The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby ...revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca2+ signaling. Among the interaction partners of Mia40 is MICU1—the regulator of the mitochondrial Ca2+ uniporter (MCU), which transfers Ca2+ across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca2+ uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca2+ levels: the dimer associates with MCU at low levels of Ca2+ and dissociates upon high Ca2+ concentrations. Our findings support a model in which mitochondrial Ca2+ uptake is regulated by a Ca2+-dependent remodeling of the uniporter complex.
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•Mia40 interactome links thiol redox to apoptosis, energy metabolism, Ca2+ signaling•MCU serves as platform for disulfide-dependent MICU1-MICU2 dimerization by Mia40•Absence of the disulfide that links MICU1 and MICU2 leads to increased Ca2+ uptake•Ca2+ uptake is controlled by Ca2+-dependent dissociation of the MICU dimer from MCU
Petrungaro et al. characterize the interactome of the human mitochondrial oxidoreductase Mia40, among which is MICU1, the regulator of the mitochondrial Ca2+ uniporter (MCU). Mia40 primes MICU1 for heterodimerization with MICU2, and the dimer associates with MCU in a Ca2+-dependent manner to control mitochondrial Ca2+ uptake.
The essential oxidoreductase Mia40/CHCHD4 mediates disulfide bond formation and protein folding in the mitochondrial intermembrane space. Here, we investigated the interactome of Mia40 thereby ...revealing links between thiol-oxidation and apoptosis, energy metabolism, and Ca(2+) signaling. Among the interaction partners of Mia40 is MICU1-the regulator of the mitochondrial Ca(2+) uniporter (MCU), which transfers Ca(2+) across the inner membrane. We examined the biogenesis of MICU1 and find that Mia40 introduces an intermolecular disulfide bond that links MICU1 and its inhibitory paralog MICU2 in a heterodimer. Absence of this disulfide bond results in increased receptor-induced mitochondrial Ca(2+) uptake. In the presence of the disulfide bond, MICU1-MICU2 heterodimer binding to MCU is controlled by Ca(2+) levels: the dimer associates with MCU at low levels of Ca(2+) and dissociates upon high Ca(2+) concentrations. Our findings support a model in which mitochondrial Ca(2+) uptake is regulated by a Ca(2+)-dependent remodeling of the uniporter complex.
Previous research suggests that European citizens share consistent attitudes towards the relative deservingness of different target groups of social policy, such as perceiving elderly people as most ...deserving, unemployed people as less deserving and immigrants as least deserving. Yet, it is unclear which criteria people apply when making these judgements. In this article, we explore the reasoning behind deservingness judgements. We analyse how four focus groups – from the middle class, the working class, young people and elderly people – discuss and rank various vignettes representing welfare target groups. Our focus groups’ rankings mirror the well-established rank order of welfare target groups, and we also introduce further target groups: median-income families, low-income earners, and well-off earners. Our analyses of reasoning patterns show that depending on the target group specific combinations of deservingness criteria suggested in the literature (e.g. need, reciprocity, identity, control) are applied, and we suggest adding a further criterion emphasizing future returns on invested resources (‘social investment’). Furthermore, by comparing focus groups, we find that different groups back up similar rankings by differing criteria, suggesting that below the surface of a ‘common deservingness culture’ linger class and other differences in perceiving welfare deservingness.
The European Green Deal calls for various economic reforms that will deeply disrupt the social order of European societies. As the European Commission makes very clear in its communications on the ...EGD, societal support for the profound changes that will inevitably accompany a ‘green transition’ hinges on social inclusion of stakeholders and social groups. This article aims to identify the social policy instruments proposed by the EGD to address the social implications of its ‘green transition’, and to explore how they relate to societal expectations. Analytically, it distinguishes between protective (redistributive) and productive (economy-oriented) social policy and argues that democratic social inclusion – which the European Commission strives to achieve – requires protective social policy. Empirically, the paper analyzes a) the socio-political instruments set out in the EGD and b) public statements made by a range of European-level actors who participated in the debates on the EGD. Our findings show that productive social policy prevails in the EGD's proposed instruments and in stakeholders’ demands, but that there are also vague indications of a more nuanced concept of social inclusion that acknowledges social conflict.
To fulfill its role in protein biogenesis, the endoplasmic reticulum (ER) depends on the Hsp70-type molecular chaperone BiP, which requires a constant ATP supply. However, the carrier that catalyzes ...ATP uptake into the ER was unknown. Here, we report that our screen of gene expression datasets for member(s) of the family of solute carriers that are co-expressed with BiP and are ER membrane proteins identifies SLC35B1 as a potential candidate. Heterologous expression of SLC35B1 in E. coli reveals that SLC35B1 is highly specific for ATP and ADP and acts in antiport mode. Moreover, depletion of SLC35B1 from HeLa cells reduces ER ATP levels and, as a consequence, BiP activity. Thus, human SLC35B1 may provide ATP to the ER and was named AXER (ATP/ADP exchanger in the ER membrane). Furthermore, we propose an ER to cytosol low energy response regulatory axis (termed lowER) that appears as central for maintaining ER ATP supply.
Cold allodynia elicited by local intraplantar injection of the chemotherapeutic agent oxaliplatin is mediated through Nav1.6-expressing peripheral sensory fibres. Activation of Nav1.6 alone elicits ...only mechanical allodynia and spontaneous pain, but when combined with inhibition of Kv channels, profound cold allodynia develops.
Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Nav pathways. Using selective inhibitors and knockout animals, we found that Nav1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K+-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Nav1.6 blockers. Intraplantar injection of the Nav1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.
Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of ...inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.
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•TRPV1 acts as an ionotropic oxytocin receptor in cells•Oxytocin potentiates TRPV1 in cells and lipid bilayers•Oxytocin interacts with TRPV1 at the extracellular pore loop region•Oxytocin attenuates capsaicin-induced nociception via TRPV1 desensitization
Oxytocin is known to suppress painful stimuli of inflammatory origin. Nersesyan et al. now find that oxytocin attenuates pain via the pain-sensing receptor TRPV1.
Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFβ ...superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.
The sensation of cold or heat depends on the activation of specific nerve endings in the skin. This involves heat‐ and cold‐sensitive excitatory transient receptor potential (TRP) channels. However, ...we show here that the mechano‐gated and highly temperature‐sensitive potassium channels of the TREK/TRAAK family, which normally work as silencers of the excitatory channels, are also implicated. They are important for the definition of temperature thresholds and temperature ranges in which excitation of nociceptor takes place and for the intensity of excitation when it occurs. They are expressed with thermo‐TRP channels in sensory neurons. TRAAK and TREK‐1 channels control pain produced by mechanical stimulation and both heat and cold pain perception in mice. Expression of TRAAK alone or in association with TREK‐1 controls heat responses of both capsaicin‐sensitive and capsaicin‐insensitive sensory neurons. Together TREK‐1 and TRAAK channels are important regulators of nociceptor activation by cold, particularly in the nociceptor population that is not activated by menthol.
Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been ...excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting
SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating
SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with
SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion.
SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.
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