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Mitochondrial dysfunction is an underlying cause of ischemia-reperfusion injury. In particular, ischemic injury induces dramatic increases in mitochondrial permeability, thereby instigating a chain of events that leads to both apoptotic and necrotic cardiomyocyte death. The mitochondrial permeability transition (MPT) pore, a large, non-specific channel that spans the inner mitochondrial membrane, is known to mediate the lethal permeability changes that initiate mitochondrial-driven cardiomyocyte death. The purpose of this review is to focus on the role of the MPT pore in ischemia-reperfusion injury, the mechanisms involved, and, in particular, what we do and do not know regarding the pore’s molecular composition.

A quantum spin liquid is a state of matter where unpaired electrons’ spins, although entangled, do not show magnetic order even at the zero temperature. The realization of a quantum spin liquid is a long-sought goal in condensed-matter physics. Although neutron scattering experiments on the two-dimensional spin-1/2 kagome lattice ZnCu3(OD)6Cl2 and triangular lattice YbMgGaO4 have found evidence for the hallmark of a quantum spin liquid at very low temperature (a continuum of magnetic excitations), the presence of magnetic and non-magnetic site chemical disorder complicates the interpretation of the data. Recently, the three-dimensional Ce3+ pyrochlore lattice Ce2Sn2O7 has been suggested as a clean, effective spin-1/2 quantum spin liquid candidate, but evidence of a spin excitation continuum is still missing. Here, we use thermodynamic, muon spin relaxation and neutron scattering experiments on single crystals of Ce2Zr2O7, a compound isostructural to Ce2Sn2O7, to demonstrate the absence of magnetic ordering and the presence of a spin excitation continuum at 35 mK. With no evidence of oxygen deficiency and magnetic/non-magnetic ion disorder seen by neutron diffraction and diffuse scattering measurements, Ce2Zr2O7 may be a three-dimensional pyrochlore lattice quantum spin liquid material with minimum magnetic and non-magnetic chemical disorder.

Mitochondria are critically involved in necrotic cell death induced by Ca 2+ overload, hypoxia and oxidative damage. The mitochondrial permeability transition (MPT) pore — a protein complex that spans both the outer and inner mitochondrial membranes — is considered the mediator of this event and has been hypothesized to minimally consist of the voltage-dependent anion channel (Vdac) in the outer membrane, the adenine-nucleotide translocase (Ant) in the inner membrane and cyclophilin-D in the matrix 1 , 2 , 3 . Here, we report the effects of deletion of the three mammalian Vdac genes on mitochondrial-dependent cell death. Mitochondria from Vdac1 -, Vdac3 -, and Vdac1 – Vdac3 -null mice exhibited a Ca 2+ - and oxidative stress-induced MPT that was indistinguishable from wild-type mitochondria. Similarly, Ca 2+ - and oxidative-stress-induced MPT and cell death was unaltered, or even exacerbated, in fibroblasts lacking Vdac1, Vdac2, Vdac3, Vdac1–Vdac3 and Vdac1–Vdac2–Vdac3. Wild-type and Vdac -deficient mitochondria and cells also exhibited equivalent cytochrome c release, caspase cleavage and cell death in response to the pro-death Bcl-2 family members Bax and Bid. These results indicate that Vdacs are dispensable for both MPT and Bcl-2 family member-driven cell death.

Loss of cardiac myocytes in heart failure is thought to occur largely through an apoptotic process. Here we show that heart failure can also be precipitated through myocyte necrosis associated with Ca2+ overload. Inducible transgenic mice with enhanced sarcolemmal L-type Ca2+ channel (LTCC) activity showed progressive myocyte necrosis that led to pump dysfunction and premature death, effects that were dramatically enhanced by acute stimulation of beta-adrenergic receptors. Enhanced Ca2+ influx-induced cellular necrosis and cardiomyopathy was prevented with either LTCC blockers or beta-adrenergic receptor antagonists, demonstrating a proximal relationship among beta-adrenergic receptor function, Ca2+ handling, and heart failure progression through necrotic cell loss. Mechanistically, loss of cyclophilin D, a regulator of the mitochondrial permeability transition pore that underpins necrosis, blocked Ca2+ influx-induced necrosis of myocytes, heart failure, and isoproterenol-induced premature death. In contrast, overexpression of the antiapoptotic factor Bcl-2 was ineffective in mitigating heart failure and death associated with excess Ca2+ influx and acute beta-adrenergic receptor stimulation. This paradigm of mitochondrial- and necrosis-dependent heart failure was also observed in other mouse models of disease, which supports the concept that heart failure is a pleiotropic disorder that involves not only apoptosis, but also necrotic loss of myocytes in association with dysregulated Ca2+ handling and beta-adrenergic receptor signaling.

The recently discovered kagome superconductor CsV3Sb5 (Tc ≃ 2.5 K) has been found to host charge order as well as a non-trivial band topology, encompassing multiple Dirac points and probable surface states. Such a complex and phenomenologically rich system is, therefore, an ideal playground for observing unusual electronic phases. Here, we report anisotropic superconducting properties of CsV3Sb5 by means of transverse-field muon spin rotation (μSR) experiments. The fits of temperature dependences of in-plane and out-of-plane components of the magnetic penetration depth suggest that the superconducting order parameter may have a two-gap (s + s)-wave symmetry. The multiband nature of superconductivity could be further supported by the different temperature dependences of the anisotropic magnetic penetration depth γλ(T) and upper critical field γBc2(T). The relaxation rates obtained from zero field μSR experiments do not show noticeable change across the superconducting transition, indicating that superconductivity does not break time reversal symmetry.

Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix 1 , 2 . Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo , whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro . Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca 2+ -overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-α-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca 2+ - and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death.

Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death 1 . Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D ( Ppif ) rendered mitochondria largely insensitive to the calcium overload–induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking δ-sarcoglycan ( Scgd −/− mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif . Moreover, the premature lethality associated with deletion of Lama2 , encoding the α-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd −/− mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases.

The exotic properties of quantum spin liquids (QSLs) have continually been of interest since Anderson’s 1973 ground-breaking idea. Geometrical frustration, quantum fluctuations, and low dimensionality are the most often evoked material’s characteristics that favor the long-range fluctuating spin state without freezing into an ordered magnet or a spin glass at low temperatures. Among the few known QSL candidates, organic crystals have the advantage of having rich chemistry capable of finely tuning their microscopic parameters. Here, we demonstrate the emergence of a QSL state in [ EDT-TTF-CONH 2 ] 2 + [ BABCO - ] (EDT-BCO), where the EDT molecules with spin-1/2 on a triangular lattice form layers which are separated by a sublattice of BCO molecular rotors. By several magnetic measurements, we show that the subtle random potential of frozen BCO Brownian rotors suppresses magnetic order down to the lowest temperatures. Our study identifies the relevance of disorder in the stabilization of QSLs.

That apoptosis is mediated by specific pathways has long been established. However, more recent data have begun to suggest that necrosis may in fact be “programmed” and not a default “accidental” pathway as previously thought. The mitochondrial permeability transition pore, a known contributor to the development of many cardiac diseases, is emerging as one among several mediators of this necrotic program. Consequently, this report briefly reviews the roles of necrosis versus apoptosis in the pathogenesis of cardiac disease and discusses the role that the mitochondrial pore plays in cardiac necrotic cell death.

Topological semimetals are three dimensional materials with symmetry-protected massless bulk excitations. As a special case, Weyl nodal-line semimetals are realized in materials having either no inversion or broken time-reversal symmetry and feature bulk nodal lines. The 111-family, including LaNiSi, LaPtSi and LaPtGe materials (all lacking inversion symmetry), belongs to this class. Here, by combining muon-spin rotation and relaxation with thermodynamic measurements, we find that these materials exhibit a fully-gapped superconducting ground state, while spontaneously breaking time-reversal symmetry at the superconducting transition. Since time-reversal symmetry is essential for protecting the normal-state topology, its breaking upon entering the superconducting state should remarkably result in a topological phase transition. By developing a minimal model for the normal-state band structure and assuming a purely spin-triplet pairing, we show that the superconducting properties across this family can be described accurately. Our results demonstrate that the 111 materials reported here provide an ideal test-bed for investigating the rich interplay between the exotic properties of Weyl nodal-line fermions and unconventional superconductivity.