HER-096 is a CDNF-derived brain-penetrating peptidomimetic that protects dopaminergic neurons in a mouse synucleinopathy model of Parkinson's disease.

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models.

EMRE is essential for mitochondrial calcium uniporter activity in a mouse model.

The mitochondrial calcium uniporter is widely accepted as the primary route of rapid calcium entry into mitochondria, where increases in matrix calcium contribute to bioenergetics but also mitochondrial permeability and cell death. Hence, regulation of uniporter activity is critical to mitochondrial homeostasis. The uniporter subunit EMRE is known to be an essential regulator of the channel-forming protein MCU in cell culture, but EMRE's impact on organismal physiology is less understood.

Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter.

Aims: Knockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice.

Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology.

Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues.

The multifaceted role of Nrf2 in mitochondrial function.

The transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) is the master regulator of the cellular redox homeostasis. Nrf2 target genes comprise of a large network of antioxidant enzymes, proteins involved in xenobiotic detoxification, repair and removal of damaged proteins, inhibition of inflammation, as well as other transcription factors. In recent years it has emerged that as part of its role as a regulator of cytoprotective gene expression, Nrf2 impacts mitochondrial function.

Strategic Positioning and Biased Activity of the Mitochondrial Calcium Uniporter in Cardiac Muscle.

Control of myocardial energetics by Ca signal propagation to the mitochondrial matrix includes local Ca delivery from sarcoplasmic reticulum (SR) ryanodine receptors (RyR2) to the inner mitochondrial membrane (IMM) Ca uniporter (mtCU). mtCU activity in cardiac mitochondria is relatively low, whereas the IMM surface is large, due to extensive cristae folding. Hence, stochastically distributed mtCU may not suffice to support local Ca transfer.

MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload.

MICU1 is a component of the mitochondrial calcium uniporter, a multiprotein complex that also includes MICU2, MCU, and EMRE. Here, we describe a mouse model of MICU1 deficiency. MICU1(-/-) mitochondria demonstrate altered calcium uptake, and deletion of MICU1 results in significant, but not complete, perinatal mortality.

Measuring In Vivo Mitophagy.

Alterations in mitophagy have been increasingly linked to aging and age-related diseases. There are, however, no convenient methods to analyze mitophagy in vivo. Here, we describe a transgenic mouse model in which we expressed a mitochondrial-targeted form of the fluorescent reporter Keima (mt-Keima).

Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter.

Mitochondrial calcium is thought to play an important role in the regulation of cardiac bioenergetics and function. The entry of calcium into the mitochondrial matrix requires that the divalent cation pass through the inner mitochondrial membrane via a specialized pore known as the mitochondrial calcium uniporter (MCU). Here, we use mice deficient of MCU expression to rigorously assess the role of mitochondrial calcium in cardiac function.

The ins and outs of mitochondrial calcium.

Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis.

Nrf2 regulates ROS production by mitochondria and NADPH oxidase.

Background: Nuclear factor (erythroid-derived 2) factor 2 (Nrf2) is a crucial transcription factor mediating protection against oxidants. Nrf2 is negatively regulated by cytoplasmic Kelch-like ECH associated protein 1 (Keap1) thereby providing inducible antioxidant defence. Antioxidant properties of Nrf2 are thought to be mainly exerted by stimulating transcription of antioxidant proteins, whereas its effects on ROS production within the cell are uncertain.

Cellular mechanisms and physiological consequences of redox-dependent signalling.

Reactive oxygen species (ROS), which were originally characterized in terms of their harmful effects on cells and invading microorganisms, are increasingly implicated in various cell fate decisions and signal transduction pathways. The mechanism involved in ROS-dependent signalling involves the reversible oxidation and reduction of specific amino acids, with crucial reactive Cys residues being the most frequent target. In this Review, we discuss the sources of ROS within cells and what is known regarding how intracellular oxidant levels are regulated.

Unresolved questions from the analysis of mice lacking MCU expression.

Entry of mitochondrial calcium is believed to play an essential role in regulating bioenergetics and initiating cell death pathways. We have recently described a mouse model lacking MCU expression. Surprisingly, these mice are viable and the cells and tissues from these animals do not exhibit any marked protection from cell death.

Rare individual amyloid-β oligomers act on astrocytes to initiate neuronal damage.

Oligomers of the amyloid-β (Aβ) peptide have been implicated in the neurotoxicity associated with Alzheimer's disease. We have used single-molecule techniques to examine quantitatively the cellular effects of adding well characterized Aβ oligomers to primary hippocampal cells and hence determine the initial pathway of damage. We found that even picomolar concentrations of Aβ (1-40) and Aβ (1-42) oligomers can, within minutes of addition, increase the levels of intracellular calcium in astrocytes but not in neurons, and this effect is saturated at a concentration of about 10 nM of oligomers.

Acetylcholine and antibodies against the acetylcholine receptor protect neurons and astrocytes against beta-amyloid toxicity.

Aggregated amyloid-β causes pathological changes in mixed cultures of neurons and astrocytes such as sporadic cytoplasmic intracellular Ca(2+)-signalling, increase in reactive oxygen species production and cell death. Some of the toxic effects of amyloid-β are mediated through the interaction of the peptide with α7-type nicotinic acetylcholine receptors at the cell surface. Here we demonstrated that affinity purified antibodies to synthetic fragment 173-193 of the α7-subunit of the nAChR are able to protect cells from amyloid-β induced cell death.

Glucocorticoids reduce intracellular calcium concentration and protects neurons against glutamate toxicity.

Glucocorticoids are steroid hormones which act through the glucocorticoid receptor. They regulate a wide variety of biological processes. Two glucocorticoids, the naturally occurring corticosterone and chemically produced dexamethasone, have been used to investigate the effect of glucocorticoids on Ca(2+)-signalling in cortical co-cultures of neurons and astrocytes.

Signalling properties of inorganic polyphosphate in the mammalian brain.

Inorganic polyphosphate is known to be present in the mammalian brain at micromolar concentrations. Here we show that polyphosphate may act as a gliotransmitter, mediating communication between astrocytes. It is released by astrocytes in a calcium-dependent manner and signals to neighbouring astrocytes through P2Y(1) purinergic receptors, activation of phospholipase C and release of calcium from the intracellular stores.

Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.

In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia. Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) signaling.

The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.

Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria.

PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.

Parkinson's disease is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive Parkinson's disease. However, their molecular contribution to pathogenesis remains unclear.

Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1.

Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear.

Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin.

Degeneration of dopaminergic neurons in the substantia nigra is characteristic for Parkinson's disease (PD), the second most common neurodegenerative disorder. Mitochondrial dysfunction is believed to contribute to the etiology of PD. Although most cases are sporadic, recent evidence points to a number of genes involved in familial variants of PD.