A novel BCAP31 variant associated with nonsyndromic auditory neuropathy spectrum disorder: mitochondrial dysfunction, cisplatin sensitivity, and amenability to mitochondrial transplantation.

Background: A novel in-frame insertion variant in the B-Cell Receptor-Associated Protein 31 (BCAP31) gene, which encodes a crucial ER membrane protein involved in the quality control and transport of transmembrane proteins, as well as in ER-mitochondria apoptotic signaling, was determined in a family demonstrating X-linked, recessive, nonsyndromic auditory neuropathy spectrum disorder (ANSD).

Methods: Exome sequencing analysiswas followed by bioinformatics analysis to identify the cause of hearing loss in a family whose pedigree indicated an X-linked recessive mode of inheritance. Immunohistochemistry was performed to locate Bcap31 in the mouse cochlea.

Mitochondrial transplantation as a novel therapeutic approach in idiopathic inflammatory myopathy.

Objectives: This study aimed to investigate the efficacy of mitochondrial transplantation as a therapeutic intervention for idiopathic inflammatory myopathy (IIM). This study used a comprehensive approach, incorporating both in vitro and in vivo IIM models, and conducted a first-in-human clinical trial to assess the effectiveness and safety of mitochondria isolated from human umbilical cord mesenchymal stem cells (PN-101).

Methods: Mitochondria isolated from umbilical cord mesenchymal stem cells were designated as PN-101.

Mitochondrial Transplantation Ameliorates Pulmonary Fibrosis by Suppressing Myofibroblast Activation.

Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development.

Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.

Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation.

P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.

Background: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies.

Preferred Migration of Mitochondria toward Cells and Tissues with Mitochondrial Damage.

Mitochondria are organelles that play a vital role in cellular survival by supplying ATP and metabolic substrates via oxidative phosphorylation and the Krebs cycle. Hence, mitochondrial dysfunction contributes to many human diseases, including metabolic syndromes, neurodegenerative diseases, cancer, and aging. Mitochondrial transfer between cells has been shown to occur naturally, and mitochondrial transplantation is beneficial for treating mitochondrial dysfunction.

Platelet-derived mitochondria transfer facilitates wound-closure by modulating ROS levels in dermal fibroblasts.

Platelets are known to improve the wound-repair capacity of mesenchymal stem cells (MSCs) by transferring mitochondria intercellularly. This study aimed to investigate whether direct transfer of mitochondria (pl-MT) isolated from platelets could enhance wound healing using a cell-based model. Wound repairs were assessed by 2D gap closure experiment in wound scratch assay using human dermal fibroblasts (hDFs).

Human platelet mitochondria improve the mitochondrial and cardiac function of donor heart.

Mitochondria transplantation emerges as an effective therapeutic strategy for ischemic-related diseases but the roles in the donor hearts for transplant remain unidentified. Here, we investigated whether the preservation of the donor heart with human platelet-derived mitochondria (pl-MT) could improve mitochondrial and cardiac function. Incubation with pl-MT resulted in the internalization of pl-MT and the enhancement of ATP production in primary cardiomyocytes.

Primary astrocytic mitochondrial transplantation ameliorates ischemic stroke.

Mitochondria are important organelles that regulate adenosine triphosphate production, intracellular calcium buffering, cell survival, and apoptosis. They play therapeutic roles in injured cells via transcellular transfer through extracellular vesicles, gap junctions, and tunneling nanotubes. Astrocytes can secrete numerous factors known to promote neuronal survival, synaptic formation, and plasticity.

Erratum to: Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

[Erratum to: BMB Reports 2022; 55(3): 136-141, PMID: 34488927, PMCID: PMC8972135] The BMB Reports would like to correct in BMB Rep. 55(3):136-141, titled "Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway". This research was supported by NRF-2016R1A2B4007640 grant (to C-H Kim).

Potential Therapeutic Effect of Micrornas in Extracellular Vesicles from Mesenchymal Stem Cells against SARS-CoV-2.

Extracellular vesicles (EVs) are cell-released, nanometer-scaled, membrane-bound materials and contain diverse contents including proteins, small peptides, and nucleic acids. Once released, EVs can alter the microenvironment and regulate a myriad of cellular physiology components, including cell-cell communication, proliferation, differentiation, and immune responses against viral infection. Among the cargoes in the vesicles, small non-coding micro-RNAs (miRNAs) have received attention in that they can regulate the expression of a variety of human genes as well as external viral genes via binding to the complementary mRNAs.

LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming.

Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling.

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway.

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response.

Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1.

Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity.

Effect of cysteine-free human fibroblast growth factor-5s mutant (FGF5sC93S) on hair growth.

Treatment for hair loss is largely limited, and any beneficial effects are often transient. Based on the critical role of the FGF5 isoform, FGF5s, in the hair growth cycle, it may be a good therapeutic candidate for the prevention of hair loss, as well as the promotion of hair growth. To investigate its potential use for hair growth, a mutant form of the FGF5s protein (FGF5sC93S) was generated, expressed, and purified.

PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons.

Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive movement disturbances caused by the selective loss of dopamine (DA) neurons in the substantia nigra. Despite the identification of the causal mechanisms underlying the pathogenesis of PD, effective treatments remain elusive. In this study, we observed that a low level of fetal bovine serum (FBS) effectively induced DA neurons in rat neural precursor cells (NPCs) by enhancing nuclear receptor-related 1 protein (NURR1) expression.

Enhanced delivery of protein fused to cell penetrating peptides to mammalian cells.

Recent progress in cellular reprogramming technology and lineage-specific cell differentiation has provided great opportunities for translational research. Because virus-based gene delivery is not a practical reprogramming protocol, protein-based reprogramming has been receiving attention as a safe way to generate reprogrammed cells. However, the poor efficiency of the cellular uptake of reprogramming proteins is still a major obstacle.

Purification of functional reprogramming factors in mammalian cell using FLAG -Tag.

Induced pluripotent stem cells (iPSCs) technology is a method for generating pluripotent stem cells in vitro from fully differentiated cells such as fibroblast cells. The potential applications of iPSC technology in cell therapy and disease modeling could influence current medical practices. Despite current advances in iPSC technology, many patient-derived reprogrammed cells are not suitable for clinical trial because most protocols rely on virus-based techniques, which pose the risk of integration of the viral genome into the chromosomes.

Efficient Generation of Dopamine Neurons by Synthetic Transcription Factor mRNAs.

Generation of functional dopamine (DA) neurons is an essential step for the development of effective cell therapy for Parkinson's disease (PD). The generation of DA neurons can be accomplished by overexpression of DA-inducible genes using virus- or DNA-based gene delivery methods. However, these gene delivery methods often cause chromosomal anomalies.

Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c-SIRT2 axis.

A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis.