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The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank–Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca 2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca 2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases. The beating heart adapts cardiac output to changes in mechanical load via incompletely understood mechanotransduction mechanisms. Here the authors show that the mechanosensitive Piezo1 channel serves as a mechanotransducer for directly converting mechanical stretch of cardiomyocytes into Ca 2+ and ROS signaling and consequently maintaining normal heart function.

FHIRM-TPM is a miniature two-photon microscope capable of imaging fluorescently labeled neurons in the brains of freely behaving mice. It allows for imaging of spines or recording of neural activity with a frame rate up to 40 Hz. Developments in miniaturized microscopes have enabled visualization of brain activities and structural dynamics in animals engaging in self-determined behaviors. However, it remains a challenge to resolve activity at single dendritic spines in freely behaving animals. Here, we report the design and application of a fast high-resolution, miniaturized two-photon microscope (FHIRM-TPM) that accomplishes this goal. With a headpiece weighing 2.15 g and a hollow-core photonic crystal fiber delivering 920-nm femtosecond laser pulses, the FHIRM-TPM is capable of imaging commonly used biosensors (GFP and GCaMP6) at high spatiotemporal resolution (0.64 μm laterally and 3.35 μm axially, 40 Hz at 256 × 256 pixels for raster scanning and 10,000 Hz for free-line scanning). We demonstrate the microscope's robustness with hour-long recordings of neuronal activities at the level of spines in mice experiencing vigorous body movements.

We have developed a miniature two-photon microscope equipped with an axial scanning mechanism and a long-working-distance miniature objective to enable multi-plane imaging over a volume of 420 × 420 × 180 μm3 at a lateral resolution of ~1 μm. Together with the detachable design that permits long-term recurring imaging, our miniature two-photon microscope can help decipher neuronal mechanisms in freely behaving animals.A two-photon miniature microscope with enlarged field of view and axial scanning capabilities has been developed and applied in freely moving mice.

The impairment of mitochondrial bioenergetics, often coupled with exaggerated reactive oxygen species (ROS) production, is a fundamental disease mechanism in organs with a high demand for energy, including the heart. Building a more robust and safer cellular powerhouse holds the promise for protecting these organs in stressful conditions. Here, we demonstrate that NADH:ubiquinone oxidoreductase subunit AB1 (NDUFAB1), also known as mitochondrial acyl carrier protein, acts as a powerful cardio-protector by conferring greater capacity and efficiency of mitochondrial energy metabolism. In particular, NDUFAB1 not only serves as a complex I subunit, but also coordinates the assembly of respiratory complexes I, II, and III, and supercomplexes, through regulating iron-sulfur biosynthesis and complex I subunit stability. Cardiac-specific deletion of Ndufab1 in mice caused defective bioenergetics and elevated ROS levels, leading to progressive dilated cardiomyopathy and eventual heart failure and sudden death. Overexpression of Ndufab1 effectively enhanced mitochondrial bioenergetics while limiting ROS production and protected the heart against ischemia-reperfusion injury. Together, our findings identify that NDUFAB1 is a crucial regulator of mitochondrial energy and ROS metabolism through coordinating the assembly of respiratory complexes and supercomplexes, and thus provide a potential therapeutic target for the prevention and treatment of heart failure.

Calcium leads the way Directional cell movement depends on an intracellular calcium gradient. In a study of migrating fibroblasts, Chaoliang Wei et al . have identified calcium flickers — high-calcium microdomains — as part of the mechanism that steers cells to their targets. The flickers are most active at the leading edge of migrating cells. In the presence of a chemotactic gradient, an asymmetric gradient of calcium flicker activity develops which promotes turning of cells towards the direction of the chemoattractant. Directional cell movement depends on an intracellular calcium gradient. This study identifies calcium flickers in migrating fibroblasts and these are most active at the leading edge of cells. In the presence of a chemotactic gradient, an asymmetric gradient of calcium flicker activity develops which promotes turning of cells towards the direction of the chemoattractant. Directional movement is a property common to all cell types during development and is critical to tissue remodelling and regeneration after damage 1 , 2 , 3 . In migrating cells, calcium has a multifunctional role in directional sensing, cytoskeleton redistribution, traction force generation, and relocation of focal adhesions 1 , 4 , 5 , 6 , 7 . Here we visualize high-calcium microdomains (‘calcium flickers’) and their patterned activation in migrating human embryonic lung fibroblasts. Calcium flicker activity is dually coupled to membrane tension (by means of TRPM7, a stretch-activated Ca 2+ -permeant channel of the transient receptor potential superfamily 8 ) and chemoattractant signal transduction (by means of type 2 inositol-1,4,5-trisphosphate receptors). Interestingly, calcium flickers are most active at the leading lamella of migrating cells, displaying a 4:1 front-to-rear polarization opposite to the global calcium gradient 6 . When exposed to a platelet-derived growth factor gradient perpendicular to cell movement, asymmetric calcium flicker activity develops across the lamella and promotes the turning of migrating fibroblasts. These findings show how the exquisite spatiotemporal organization of calcium microdomains can orchestrate complex cellular processes such as cell migration.

Chinese indigenous sheep can be classified into three types based on tail morphology: fat-tailed, fat-rumped, and thin-tailed sheep, of which the typical breeds are large-tailed Han sheep, Altay sheep, and Tibetan sheep, respectively. To unravel the molecular genetic basis underlying the phenotypic differences among Chinese indigenous sheep with these three different tail types, we used ovine high-density 600K single nucleotide polymorphism (SNP) arrays to detect genome-wide associations, and performed general linear model analysis to identify candidate genes, using genotyping technology to validate the candidate genes. Tail type is an important economic trait in sheep. However, the candidate genes associated with tail type are not known. The objective of this study was to identify SNP markers, genes, and chromosomal regions related to tail traits. We performed a genome-wide association study (GWAS) using data from 40 large-tailed Han sheep, 40 Altay sheep (cases) and 40 Tibetan sheep (controls). A total of 31 significant (P<0.05) SNPs associated with tail-type traits were detected. For significant SNPs' loci, we determined their physical location and performed a screening of candidate genes within each region. By combining information from previously reported and annotated biological functional genes, we identified SPAG17, Tbx15, VRTN, NPC2, BMP2 and PDGFD as the most promising candidate genes for tail-type traits. Based on the above identified candidate genes for tail-type traits, BMP2 and PDGFD genes were selected to investigate the relationship between SNPs within the tails in the Altay and Tibetan populations. rs119 T>C in exon1 of the BMP2 gene and one SNP in exon4 (rs69 C>A) of the PDGFD gene were detected. rs119 was of the TT genotype in Altay sheep, while it was of the CC genotype in Tibetan sheep. On rs69 of the PDGFD gene, Altay sheep presented with the CC genotype; however, Tibetan sheep presented with the AA genotype.

Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca 2+ uniport while inhibiting vicious membrane permeability transition. Importantly, ROMO1 overexpression reverses mitochondrial cysteinome oxidations in multiple organs and slows functional decline in aged male mice. These findings unravel a redox regulatory mechanism of the mitochondrial cysteinome and mark ROMO1 as a potential target for combating oxidative stress and improving healthspan. As a major source of reactive oxygen species, mitochondria face a challenge to maintain their redox state. Here the authors show that ROMO1 overexpression prevents deleterious oxidation of the mitochondrial cysteinome and exerts beneficial effects on mitochondrial function.

Mitochondrial superoxide dismutase 2 (SOD2) is a major antioxidant defense enzyme. Here we provide evidence that SOD2 plays critical roles in maintaining calcium homeostasis in newly generated embryonic cerebral cortical neurons, which is essential for normal mitochondrial function and subcellular distribution, and neurite outgrowth. Primary cortical neurons in cultures established from embryonic day 15 SOD2+/+ and SOD2−/− mice appear similar during the first 24 h in culture. During the ensuing two days in culture, SOD2−/− neurons exhibit a profound reduction of neurite outgrowth and their mitochondria become fragmented and accumulate in the cell body. The structural abnormalities of the mitochondria are associated with reduced levels of phosphorylated (S637) dynamin related protein 1 (Drp1), a major mitochondrial fission-regulating protein, whereas mitochondrial fusion regulating proteins (OPA1 and MFN2) are relatively unaffected. Mitochondrial fission and Drp1 dephosphorylation coincide with impaired mitochondrial Ca2+ buffering capacity and an elevation of cytosolic Ca2+ levels. Treatment of SOD2−/− neurons with the Ca2+ chelator BAPTA-AM significantly increases levels of phosphorylated Drp1, reduces mitochondrial fragmentation and enables neurite outgrowth.

Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca 2+ release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca 2+ release. Heart muscle cells exhibit exquisitely organized subcellular features that enable efficient and coordinated heart muscle contraction, but little is known about how it is achieved. Here the authors show that CMYA5 organizes cardiomyocyte calcium release units and aligns them to sarcomeres, leading to abnormal calcium release, cardiac dysfunction, and inability to tolerate pressure overload, when absent.

Dear Editor, Recent advent of light-sheet fluorescent microscopy （LSFM） has revolutionized three-dimensional biological imaging with high temporal resolution and minimal photodamage, enabling long-term fluorescence imaging of tissues and small organisms [1-2]. By combining two-photon fluorescence excitation with LSFM, Truong et al. [3] have created a two-photon digital scanned lightsheet microscope （2P-DSLM）, allowing for deep-tissue imaging of highly scattering Drosophila embryos and fast beating hearts of zebrafish. Similar to classical LSFM configurations, a 2P-DSLM uses a low numerical aperture （NA 〈 0.1） to achieve a long and homogenous illumination. This leads to a thick light sheet and thus reduces axial resolution and image contrast. On the other hand, Betzig and colleagues have used a Bessel beam to generate thin single-photon light sheet that yields superb axial resolution [4]. However, the field of view and the penetration depth are limited in such system.