bims-mitrat 2024-06-23 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–06–23
fourteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.
Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.
Is mitochondrial morphology important for cellular physiology?
Exploring the Role of Extracellular Vesicles in Skeletal Muscle Regeneration.
Playing pin-the-tail-on-the-protein in extracellular vesicle (EV) proteomics.
The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy.
Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.
Mitochondrial biology: Unique membrane remodeling from the matrix.
Extracellular vesicles.
Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.
Cellular senescence in normal physiology.
An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.
A multimodal exercise countermeasure prevents the negative impact of head-down tilt bed rest on muscle volume and mitochondrial health in older adults.
Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies.

J Strength Cond Res. 2024 Jul 01. 38(7): 1189-1199

Mitochondria Transplantation: Rescuing Innate Muscle Bioenergetic Impairment in a Model of Aging and Exercise Intolerance.

Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, Mohamed Ghamloush, Belal Bazzi, Abdallah Mrech, Paul T Morse, Steven L Britton, Lauren G Koch, James D McCully, Maik Hüttemann, Moh H Malek.

ABSTRACT: Arroum, T, Hish, GA, Burghardt, KJ, Ghamloush, M, Bazzi, B, Mrech, A, Morse, PT, Britton, SL, Koch, LG, McCully, JD, Hüttemann, M, and Malek, MH. Mitochondria transplantation: Rescuing innate muscle bioenergetic impairment in a model of aging and exercise intolerance. J Strength Cond Res 38(7): 1189-1199, 2024-Mitochondria, through oxidative phosphorylation, are crucial for energy production. Disease, genetic impairment, or deconditioning can harm muscle mitochondria, affecting energy production. Endurance training enhances mitochondrial function but assumes mobility. Individuals with limited mobility lack effective treatments for mitochondrial dysfunction because of disease or aging. Mitochondrial transplantation replaces native mitochondria that have been damaged with viable, respiration-competent mitochondria. Here, we used a rodent model selectively bred for low-capacity running (LCR), which exhibits innate mitochondrial dysfunction in the hind limb muscles. Hence, the purpose of this study was to use a distinct breed of rats (i.e., LCR) that display hereditary skeletal muscle mitochondrial dysfunction to evaluate the consequences of mitochondrial transplantation. We hypothesized that the transplantation of mitochondria would effectively alleviate mitochondrial dysfunction in the hind limb muscles of rats when compared with placebo injections. In addition, we hypothesized that rats receiving the mitochondrial transplantation would experience an improvement in their functional capacity, as evaluated through incremental treadmill testing. Twelve aged LCR male rats (18 months old) were randomized into 2 groups (placebo or mitochondrial transplantation). One LCR rat of the same age and sex was used as the donor to isolate mitochondria from the hindlimb muscles. Isolated mitochondria were injected into both hindlimb muscles (quadriceps femoris, tibialis anterior (TA), and gastrocnemius complex) of a subset LCR (n = 6; LCR-M) rats. The remaining LCR (n = 5; LCR-P) subset received a placebo injection containing only the vehicle without the isolated mitochondria. Four weeks after mitochondrial transplantation, rodents were euthanized and hindlimb muscles harvested. The results indicated a significant (p < 0.05) increase in mitochondrial markers for glycolytic (plantaris and TA) and mixed (quadricep femoris) muscles, but not oxidative muscle (soleus). Moreover, we found significant (p < 0.05) epigenetic changes (i.e., hypomethylation) at the global and site-specific levels for a key mitochondrial regulator (transcription factor A mitochondrial) between the placebo and mitochondrial transplantation groups. To our knowledge, this is the first study to examine the efficacy of mitochondrial transplantation in a rodent model of aging with congenital skeletal muscle dysfunction.

DOI: https://doi.org/10.1519/JSC.0000000000004793
Neural Regen Res. 2025 Mar 01. 20(3): 794-796

Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging.

Neville Ng, Michelle Newbery, Nicole Miles, Lezanne Ooi.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-02106
Trends Endocrinol Metab. 2024 Jun 11. pii: S1043-2760(24)00123-1. [Epub ahead of print]

Is mitochondrial morphology important for cellular physiology?

Timothy Wai.

  Mitochondria are double membrane-bound organelles the network morphology of which in cells is shaped by opposing events of fusion and fission executed by dynamin-like GTPases. Mutations in these genes can perturb the form and functions of mitochondria in cell and animal models of mitochondrial diseases. An expanding array of chemical, mechanical, and genetic stressors can converge on mitochondrial-shaping proteins and disrupt mitochondrial morphology. In recent years, studies aimed at disentangling the multiple roles of mitochondrial-shaping proteins beyond fission or fusion have provided insights into the homeostatic relevance of mitochondrial morphology. Here, I review the pleiotropy of mitochondrial fusion and fission proteins with the aim of understanding whether mitochondrial morphology is important for cell and tissue physiology.

Keywords:  fission and fusion; genetic disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology

DOI:  https://doi.org/10.1016/j.tem.2024.05.005
Int J Mol Sci. 2024 May 27. pii: 5811. [Epub ahead of print]25(11):

Exploring the Role of Extracellular Vesicles in Skeletal Muscle Regeneration.

Cristiana Porcu, Gabriella Dobrowolny, Bianca Maria Scicchitano.

  Skeletal muscle regeneration entails a multifaceted process marked by distinct phases, encompassing inflammation, regeneration, and remodeling. The coordination of these phases hinges upon precise intercellular communication orchestrated by diverse cell types and signaling molecules. Recent focus has turned towards extracellular vesicles (EVs), particularly small EVs, as pivotal mediators facilitating intercellular communication throughout muscle regeneration. Notably, injured muscle provokes the release of EVs originating from myofibers and various cell types, including mesenchymal stem cells, satellite cells, and immune cells such as M2 macrophages, which exhibit anti-inflammatory and promyogenic properties. EVs harbor a specific cargo comprising functional proteins, lipids, and nucleic acids, including microRNAs (miRNAs), which intricately regulate gene expression in target cells and activate downstream pathways crucial for skeletal muscle homeostasis and repair. Furthermore, EVs foster angiogenesis, muscle reinnervation, and extracellular matrix remodeling, thereby modulating the tissue microenvironment and promoting effective tissue regeneration. This review consolidates the current understanding on EVs released by cells and damaged tissues throughout various phases of muscle regeneration with a focus on EV cargo, providing new insights on potential therapeutic interventions to mitigate muscle-related pathologies.

Keywords:  extracellular vesicles; miRNAs; muscle regeneration; skeletal muscle damage

DOI:  https://doi.org/10.3390/ijms25115811
Proteomics. 2024 Jun 20. e2400074

Playing pin-the-tail-on-the-protein in extracellular vesicle (EV) proteomics.

Natalie P Turner.

  Extracellular vesicles (EVs) are anucleate particles enclosed by a lipid bilayer that are released from cells via exocytosis or direct budding from the plasma membrane. They contain an array of important molecular cargo such as proteins, nucleic acids, and lipids, and can transfer these cargoes to recipient cells as a means of intercellular communication. One of the overarching paradigms in the field of EV research is that EV cargo should reflect the biological state of the cell of origin. The true relationship or extent of this correlation is confounded by many factors, including the numerous ways one can isolate or enrich EVs, overlap in the biophysical properties of different classes of EVs, and analytical limitations. This presents a challenge to research aimed at detecting low-abundant EV-encapsulated nucleic acids or proteins in biofluids for biomarker research and underpins technical obstacles in the confident assessment of the proteomic landscape of EVs that may be affected by sample-type specific or disease-associated proteoforms. Improving our understanding of EV biogenesis, cargo loading, and developments in top-down proteomics may guide us towards advanced approaches for selective EV and molecular cargo enrichment, which could aid EV diagnostics and therapeutics research.

Keywords:  extracellular vesicles; proteoform; proteomics; top‐down proteomics; transcriptomics

DOI:  https://doi.org/10.1002/pmic.202400074
Circ Res. 2024 Jun 21. 135(1): 198-221

The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy.

Alin Rai, Bethany Claridge, Jonathan Lozano, David W Greening.

  From their humble discovery as cellular debris to cementing their natural capacity to transfer functional molecules between cells, the long-winded journey of extracellular vesicles (EVs) now stands at the precipice as a next-generation cell-free therapeutic tool to revolutionize modern-day medicine. This perspective provides a snapshot of the discovery of EVs to their emergence as a vibrant field of biology and the renaissance they usher in the field of biomedical sciences as therapeutic agents for cardiovascular pathologies. Rapid development of bioengineered EVs is providing innovative opportunities to overcome biological challenges of natural EVs such as potency, cargo loading and enhanced secretion, targeting and circulation half-life, localized and sustained delivery strategies, approaches to enhance systemic circulation, uptake and lysosomal escape, and logistical hurdles encompassing scalability, cost, and time. A multidisciplinary collaboration beyond the field of biology now extends to chemistry, physics, biomaterials, and nanotechnology, allowing rapid development of designer therapeutic EVs that are now entering late-stage human clinical trials.

Keywords:  bioengineering; exosomes; extracellular vesicles; heart; therapeutics

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323054
Biochimie. 2024 Jun 19. pii: S0300-9084(24)00141-X. [Epub ahead of print]

Mitochondrial proteases modulate mitochondrial stress signalling and cellular homeostasis in health and disease.

Nicoleta Moisoi.

Maintenance of mitochondrial homeostasis requires a plethora of coordinated quality control and adaptations' mechanisms in which mitochondrial proteases play a key role. Their activation or loss of function reverberate beyond local mitochondrial biochemical and metabolic remodelling into coordinated cellular pathways and stress responses that feedback onto the mitochondrial functionality and adaptability. Mitochondrial proteolysis modulates molecular and organellar quality control, metabolic adaptations, lipid homeostasis and regulates transcriptional stress responses. Defective mitochondrial proteolysis results in disease conditions most notably, mitochondrial diseases, neurodegeneration and cancer. Here, it will be discussed how mitochondrial proteases and mitochondria stress signalling impact cellular homeostasis and determine the cellular decision to survive or die, how these processes may impact disease etiopathology, and how modulation of proteolysis may offer novel therapeutic strategies.

DOI: https://doi.org/10.1016/j.biochi.2024.06.005
Curr Biol. 2024 Jun 17. pii: S0960-9822(24)00608-0. [Epub ahead of print]34(12): R581-R583

Mitochondrial biology: Unique membrane remodeling from the matrix.

Jason A Mears.

A new study reports the identification of a fission yeast dynamin superfamily protein, Mmc1, that self-assembles on the matrix side of the inner mitochondrial membrane and interacts with subunits of the mitochondrial contact site and cristae organizing system to maintain cristae architecture.

DOI: https://doi.org/10.1016/j.cub.2024.05.010
Genetics. 2024 Jun 17. pii: iyae088. [Epub ahead of print]

Extracellular vesicles.

Juan Wang, Maureen M Barr, Ann M Wehman.

  Extracellular vesicles (EVs) encompass a diverse array of membrane-bound organelles released outside cells in response to developmental and physiological cell needs. EVs play important roles in remodeling the shape and content of differentiating cells and can rescue damaged cells from toxic or dysfunctional content. EVs can send signals and transfer metabolites between tissues and organisms to regulate development, respond to stress or tissue damage, or alter mating behaviors. While many EV functions have been uncovered by characterizing ex vivo EVs isolated from body fluids and cultured cells, research using the nematode Caenorhabditis elegans has provided insights into the in vivo functions, biogenesis, and uptake pathways. The C. elegans EV field has also developed methods to analyze endogenous EVs within the organismal context of development and adult physiology in free-living, behaving animals. In this review, we summarize major themes that have emerged for C. elegans EVs and their relevance to human health and disease. We also highlight the diversity of biogenesis mechanisms, locations, and functions of worm EVs and discuss open questions and unexplored topics tenable in C. elegans, given the nematode model is ideal for light and electron microscopy, genetic screens, genome engineering, and high-throughput omics.

Keywords:   Caenorhabditis elegans ; cilia; exosome; extracellular vesicle; microvesicle; midbody remnant; spermatogenesis

DOI:  https://doi.org/10.1093/genetics/iyae088
Mitochondrion. 2024 Jun 17. pii: S1567-7249(24)00080-1. [Epub ahead of print]78 101922

Beyond the membrane: Exploring non-viral methods for mitochondrial gene delivery.

Dilpreet Singh.

  Mitochondrial disorders, stemming from mutations in mitochondrial DNA (mtDNA), present a significant therapeutic challenge due to their complex pathophysiology and broad spectrum of clinical manifestations. Traditional gene therapy approaches, primarily reliant on viral vectors, face obstacles such as potential immunogenicity, insertional mutagenesis, and the specificity of targeting mtDNA. This review delves into non-viral methods for mitochondrial gene delivery, emerging as a promising alternative to overcome these limitations. Focusing on lipid-based nanoparticles, polymer-based vectors, and mitochondrial-targeted peptides, the mechanisms of action, advantages, and current applications in treating mitochondrial diseases was well elucidated. Non-viral vectors offer several benefits, including reduced immunogenicity, enhanced safety profiles, and the flexibility to carry a wide range of genetic material. We examine case studies where these methods have been applied, highlighting their potential in correcting pathogenic mtDNA mutations and mitigating disease phenotypes. Despite their promise, challenges such as delivery efficiency, specificity, and long-term expression stability persist. The review underscores the need for ongoing research to refine these delivery systems carry a wide range of genetic material. We examine case studies where these methods settings. As we advance our understanding of mitochondrial biology and gene delivery technologies, non-viral methods hold the potential to revolutionize the treatment of mitochondrial disorders, offering hope for therapies that can precisely target and correct the underlying genetic defects.

Keywords:  Gene therapy; Lipid-based nanoparticles; Mitochondrial disorders; Mitochondrial gene delivery; Mitochondrial-targeted peptides; Non-viral vectors; Polymer-based vectors; Precision medicine

DOI:  https://doi.org/10.1016/j.mito.2024.101922
Science. 2024 Jun 21. 384(6702): 1300-1301

Cellular senescence in normal physiology.

João Pedro de Magalhães.

Long associated with aging, senescent cells can promote health and have physiological roles.

DOI: https://doi.org/10.1126/science.adj7050
Int J Mol Sci. 2024 May 31. pii: 6056. [Epub ahead of print]25(11):

An Amino Acid Mixture to Counteract Skeletal Muscle Atrophy: Impact on Mitochondrial Bioenergetics.

Francesco Bellanti, Aurelio Lo Buglio, Giuseppe Pannone, Maria Carmela Pedicillo, Ilenia Sara De Stefano, Angela Pignataro, Cristiano Capurso, Gianluigi Vendemiale.

  Skeletal muscle atrophy (SMA) is caused by a rise in muscle breakdown and a decline in protein synthesis, with a consequent loss of mass and function. This study characterized the effect of an amino acid mixture (AA) in models of SMA, focusing on mitochondria. C57/Bl6 mice underwent immobilization of one hindlimb (I) or cardiotoxin-induced muscle injury (C) and were compared with controls (CTRL). Mice were then administered AA in drinking water for 10 days and compared to a placebo group. With respect to CTRL, I and C reduced running time and distance, along with grip strength; however, the reduction was prevented by AA. Tibialis anterior (TA) muscles were used for histology and mitochondria isolation. I and C resulted in TA atrophy, characterized by a reduction in both wet weight and TA/body weight ratio and smaller myofibers than those of CTRL. Interestingly, these alterations were lightly observed in mice treated with AA. The mitochondrial yield from the TA of I and C mice was lower than that of CTRL but not in AA-treated mice. AA also preserved mitochondrial bioenergetics in TA muscle from I and C mice. To conclude, this study demonstrates that AA prevents loss of muscle mass and function in SMA by protecting mitochondria.

Keywords:  amino acids; cardiotoxin; immobilization; sarcopenia

DOI:  https://doi.org/10.3390/ijms25116056
J Physiol. 2024 Jun 15.

A multimodal exercise countermeasure prevents the negative impact of head-down tilt bed rest on muscle volume and mitochondrial health in older adults.

Maude Dulac, Guy Hajj-Boutros, Vita Sonjak, Andréa Faust, Sabah N A Hussain, Stéphanie Chevalier, Isabelle J Dionne, José A Morais, Gilles Gouspillou.

  Mitochondrial dysfunctions are thought to contribute to muscle atrophy and weakness that develop during ageing and mechanical unloading caused by immobilization, bed rest and microgravity. Older adults are at greater risk of developing muscle and mitochondrial dysfunctions in response to unloading. Although exercise is well known to promote muscle and mitochondrial health, its protective effect during mechanical unloading in older adults remains largely unexplored. Here, we investigated the impact of 14 days of head-down tilt bed rest (HDBR) with and without a multimodal exercise countermeasure in older men and women (55-65 years). Leg muscle volume was assessed using magnetic resonance imaging. Biopsies of the vastus lateralis were performed to assess markers of mitochondrial content, respiration, reactive oxygen species (ROS) production and calcium retention capacity (mCRC). Indices of mitochondrial quality control (MQC), including markers of fusion (MFN1 and 2), fission (Drp1), mitophagy (Parkin) and autophagy (p62 and LC3I and II) were measured using immunoblots. Muscle cross-sections were stained for neural cell adhesion molecule (NCAM, a marker of denervation). HDBR triggered muscle atrophy, decreased mitochondrial content and respiration and increased mitochondrial ROS production. HDBR had no impact on mCRC or MQC markers but increased markers of autophagy and denervation. Exercise prevented the deleterious effects of HDBR on leg muscle volume, mitochondrial ROS production and markers of autophagy and denervation. Exercise also increased mitochondrial content and respiration without altering mCRC and MQC markers. Collectively, our results indicate that an exercise countermeasure that can be performed in bed is effective in protecting muscle and mitochondrial health during HDBR in older adults. KEY POINTS: Conditions associated with muscle unloading, such as immobilization, bed rest or microgravity, result in muscle atrophy and weakness, particularly in older adults. Mitochondrial dysfunctions are thought to contribute to muscle atrophy caused by unloading and ageing. However, whether exercise can counteract the deleterious effects of unloading in older adults remains largely unexplored. Here, we report that older adults exposed to 14 days of head-down tilt bed rest (HDBR) displayed upper leg muscle atrophy, a decrease in mitochondrial content and respiration, an increase in H2O2 emission, and an increase in autophagy and denervation markers. No impact of HDBR on mitochondrial quality control was observed. A multimodal exercise countermeasure prevented the deleterious effects of HDBR on upper leg muscle volume, mitochondrial reactive oxygen species emission, and markers of autophagy and denervation and increased mitochondrial content and respiration. These findings highlight the effectiveness of exercise in promoting muscle and mitochondrial health in older adults undergoing bed rest.

Keywords:  ageing; atrophy; autophagy; disuse; inactivity; mitochondria; mitochondrial dynamics; neuromuscular junction; skeletal muscle; space flight; weakness

DOI:  https://doi.org/10.1113/JP285897
Clin Sci (Lond). 2024 Jun 19. 138(12): 741-756

Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies.

Colleen S Deane, Matthew Piasecki, Philip J Atherton.

  Periods of skeletal muscle disuse lead to rapid declines in muscle mass (atrophy), which is fundamentally underpinned by an imbalance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). The complex interplay of molecular mechanisms contributing to the altered regulation of muscle protein balance during disuse have been investigated but rarely synthesised in the context of humans. This narrative review discusses human models of muscle disuse and the ensuing inversely exponential rate of muscle atrophy. The molecular processes contributing to altered protein balance are explored, with a particular focus on growth and breakdown signalling pathways, mitochondrial adaptations and neuromuscular dysfunction. Finally, key research gaps within the disuse atrophy literature are highlighted providing future avenues to enhance our mechanistic understanding of human disuse atrophy.

Keywords:  atrophy; disuse; skeletal muscle

DOI:  https://doi.org/10.1042/CS20231198