Fibroblast inflammatory priming determines regenerative versus fibrotic skin repair in reindeer.

Adult mammalian skin wounds heal by forming fibrotic scars. We report that full-thickness injuries of reindeer antler skin (velvet) regenerate, whereas back skin forms fibrotic scar. Single-cell multi-omics reveal that uninjured velvet fibroblasts resemble human fetal fibroblasts, whereas back skin fibroblasts express inflammatory mediators mimicking pro-fibrotic adult human and rodent fibroblasts. Consequently, injury elicits site-specific immune responses: back skin fibroblasts amplify myeloid infiltration and maturation during repair, whereas velvet fibroblasts adopt an immunosuppressive phenotype that restricts leukocyte recruitment and hastens immune resolution. Ectopic transplantation of velvet to scar-forming back skin is initially regenerative, but progressively transitions to a fibrotic phenotype akin to the scarless fetal-to-scar-forming transition reported in humans. Skin regeneration is diminished by intensifying, or enhanced by neutralizing, these pathologic fibroblast-immune interactions. Reindeer represent a powerful comparative model for interrogating divergent wound healing outcomes, and our results nominate decoupling of fibroblast-immune interactions as a promising approach to mitigate scar.

Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.

Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson's disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

Mitochondria Targeted Viral Replication and Survival Strategies-Prospective on SARS-CoV-2.

SARS-CoV-2 is a positive sense RNA coronavirus that constitutes a new threat for the global community and economy. While vaccines against SARS-CoV-2 are being developed, the mechanisms through which this virus takes control of an infected cell to replicate remains poorly understood. Upon infection, viruses completely rely on host cell molecular machinery to survive and replicate. To escape from the immune response and proliferate, viruses strategically modulate cellular metabolism and alter subcellular organelle architecture and functions. One way they do this is by modulating the structure and function of mitochondria, a critical cellular metabolic hub but also a key platform for the regulation of cellular immunity. This versatile nature of mitochondria defends host cells from viruses through several mechanisms including cellular apoptosis, ROS signaling, MAVS activation and mitochondrial DNA-dependent immune activation. These events are regulated by mitochondrial dynamics, a process by which mitochondria alter their structure (including their length and connectivity) in response to stress or other cues. It is therefore not surprising that viruses, including coronaviruses hijack these processes for their survival. In this review, we highlight how positive sense RNA viruses modulate mitochondrial dynamics and metabolism to evade mitochondrial mediated immune response in order to proliferate.

Mitochondrial interaction with the endosomal compartment in endocytosis and mitochondrial transfer.

Mitochondria are essential organelles required for cellular processes ranging from energy production to cellular differentiation. To perform these functions, mitochondria physically and functionally interact with other organelles such as the endoplasmic reticulum (ER) and endosomes. While the role of ER-mitochondria contact sites is well established, the interaction between mitochondria and endosomes has only recently been reported. These interactions are involved in lipid and ion transfer and potentially play a crucial role in mitochondria quality control and the release of mitochondrial components within extracellular vesicles. Here, we will discuss the current view of mitochondria-endosome interaction, both physically and functionally.

Mitochondria and Lysosomes: Discovering Bonds.

In the last decade, the traditional view of lysosomes has been challenged by the recognition that lysosomes are not only degradative organelles, but also metabolic sensors that play a key role in the regulation of metabolism and cell growth. Similarly, mitochondria are now seen as crucial metabolic hubs dictating cell fate decisions, not just ATP-producing machines. Importantly, these functions are generally performed as a coordinate response of distinct organelles that are physically and functionally connected. While the association between mitochondria and the endoplasmic reticulum is well known, a similar interaction between mitochondria and lysosomes is now emerging. This interaction could be required to shuttle amino acids, lipids and ions such as Ca2+ between the two organelles, thereby modulating their metabolic functions. In addition, a tethering complex linking the two organelles has recently been described in yeast, although the mammalian counterpart has yet to be identified. Here, we discuss the implications of these recent findings.

Loss of Mitochondrial Function Impairs Lysosomes.

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.

Self-propelled carbon nanotube based microrockets for rapid capture and isolation of circulating tumor cells.

Here, we report a non-invasive strategy for isolating cancer cells by autonomously propelled carbon nanotube (CNT) microrockets. H2O2-driven oxygen (O2) bubble-propelled microrockets were synthesized using CNT and Fe3O4 nanoparticles in the inner surface and covalently conjugating transferrin on the outer surface. Results show that self-propellant microrockets can specifically capture cancer cells.

Calcium phosphate nanocapsule crowned multiwalled carbon nanotubes for pH triggered intracellular anticancer drug release.

We report calcium phosphate (CaP) nanocapsule crowned multiwalled carbon nanotubes (CNT-GSH-G4-CaP) as a novel platform for intracellular delivery of an anticancer drug. As a proof-of-concept, CNT-GSH-G4-CaP demonstrates release of anticancer drug doxorubicin hydrochloride (DOX) within intracellular lysosomes from the interior cavity of CNT upon pH triggered CaP dissolution. Importantly, we found that the CNT with a CaP nanolid can efficiently prevent untimely drug release at physiological pH but promotes DOX release at increased acidic milieu as observed in subcellular compartments such as lysosomes (∼5.0). This "zero premature release" characteristic is of clinical significance in delivering cytotoxic drugs, by reducing systemic toxicity and thus beneficial for the effective anticancer treatment. We envision that this pH triggered CaP crowned CNT nanosystem would lead to a new generation of self-regulated platforms for intracellular delivery of a variety of anticancer drugs.

Absence of the calcium-binding protein calretinin, not of calbindin D-28k, causes a permanent impairment of murine adult hippocampal neurogenesis.

Calretinin (CR) and calbindin D-28k (CB) are cytosolic EF-hand Ca(2+)-binding proteins and function as Ca(2+) buffers affecting the spatiotemporal aspects of Ca(2+) transients and possibly also as Ca(2+) sensors modulating signaling cascades. In the adult hippocampal circuitry, CR and CB are expressed in specific principal neurons and subsets of interneurons. In addition, CR is transiently expressed within the neurogenic dentate gyrus (DG) niche. CR and CB expression during adult neurogenesis mark critical transition stages, onset of differentiation for CR, and the switch to adult-like connectivity for CB. Absence of either protein during these stages in null-mutant mice may have functional consequences and contribute to some aspects of the identified phenotypes. We report the impact of CR- and CB-deficiency on the proliferation and differentiation of progenitor cells within the subgranular zone (SGZ) neurogenic niche of the DG. Effects were evaluated (1) two and four weeks postnatally, during the transition period of the proliferative matrix to the adult state, and (2) in adult animals (3 months) to trace possible permanent changes in adult neurogenesis. The absence of CB from differentiated DG granule cells has no retrograde effect on the proliferative activity of progenitor cells, nor affects survival or migration/differentiation of newborn neurons in the adult DG including the SGZ. On the contrary, lack of CR from immature early postmitotic granule cells causes an early loss in proliferative capacity of the SGZ that is maintained into adult age, when it has a further impact on the migration/survival of newborn granule cells. The transient CR expression at the onset of adult neurogenesis differentiation may thus have two functions: (1) to serve as a self-maintenance signal for the pool of cells at the same stage of neurogenesis contributing to their survival/differentiation, and (2) it may contribute to retrograde signaling required for maintenance of the progenitor pool.