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NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity

Antioxidants ◽

10.3390/antiox9020171 ◽

2020 ◽

Vol 9 (2) ◽

pp. 171 ◽

Cited By ~ 1

Author(s):

Anne D. Hafstad ◽

Synne S. Hansen ◽

Jim Lund ◽

Celio X. C. Santos ◽

Neoma T. Boardman ◽

...

Keyword(s):

Nadph Oxidase ◽

Mitochondrial Function ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Mechanical Efficiency ◽

Ros Production ◽

Knock Out ◽

Obesity And Diabetes ◽

Mitochondrial Ros ◽

Nadph Oxidase 2 ◽

Knock Out Mice

Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.

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Isometric training improves fatigue resistance in dystrophin-deficient muscle

The Journal of General Physiology ◽

10.1085/jgp.2021ecc38 ◽

2021 ◽

Vol 154 (9) ◽

Author(s):

Nao Yamauchi ◽

Iori Kimura ◽

Yuki Ashida ◽

Azuma Naito ◽

Nao Tokuda ◽

...

Keyword(s):

Fatigue Resistance ◽

Mitochondrial Function ◽

Citrate Synthase ◽

Blue Dye ◽

Rich Domain ◽

Flexor Muscles ◽

Domain 3 ◽

Plantar Flexor Muscles ◽

Cysteine Rich Domain

Eccentric contractions, in which the muscle is stretched during contraction, cause substantially greater damage than isometric (ISO) contractions, in which the length of the muscle does not change during contraction. Here, we tested the hypothesis that ISO training improves fatigue resistance in skeletal muscle from dystrophin-deficient mdx52 mice (15–22 wk old). ISO training (100 Hz stimulation frequency, 0.25-s contractions every 0.5 s, 6 sets of 60 contractions) was performed on the left plantar flexor muscles in vivo with supramaximal electrical stimulation every other day for 4 wk. Compared with the normal control muscle, resistance to fatigue was reduced in the nontrained muscle from mdx52 mice, which was accompanied by a reduction in citrate synthase activity and the LC3BII/I ratio and an increase in the phosphorylation levels of Akt Ser473 and the expression levels of p62. ISO training restored these alterations and markedly increased in vivo fatigue resistance and PGC-1α expression in mdx52 muscles. Moreover, an increased number of Evans Blue dye-positive fibers was significantly reduced by ISO training in mdx52 muscles. In contrast, ISO training did not restore a reduction in the amount of SH3 and cysteine-rich domain 3 in mdx muscles. Thus, our data suggest that mitochondrial function is impaired in dystrophin-deficient muscles, which is likely to be induced by the defective autophagy due to persistent activation of Akt. ISO training inhibits the aberrant activation of Akt presumably by up-regulating the PGC-1α expression, which results in improved mitochondrial function and thus fatigue resistance in dystrophin-deficient muscles.

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The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors

Frontiers in Immunology ◽

10.3389/fimmu.2015.00342 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 10

Author(s):

Nicholas V. L. Yap ◽

Fiona J. Whelan ◽

Dawn M. E. Bowdish ◽

G. Brian Golding

Keyword(s):

Scavenger Receptor ◽

Scavenger Receptors ◽

Class A ◽

Rich Domain ◽

Cysteine Rich Domain

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Studies on the structure and binding properties of the cysteine-rich domain of rat low affinity nerve growth factor receptor (p75NGFR).

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)42451-9 ◽

1992 ◽

Vol 267 (12) ◽

pp. 8352-8359

Author(s):

A.N. Baldwin ◽

C.M. Bitler ◽

A.A. Welcher ◽

E.M. Shooter

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Growth Factor Receptor ◽

Nerve Growth Factor Receptor ◽

Binding Properties ◽

Nerve Growth ◽

Rich Domain ◽

Cysteine Rich Domain

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The unusual structure of the PiggyMac cysteine-rich domain reveals zinc finger diversity in PiggyBac-related transposases

Mobile DNA ◽

10.1186/s13100-021-00240-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marc Guérineau ◽

Luiza Bessa ◽

Séverine Moriau ◽

Ewen Lescop ◽

François Bontems ◽

...

Keyword(s):

Zinc Finger ◽

Dna Cleavage ◽

Trichoplusia Ni ◽

Catalytic Domain ◽

Structural Diversity ◽

Paramecium Tetraurelia ◽

Lysine Methylation ◽

Unusual Structure ◽

Rich Domain ◽

Cysteine Rich Domain

Abstract Background Transposons are mobile genetic elements that colonize genomes and drive their plasticity in all organisms. DNA transposon-encoded transposases bind to the ends of their cognate transposons and catalyze their movement. In some cases, exaptation of transposon genes has allowed novel cellular functions to emerge. The PiggyMac (Pgm) endonuclease of the ciliate Paramecium tetraurelia is a domesticated transposase from the PiggyBac family. It carries a core catalytic domain typical of PiggyBac-related transposases and a short cysteine-rich domain (CRD), flanked by N- and C-terminal extensions. During sexual processes Pgm catalyzes programmed genome rearrangements (PGR) that eliminate ~ 30% of germline DNA from the somatic genome at each generation. How Pgm recognizes its DNA cleavage sites in chromatin is unclear and the structure-function relationships of its different domains have remained elusive. Results We provide insight into Pgm structure by determining the fold adopted by its CRD, an essential domain required for PGR. Using Nuclear Magnetic Resonance, we show that the Pgm CRD binds two Zn2+ ions and forms an unusual binuclear cross-brace zinc finger, with a circularly permutated treble-clef fold flanked by two flexible arms. The Pgm CRD structure clearly differs from that of several other PiggyBac-related transposases, among which is the well-studied PB transposase from Trichoplusia ni. Instead, the arrangement of cysteines and histidines in the primary sequence of the Pgm CRD resembles that of active transposases from piggyBac-like elements found in other species and of human PiggyBac-derived domesticated transposases. We show that, unlike the PB CRD, the Pgm CRD does not bind DNA. Instead, it interacts weakly with the N-terminus of histone H3, whatever its lysine methylation state. Conclusions The present study points to the structural diversity of the CRD among transposases from the PiggyBac family and their domesticated derivatives, and highlights the diverse interactions this domain may establish with chromatin, from sequence-specific DNA binding to contacts with histone tails. Our data suggest that the Pgm CRD fold, whose unusual arrangement of cysteines and histidines is found in all PiggyBac-related domesticated transposases from Paramecium and Tetrahymena, was already present in the ancestral active transposase that gave rise to ciliate domesticated proteins.

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A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A

Human Molecular Genetics ◽

10.1093/hmg/6.4.587 ◽

1997 ◽

Vol 6 (4) ◽

pp. 587-590 ◽

Cited By ~ 31

Author(s):

W Hoppner

Keyword(s):

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Distinct Phenotype ◽

Rich Domain ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Cysteine Rich Domain

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Elucidation of Binding Determinants and Functional Consequences of Ras/Raf-Cysteine-rich Domain Interactions

Journal of Biological Chemistry ◽

10.1074/jbc.m000397200 ◽

2000 ◽

Vol 275 (29) ◽

pp. 22172-22179 ◽

Cited By ~ 65

Author(s):

Jason G. Williams ◽

Jonelle K. Drugan ◽

Gwan-Su Yi ◽

Geoffrey J. Clark ◽

Channing J. Der ◽

...

Keyword(s):

Rich Domain ◽

Domain Interactions ◽

Functional Consequences ◽

Binding Determinants ◽

Cysteine Rich Domain

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Mitochondrial function in flying honeybees (Apis mellifera): respiratory chain enzymes and electron flow from complex III to oxygen

Journal of Experimental Biology ◽

10.1242/jeb.203.5.905 ◽

2000 ◽

Vol 203 (5) ◽

pp. 905-911 ◽

Cited By ~ 9

Author(s):

R.K. Suarez ◽

J.F. Staples ◽

J.R. Lighton ◽

O. Mathieu-Costello

Keyword(s):

Surface Area ◽

Muscle Mass ◽

Respiratory Chain ◽

Mitochondrial Function ◽

Electron Flow ◽

Complex Iii ◽

High Mass ◽

Metabolic Rates ◽

Turnover Rates ◽

Respiratory Enzymes

The biochemical bases for the high mass-specific metabolic rates of flying insects remain poorly understood. To gain insights into mitochondrial function during flight, metabolic rates of individual flying honeybees were measured using respirometry, and their thoracic muscles were fixed for electron microscopy. Mitochondrial volume densities and cristae surface densities, combined with biochemical data concerning cytochrome content per unit mass, were used to estimate respiratory chain enzyme densities per unit cristae surface area. Despite the high content of respiratory enzymes per unit muscle mass, these are accommodated by abundant mitochondria and high cristae surface densities such that enzyme densities per unit cristae surface area are similar to those found in mammalian muscle and liver. These results support the idea that a unit area of mitochondrial inner membrane constitutes an invariant structural unit. Rates of O(2) consumption per unit cristae surface area are much higher than those estimated in mammals as a consequence of higher enzyme turnover rates (electron transfer rates per enzyme molecule) during flight. Cytochrome c oxidase, in particular, operates close to its maximum catalytic capacity (k(cat)). Thus, high flux rates are achieved via (i) high respiratory enzyme content per unit muscle mass and (ii) the operation of these enzymes at high fractional velocities.

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