Bioarchaeological and palaeogenomic portrait of two Pompeians that died during the eruption of Vesuvius in 79 AD

The archaeological site of Pompeii is one of the 54 UNESCO World Heritage sites in Italy, thanks to its uniqueness: the town was completely destroyed and buried by a Vesuvius’ eruption in 79 AD. In this work, we present a multidisciplinary approach with bioarchaeological and palaeogenomic analyses of two Pompeian human remains from the Casa del Fabbro. We have been able to characterize the genetic profle of the frst Pompeian’ genome, which has strong afnities with the surrounding central Italian population from the Roman Imperial Age. Our fndings suggest that, despite the extensive connection between Rome and other Mediterranean populations, a noticeable degree of genetic homogeneity exists in the Italian peninsula at that time. Moreover, palaeopathological analyses identifed the presence of spinal tuberculosis and we further investigated the presence of ancient DNA from Mycobacterium tuberculosis. In conclusion, our study demonstrates the power of a combined approach to investigate ancient humans and confrms the possibility to retrieve ancient DNA from Pompeii human remains. Our initial fndings provide a foundation to promote an intensive and extensive paleogenetic analysis in order to reconstruct the genetic history of population from Pompeii, a unique archaeological site

Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models

SummaryIncreased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4−/−), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15sm/sm), with Opa1 transgenic (Opa1tg) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4−/−::Opa1tg mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15sm/sm::Opa1tg mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15sm/sm::Opa1tg mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease

Targeting mitochondrial shape: at the heart of cardioprotection

There remains an unmet need to identify novel therapeutic strategies capable of protecting the myocardium against the detrimental effects of acute ischemia-reperfusion injury (IRI), to reduce myocardial infarct (MI) size and prevent the onset of heart failure (HF) following acute myocardial infarction (AMI). In this regard, perturbations in mitochondrial morphology with an imbalance in mitochondrial fusion and fission can disrupt mitochondrial metabolism, calcium homeostasis, and reactive oxygen species production, factors which are all known to be critical determinants of cardiomyocyte death following acute myocardial IRI. As such, therapeutic approaches directed at preserving the morphology and functionality of mitochondria may provide an important strategy for cardioprotection. In this article, we provide an overview of the alterations in mitochondrial morphology which occur in response to acute myocardial IRI, and highlight the emerging therapeutic strategies for targeting mitochondrial shape to preserve mitochondrial function which have the future therapeutic potential to improve health outcomes in patients presenting with AMI

The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria

Components of the death receptors-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIPL), a well- known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca2+-release as well as ER-mitochondria tethering were decreased in c-FLIP-/- mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re-introduction of c-FLIPL and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIPL emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4

Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g

Crista junctions (CJs) are important for mitochondrial organization and function, but the molecular basis of their formation and architecture is obscure. We have identified and characterized a mitochondrial membrane protein in yeast, Fcj1 (formation of CJ protein 1), which is specifically enriched in CJs. Cells lacking Fcj1 lack CJs, exhibit concentric stacks of inner membrane in the mitochondrial matrix, and show increased levels of F1FO–ATP synthase (F1FO) supercomplexes. Overexpression of Fcj1 leads to increased CJ formation, branching of cristae, enlargement of CJ diameter, and reduced levels of F1FO supercomplexes. Impairment of F1FO oligomer formation by deletion of its subunits e/g (Su e/g) causes CJ diameter enlargement and reduction of cristae tip numbers and promotes cristae branching. Fcj1 and Su e/g genetically interact. We propose a model in which the antagonism between Fcj1 and Su e/g locally modulates the F1FO oligomeric state, thereby controlling membrane curvature of cristae to generate CJs and cristae tips

Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondria! energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/beta-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondria! ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondria! energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologie

Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction

Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondria! energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/beta-catenin signaling in vitro in colon cancer cells and in vivo in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondria! ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondria! energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologie