bims-mitrat 2024-10-13 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒10‒13
twelve papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondria at the crossroad of dysregulated inflammatory and metabolic processes in bipolar disorders.
Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes.
Effects of age on human skeletal muscle: A systematic review and meta-analysis of myosin heavy chain isoform protein expression, fiber size and distribution.
Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.
Mitochondrial RNA maturation.
A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts.
Modulation of mitochondrial permeability transition pores in reperfusion injury: Mechanisms and therapeutic approaches.
Synaptic Mitochondria: a crucial factor in the aged hippocampus.
Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.
Isolation of small extracellular vesicles from regenerating muscle tissue using tangential flow filtration and size exclusion chromatography.
ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.
Selection promotes age-dependent degeneration of the mitochondrial genome.

Brain Behav Immun. 2024 Oct 06. pii: S0889-1591(24)00646-9. [Epub ahead of print]123 456-465

Mitochondria at the crossroad of dysregulated inflammatory and metabolic processes in bipolar disorders.

Jérémy Bernard, Ryad Tamouza, Ophélia Godin, Michael Berk, Ana C Andreazza, Marion Leboyer.

  In last few decades, considerable evidence has emphasized the significant involvement of mitochondria, often referred to as the "powerhouse of the cell," in the pathophysiology of bipolar disorder (BD). Given crucial mitochondrial functions in cellular metabolism and inflammation, both of which are compromised in BD, this perspective review examines the central role of mitochondria in inflammation and metabolism within the context of this disorder. We first describe the significance of mitochondria in metabolism before presenting the dysregulated inflammatory and metabolic processes. Then, we present a synthetic and hypothetical model of the importance of mitochondria in those dysfunctional pathways. The article also reviews different techniques for assessing mitochondrial function and discuss diagnostic and therapeutic implications. This review aims to improve the understanding of the inflammatory and metabolic comorbidities associated with bipolar disorders along with mitochondrial alterations within this context.

Keywords:  Bipolar disorder; Inflammation; Metabolic syndrome; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.bbi.2024.10.008
Stem Cell Res Ther. 2024 Oct 10. 15(1): 359

Connexin 43 regulates intercellular mitochondrial transfer from human mesenchymal stromal cells to chondrocytes.

Rebecca M Irwin, Matthew A Thomas, Megan J Fahey, María D Mayán, James W Smyth, Michelle L Delco.

  BACKGROUND: The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and has potential for treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte mitochondrial transfer has been documented, but the mechanism of transfer is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) and the truncated, internally translated isoform GJA1-20k have been implicated in mitochondrial transfer between highly oxidative cells, but have not been explored in orthopaedic tissues. Here, our goal was to investigate the role of Cx43 in MSC to chondrocyte mitochondrial transfer. In this study, we tested the hypotheses that (a) mitochondrial transfer from MSCs to chondrocytes is increased when chondrocytes are under oxidative stress and (b) MSC Cx43 expression mediates mitochondrial transfer to chondrocytes.METHODS: Oxidative stress was induced in immortalized human chondrocytes using tert-Butyl hydroperoxide (t-BHP) and cells were evaluated for mitochondrial membrane depolarization and reactive oxygen species (ROS) production. Human bone-marrow derived MSCs were transduced for mitochondrial fluorescence using lentiviral vectors. MSC Cx43 expression was knocked down using siRNA or overexpressed (GJA1 + and GJA1-20k+) using lentiviral transduction. Chondrocytes and MSCs were co-cultured for 24 h in direct contact or separated using transwells. Mitochondrial transfer was quantified using flow cytometry. Co-cultures were fixed and stained for actin and Cx43 to visualize cell-cell interactions during transfer.
RESULTS: Mitochondrial transfer was significantly higher in t-BHP-stressed chondrocytes. Contact co-cultures had significantly higher mitochondrial transfer compared to transwell co-cultures. Confocal images showed direct cell contacts between MSCs and chondrocytes where Cx43 staining was enriched at the terminal ends of actin cellular extensions containing mitochondria in MSCs. MSC Cx43 expression was associated with the magnitude of mitochondrial transfer to chondrocytes; knocking down Cx43 significantly decreased transfer while Cx43 overexpression significantly increased transfer. Interestingly, GJA1-20k expression was highly correlated with incidence of mitochondrial transfer from MSCs to chondrocytes.
CONCLUSIONS: Overexpression of GJA1-20k in MSCs increases mitochondrial transfer to chondrocytes, highlighting GJA1-20k as a potential target for promoting mitochondrial transfer from MSCs as a regenerative therapy for cartilage tissue repair in OA.

Keywords:  Arthritis; Cx43; GJA1; GJA1-20k; Gap junctions; MSCs; Osteoarthritis; Regenerative medicine

DOI:  https://doi.org/10.1186/s13287-024-03932-9
Am J Physiol Cell Physiol. 2024 Oct 07.

Effects of age on human skeletal muscle: A systematic review and meta-analysis of myosin heavy chain isoform protein expression, fiber size and distribution.

Christopher Lee, Philip C Woods, Amanda E Paluch, Mark S Miller.

  Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 years) and older (≥ 60 years) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, while smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsied provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression towards faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis, and incorporate an objective measurement of physical activity.

Keywords:  MHC; aging; physical activity; sarcopenia; sex

DOI:  https://doi.org/10.1152/ajpcell.00347.2024
Ageing Res Rev. 2024 Oct 05. pii: S1568-1637(24)00340-4. [Epub ahead of print]101 102522

Mitochondrial Extracellular Vesicles (mitoEVs): Emerging mediators of cell-to-cell communication in health, aging and age-related diseases.

Roberto Iorio, Sabrina Petricca, Giovanna Di Emidio, Stefano Falone, Carla Tatone.

  Mitochondria are metabolic and signalling hubs that integrate a plethora of interconnected processes to maintain cell homeostasis. They are also dormant mediators of inflammation and cell death, and with aging damages affecting mitochondria gradually accumulate, resulting in the manifestation of age-associated disorders. In addition to coordinate multiple intracellular functions, mitochondria mediate intercellular and inter-organ cross talk in different physiological and stress conditions. To fulfil this task, mitochondrial signalling has evolved distinct and complex conventional and unconventional routes of horizontal/vertical mitochondrial transfer. In this regard, great interest has been focused on the ability of extracellular vesicles (EVs), such as exosomes and microvesicles, to carry selected mitochondrial cargoes to target cells, in response to internal and external cues. Over the past years, the field of mitochondrial EVs (mitoEVs) has grown exponentially, revealing unexpected heterogeneity of these structures associated with an ever-expanding mitochondrial function, though the full extent of the underlying mechanisms is far from being elucidated. Therefore, emerging subsets of EVs encompass exophers, migrasomes, mitophers, mitovesicles, and mitolysosomes that can act locally or over long-distances to restore mitochondrial homeostasis and cell functionality, or to amplify disease. This review provides a comprehensive overview of our current understanding of the biology and trafficking of MitoEVs in different physiological and pathological conditions. Additionally, a specific focus on the role of mitoEVs in aging and the onset and progression of different age-related diseases is discussed.

Keywords:  Age-related diseases; Bioenergetic remodelling; Cancer; Intercellular communication; Mitochondria-specific ectocytosis; Mitochondrial derived vesicles (MDVs); Mitochondrial extracellular vesicles (mitoEVs); Mitochondrial quality control (MQC)

DOI:  https://doi.org/10.1016/j.arr.2024.102522
RNA Biol. 2024 Jan;21(1): 28-39

Mitochondrial RNA maturation.

Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.

  The vast majority of oxygen-utilizing eukaryotes need to express their own mitochondrial genome, mtDNA, to survive. In comparison to size of their nuclear genome, mtDNA is minimal, even in the most exceptional examples. Having evolved from bacteria in an endosymbiotic event, it might be expected that the process of mtDNA expression would be relatively simple. The aim of this short review is to illustrate just how wrong this assumption is. The production of functional mitochondrial RNA across species evolved in many directions. Organelles use a dizzying array of RNA processing, modifying, editing, splicing and maturation events that largely require the import of nuclear-encoded proteins from the cytosol. These processes are sometimes driven by the unusual behaviour of the mitochondrial genome from which the RNA is originally transcribed, but in many examples the complex processes that are essential for the production of functional RNA in the organelle, are fascinating and bewildering.

Keywords:  Mitochondrial; maturation; messenger RNA; modifications; processing; translation

DOI:  https://doi.org/10.1080/15476286.2024.2414157
J Cell Physiol. 2024 Oct 09. e31458

A combination of major histocompatibility complex (MHC) I overexpression and type I interferon induce mitochondrial dysfunction in human skeletal myoblasts.

Anastasia Thoma, Razan Alomosh, Holly L Bond, Tania Akter-Miah, Nasser Al-Shanti, Hans Degens, Vanja Pekovic-Vaughan, Adam P Lightfoot.

  The overexpression of major histocompatibility complex (MHC) I on the surface of muscle fibers is a characteristic hallmark of the idiopathic inflammatory myopathies (IIMs), collectively termed myositis. Alongside MHC-I overexpression, subtypes of myositis, display a distinct type I interferon (IFN) signature. This study examined the combinational effects of elevated MHC-I and type I IFNs (IFNα/β) on mitochondrial function, as mitochondrial dysfunction is often seen in IIMs. Human skeletal muscle myoblasts were transfected with an MHC-I isoform using the mammalian HLA-A2/Kb vector. Mitochondrial respiration, mitochondrial membrane potential, and reactive oxygen/nitrogen species generation were assessed with or without IFNα and IFNβ. We show that MHC-I overexpression in human skeletal muscle myoblasts led to decreased basal glycolysis and mitochondrial respiration, cellular spare respiratory capacity, adenosine triphosphate-linked respiration, and an increased proton leak, which were all exaggerated by type I IFNs. Mitochondrial membrane depolarization was induced by MHC-I overexpression both in absence and presence of type I IFNs. Human myoblasts overexpressing MHC-I showed elevated nitric oxide generation that was abolished when combined with IFN. MHC-I on its own did not result in an increased reactive oxygen species (ROS) production, but IFN on their own, or combined with MHC-I overexpression did induce elevated ROS generation. Surprisingly, we observed no gross changes in mitochondrial reticular structure or markers of mitochondrial dynamics. We present new evidence that MHC-I overexpression and type I IFNs aggravate the effects each has on mitochondrial function in human skeletal muscle cells, providing novel insights into their mechanisms of action and suggesting important implications in the further study of myositis pathogenesis.

Keywords:  idiopathic inflammatory myopathies; major histocompatibility complex I; mitochondria; myositis; reactive and nitric oxygen species; type I interferon

DOI:  https://doi.org/10.1002/jcp.31458
Eur J Clin Invest. 2024 Oct 10. e14331

Modulation of mitochondrial permeability transition pores in reperfusion injury: Mechanisms and therapeutic approaches.

Giampaolo Morciano, Paolo Pinton.

  Ischemia/reperfusion injury is attracting continuous interest in science for two reasons: because it affects several clinical conditions and because it has been identified, albeit in broad terms, the molecular entity becoming activated by the reperfusion damage paradoxes. Indeed, calcium, oxygen-dependent oxidative stress and pH would activate conformational changes in the mitochondrial cristae embedded F1/FO ATP synthase, allowing the formation of pores in the inner mitochondrial membrane thus increasing its permeability. This is a key determinant for mitochondrial stress, cell death and tissue dysfunction. Targeting each of these factors has never contributed to improved clinical outcome of the patients affected by reperfusion damage; now, the focus on the PTP opening could represent the closest target to solve this pathway made by extensive cell death when the tissues become revascularized. In this review, we summarized last knowledge about the structure, the modulation and the therapeutic targeting of the PTP, focusing on ATP synthase and cardiac ischemia/reperfusion.

Keywords:  calcium; cardiovascular diseases; mitochondria; permeability transition pore; subunit c

DOI:  https://doi.org/10.1111/eci.14331
Ageing Res Rev. 2024 Oct 04. pii: S1568-1637(24)00342-8. [Epub ahead of print] 102524

Synaptic Mitochondria: a crucial factor in the aged hippocampus.

Karina A Cicali, Cheril Tapia-Rojas.

  Aging is a multifaceted biological process characterized by progressive molecular and cellular damage accumulation. The brain hippocampus undergoes functional deterioration with age, caused by cellular deficits, decreased synaptic communication, and neuronal death, ultimately leading to memory impairment. One of the factors contributing to this dysfunction is the loss of mitochondrial function. In neurons, mitochondria are categorized into synaptic and non-synaptic pools based on their location. Synaptic mitochondria, situated at the synapses, play a crucial role in maintaining neuronal function and synaptic plasticity, whereas non-synaptic mitochondria are distributed throughout other neuronal compartments, supporting overall cellular metabolism and energy supply. The proper function of synaptic mitochondria is essential for synaptic transmission as they provide the energy required and regulate calcium homeostasis at the communication sites between neurons. Maintaining the structure and functionality of synaptic mitochondria involves intricate processes, including mitochondrial dynamics such as fission, fusion, transport, and quality control mechanisms. These processes ensure that mitochondria remain functional, replace damaged organelles, and sustain cellular homeostasis at synapses. Notably, deficiencies in these mechanisms have been increasingly associated with aging and the onset of age-related neurodegenerative diseases. Synaptic mitochondria from the hippocampus are particularly vulnerable to age-related changes, including alterations in morphology and a decline in functionality, which significantly contribute to decreased synaptic activity during aging. This review comprehensively explores the critical roles that mitochondrial dynamics and quality control mechanisms play in preserving synaptic activity and neuronal function. It emphasizes the emerging evidence linking the deterioration of synaptic mitochondria to the aging process and the development of neurodegenerative diseases, highlighting the importance of these organelles from hippocampal neurons as potential therapeutic targets for mitigating cognitive decline and synaptic degeneration associated with aging. The novelty of this review lies in its focus on the unique vulnerability of hippocampal synaptic mitochondria to aging, underscoring their importance in maintaining brain function across the lifespan.

Keywords:  Aging; Cognitive Decline; Mitochondria; Mitochondrial Dysfunction; Non-synaptic; Synaptic

DOI:  https://doi.org/10.1016/j.arr.2024.102524
Cell Biochem Funct. 2024 Sep;42(7): e4131

Targeting Mitochondria: Influence of Metabolites on Mitochondrial Heterogeneity.

Amie N Joof, Fangyuan Ren, Yan Zhou, Mengyu Wang, Jiani Li, Yurong Tan.

  Mitochondria are vital organelles that provide energy for the metabolic processes of cells. These include regulating cellular metabolism, autophagy, apoptosis, calcium ions, and signaling processes. Despite their varying functions, mitochondria are considered semi-independent organelles that possess their own genome, known as mtDNA, which encodes 13 proteins crucial for oxidative phosphorylation. However, their diversity reflects an organism's adaptation to physiological conditions and plays a complex function in cellular metabolism. Mitochondrial heterogeneity exists at the single-cell and tissue levels, impacting cell shape, size, membrane potential, and function. This heterogeneity can contribute to the progression of diseases such as neurodegenerative diseases, metabolic diseases, and cancer. Mitochondrial dynamics enhance the stability of cells and sufficient energy requirement, but these activities are not universal and can lead to uneven mitochondria, resulting in heterogeneity. Factors such as genetics, environmental compounds, and signaling pathways are found to affect these cellular processes and heterogeneity. Additionally, the varying roles of metabolites such as NADH and ATP affect glycolysis's speed and efficiency. An imbalance in metabolites can impair ATP production and redox potential in the mitochondria. Therefore, this review will explore the influence of metabolites in shaping mitochondrial morphology, how these changes contribute to age-related diseases and the therapeutic targets for regulating mitochondrial heterogeneity.

Keywords:  ATP; diseases; fusion/fission; heterogeneity; metabolites; mitochondria; signaling pathway; therapeutic target

DOI:  https://doi.org/10.1002/cbf.4131
Skelet Muscle. 2024 Oct 11. 14(1): 22

Isolation of small extracellular vesicles from regenerating muscle tissue using tangential flow filtration and size exclusion chromatography.

Uxia Gurriaran-Rodriguez, Yves De Repentigny, Rashmi Kothary, Michael A Rudnicki.

  We have recently made the strikingly discovery that upon a muscle injury, Wnt7a is upregulated and secreted from new regenerating myofibers on the surface of exosomes to elicit its myogenerative response distally. Despite recent advances in extracellular vesicle (EVs) isolation from diverse tissues, there is still a lack of specific methodology to purify EVs from muscle tissue. To eliminate contamination with non-EV secreted proteins and cytoplasmic fragments, which are typically found when using classical methodology, such as ultracentrifugation, we adapted a protocol combining Tangential Flow Filtration (TFF) and Size Exclusion Chromatography (SEC). We found that this approach allows simultaneous purification of Wnt7a, bound to EVs (retentate fraction) and free non-EV Wnt7a (permeate fraction). Here we described this optimized protocol designed to specifically isolate EVs from hind limb muscle explants, without cross-contamination with other sources of non-EV bounded proteins. The first step of the protocol is to remove large EVs with sequential centrifugation. Extracellular vesicles are then concentrated and washed in exchange buffer by TFF. Lastly, SEC is performed to remove any soluble protein traces remaining after TFF. Overall, this procedure can be used to isolate EVs from conditioned media or biofluid that contains EVs derived from any cell type or tissue, improving reproducibility, efficiency, and purity of EVs preparations. Our purification protocol results in high purity EVs that maintain structural integrity and thus fully compatible with in vitro and in vivo bioactivity and analytic assays.

Keywords:  Myoregeneration; Skeletal muscle; Tangential flow filtration; Tissue derived extracellular vesicles

DOI:  https://doi.org/10.1186/s13395-024-00355-1
Commun Biol. 2024 Oct 10. 7(1): 1294

ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca2+ uptake and oxidative metabolism.

Giulia Dematteis, Laura Tapella, Claudio Casali, Maria Talmon, Elisa Tonelli, Simone Reano, Adele Ariotti, Emanuela Pessolano, Justyna Malecka, Gabriela Chrostek, Gabrielė Kulkovienė, Danielius Umbrasas, Carla Distasi, Mariagrazia Grilli, Graham Ladds, Nicoletta Filigheddu, Luigia Grazia Fresu, Katsuhiko Mikoshiba, Carlos Matute, Paula Ramos-Gonzalez, Aiste Jekabsone, Tito Calì, Marisa Brini, Marco Biggiogera, Fabio Cavaliere, Riccardo Miggiano, Armando A Genazzani, Dmitry Lim.

IP3 receptor (IP3R)-mediated Ca2+ transfer at the mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) drives mitochondrial Ca2+ uptake and oxidative metabolism and is linked to different pathologies, including Parkinson's disease (PD). The dependence of Ca2+ transfer efficiency on the ER-mitochondria distance remains unexplored. Employing molecular rulers that stabilize ER-mitochondrial distances at 5 nm resolution, and using genetically encoded Ca2+ indicators targeting the ER lumen and the sub-mitochondrial compartments, we now show that a distance of ~20 nm is optimal for Ca2+ transfer and mitochondrial oxidative metabolism due to enrichment of IP3R at MERCS. In human iPSC-derived astrocytes from PD patients, 20 nm MERCS were specifically reduced, which correlated with a reduction of mitochondrial Ca2+ uptake. Stabilization of the ER-mitochondrial interaction at 20 nm, but not at 10 nm, fully rescued mitochondrial Ca2+ uptake in PD astrocytes. Our work determines with precision the optimal distance for Ca2+ flux between ER and mitochondria and suggests a new paradigm for fine control over mitochondrial function.

DOI: https://doi.org/10.1038/s42003-024-06933-9
bioRxiv. 2024 Sep 28. pii: 2024.09.27.615276. [Epub ahead of print]

Selection promotes age-dependent degeneration of the mitochondrial genome.

Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.

Somatic mutations in mitochondrial genomes (mtDNA) accumulate exponentially during aging. Using single cell sequencing, we characterize the spectrum of age-accumulated mtDNA mutations in mouse and human liver and identify directional forces that accelerate the accumulation of mutations beyond the rate predicted by a neutral model. "Driver" mutations that give genomes a replicative advantage rose to high cellular abundance and carried along "passenger" mutations, some of which are deleterious. In addition, alleles that alter mtDNA-encoded proteins selectively increased in abundance overtime, strongly supporting the idea of a "destructive" selection that favors genomes lacking function. Overall, this combination of selective forces acting in hepatocytes promotes somatic accumulation of mutations in coding regions of mtDNA that are otherwise conserved in evolution. We propose that these selective processes could contribute to the population prevalence of mtDNA mutations, accelerate the course of heteroplasmic mitochondrial diseases and promote age-associated erosion of the mitochondrial genome.

DOI: https://doi.org/10.1101/2024.09.27.615276