Mitochondria are implicated in many important cellular functions covering the whole life cycle from mitochondrial biogenesis to cell death. Mitochondrial homeostasis is tightly regulated, and ...mitochondrial dysfunction is frequently associated with severe human pathologies (eg, cardiovascular diseases, cancer, and neurodegeneration). The permeability transition pore (PTP) is an unselective voltage-dependent mitochondrial channel. Despite the extensive use of electrophysiology, biochemistry, pharmacology, and genetic invalidation in mice, the molecular identity of PTP is still unknown. Nevertheless, PTP is central to mitochondrial vital functions and can play a lethal role in many pathophysiological conditions. This review recapitulates the current knowledge of the various modes of conductance of the PTP channel and discusses their implication in the physiological roles of PTP and their regulation. Based on its involvement in normal physiology and human pathology, a better understanding of this channel and its roles remains a major goal for basic scientists and clinicians.
The opening of the Equatorial and South Atlantic Oceans is still a matter of debate, particularly as concerns the locations of the intraplate deformation. We propose here a critical review of the ...kinematic models published since Bullard et al., 1965, based on a series of constraints: new interpretation of the magnetic anomalies, seafloor isochrons, flow lines, fracture zones, continental and oceanic homologous structures and radiometric dating of igneous rocks. All of these models present numerous unexplained misfits (gaps, overlaps and misalignments). We present here a new evolution of the Equatorial and South Atlantic Ocean from the tightest reconstruction to Chron C34. This new model confirms the hypothesis of a northward propagation of the South American deformation proposed by Eagles, but rejuvenates slightly the ages for this propagation and refines the plate reconstructions. In particular, we highlight the role of the kinematic «buffer» Santos block, located between the salty Aptian Central segment in the North and the Volcanic Hauterivian Austral segment in the South. The new initial fit presented in this study represents the tightest reconstruction that could be obtained and constitutes the base canvas on which the problem of the continental margin genesis should be addressed.
Inhibitor of apoptosis (IAP) proteins cIAP1, cIAP2, and XIAP (X‐linked IAP) regulate apoptosis and cytokine receptor signalling, but their overlapping functions make it difficult to distinguish their ...individual roles. To do so, we deleted the genes for IAPs separately and in combination. While lack of any one of the IAPs produced no overt phenotype in mice, deletion of cIap1 with cIap2 or Xiap resulted in mid‐embryonic lethality. In contrast, Xiap−/−cIap2−/− mice were viable. The death of cIap2−/−cIap1−/− double mutants was rescued to birth by deletion of tumour necrosis factor (TNF) receptor 1, but not TNFR2 genes. Remarkably, hemizygosity for receptor‐interacting protein kinase 1 (Ripk1) allowed Xiap−/−cIap1−/− double mutants to survive past birth, and prolonged cIap2−/−cIap1−/− embryonic survival. Similarly, deletion of Ripk3 was able to rescue the mid‐gestation defect of cIap2−/−cIap1−/− embryos, as these embryos survived to E15.5. cIAPs are therefore required during development to limit activity of RIP kinases in the TNF receptor 1 signalling pathway.
The inhibitor of apoptosis proteins cIAP1, cIAP2, and XIAP exert overlapping functions in apoptosis and cytokine signalling. A series of single‐ and double‐knockout mice reveal an essential function of IAP proteins in preventing TNF receptor 1‐induced, RIP kinase 1‐ and 3‐dependent cell death during embryogenesis.
Phospholipids (PLs) are amphiphilic molecules that were essential for life to become cellular. PLs have not only a key role in compartmentation as they are the main components of membrane, but they ...are also involved in cell signaling, cell metabolism, and even cell pathophysiology. Considered for a long time to simply be structural elements of membranes, phospholipids are increasingly being viewed as sensors of their environment and regulators of many metabolic processes. After presenting their main characteristics, we expose the increasing methods of PL detection and identification that help to understand their key role in life processes. Interest and importance of PL homeostasis is growing as pathogenic variants in genes involved in PL biosynthesis and/or remodeling are linked to human diseases. We here review diseases that involve deregulation of PL homeostasis and present a predominantly muscular phenotype.
A role for cellular inhibitors of apoptosis (IAPs cIAPs) in preventing CD95 death has been suspected but not previously explained mechanistically. In this study, we find that the loss of cIAPs leads ...to a dramatic sensitization to CD95 ligand (CD95L) killing. Surprisingly, this form of cell death can only be blocked by a combination of RIP1 (receptor-interacting protein 1) kinase and caspase inhibitors. Consistently, we detect a large increase in RIP1 levels in the CD95 death-inducing signaling complex (DISC) and in a secondary cytoplasmic complex (complex II) in the presence of IAP antagonists and loss of RIP1-protected cells from CD95L/IAP antagonist-induced death. Cells resistant to CD95L/IAP antagonist treatment could be sensitized by short hairpin RNA-mediated knockdown of cellular FLICE-inhibitory protein (cFLIP). However, only cFLIPL and not cFLIPS interfered with RIP1 recruitment to the DISC and complex II and protected cells from death. These results demonstrate a fundamental role for RIP1 in CD95 signaling and provide support for a physiological role of caspase-independent death receptor-mediated cell death.
Heart failure is associated with profound alterations of energy metabolism thought to play a major role in the progression of this syndrome. SIRT1 is a metabolic sensor of cellular energy and exerts ...essential functions on energy metabolism, oxidative stress response, apoptosis, or aging. Importantly, SIRT1 deacetylates the peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), the master regulator of energy metabolism involved in mitochondrial biogenesis and fatty acid utilization. However, the exact role of SIRT1 in controlling cardiac energy metabolism is still incompletely understood and conflicting results have been obtained. We generated a cardio-specific inducible model of Sirt1 gene deletion in mice (
) to decipher the role of SIRT1 in control conditions and following cardiac stress induced by pressure overload. SIRT1 deficiency induced a progressive cardiac dysfunction, without overt alteration in mitochondrial content or properties. Sixteen weeks after
deletion an increase in mitochondrial reactive oxygen species (ROS) production and a higher rate of oxidative damage were observed, suggesting disruption of the ROS production/detoxification balance. Following pressure overload, cardiac dysfunction and alteration in mitochondrial properties were exacerbated in
mice. Overall the results demonstrate that SIRT1 plays a cardioprotective role on cardiac energy metabolism and thereby on cardiac function.
SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory ...failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.
Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often ...referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions.
The majority of Earth volcanism takes place in the deep ocean. Deep-sea volcanoes are particularly complicated to study due to their remoteness. Very different methods can be used and their ...combination can lead to crucial information about submarine volcanoes behavior. In Mayotte, Comoros archipelago, efforts have been made to study and monitor the deep volcanic activity (∼3000 m) currently occurring east of Mayotte through various methods and campaigns on land and at sea. In October 2020, a line of 10 Ocean Bottom Seismometers was deployed during 10 days, leading to a hand-picked catalog of more than a thousand of hydro-acoustic signals, which have been associated with reactions between hot lava and deep cold ocean waters. During the same period, repeated swath bathymetry surveys were performed over an active lava flow field. We compare the time evolution of the hydro-acoustic events locations and bathymetry differences observed between each survey. While bathymetric information gives absolute location of new lava flows, hydro-acoustic events give detailed relative time variations leading to short-term spatial evolution. Bathymetric information thus provides snapshots of the eruptive area evolution at specific times, when hydro-acoustic signals show its continuous evolution. By combining both complementary analyses we are able to clearly define the detailed evolution of the lava flows pattern in the short time period of 10 days. Applied to the data already acquired on Mayotte since 2019, this method could allow us to estimate more precisely the volcano effusion rate and its evolution, giving further insights on the feeding system.
A single missense variant of the
/LAP2α gene, encoding LAP2 proteins, has been associated with cardiomyopathy in two brothers. To further evaluate its role in cardiac muscle, we included
in our ...cardiomyopathy diagnostic gene panel. A screening of ~5000 patients revealed three novel rare
heterozygous variants in six males diagnosed with hypertrophic or dilated cardiomypathy. We identified in different cellular models that (1) the frameshift variant LAP2α p.(Gly395Glufs*11) induced haploinsufficiency, impeding cell proliferation and/or producing a truncated protein mislocalized in the cytoplasm; (2) the C-ter missense variant LAP2α p.(Ala240Thr) led to a reduced proximity events between LAP2α and the nucleosome binding protein HMGN5; and (3) the LEM-domain missense variant p.(Leu124Phe) decreased both associations of LAP2α/β with the chromatin-associated protein BAF and inhibition of the E2F1 transcription factor activity which is known to be dependent on Rb, partner of LAP2α. Additionally, the LAP2α expression was lower in the left ventricles of male mice compared to females. In conclusion, our study reveals distinct altered properties of LAP2 induced by these
/LAP2 variants, leading to altered cell proliferation, chromatin structure or gene expression-regulation pathways, and suggests a potential sex-dependent role of LAP2 in myocardial function and disease.
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