bims-mitrat 2024-09-15 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒09‒15
twelve papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses.
A promising therapeutic: Exosome-mediated mitochondrial transplantation.
An Engineered Hierarchical Hydrogel with Immune Responsiveness and Targeted Mitochondrial Transfer to Augmented Bone Regeneration.
Robust Mitochondrial Isolation from Rodent Cardiac Tissue.
Neurodegenerative disorders, metabolic icebergs, and mitohormesis.
Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.
Long-term effects of the chronic administration of doxorubicin on aged skeletal muscle: An exploratory study in mice.
Tunneling Nanotubes in the Brain.
Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction.
Organelle Communication with the Nucleus.
Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.
Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.

Acta Physiol (Oxf). 2024 Sep 12. e14215

Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses.

Javier Díaz-Lara, Elizabeth Reisman, Javier Botella, Bianka Probert, Louise M Burke, David J Bishop, Matthew J Lee.

  AIM: To investigate how delayed post-exercise carbohydrate intake affects muscle glycogen, metabolic- and mitochondrial-related molecular responses, and subsequent high-intensity interval exercise (HIIE) capacity.METHODS: In a double-blind cross-over design, nine recreationally active men performed HIIE (10 × 2-min cycling, ~94% W˙peak) in the fed state, on two occasions. During 0-3 h post-HIIE, participants drank either carbohydrates ("Immediate Carbohydrate" [IC], providing 2.4 g/kg) or water ("Delayed Carbohydrate" [DC]); total carbohydrate intake over 24 h post-HIIE was matched (~7 g/kg/d). Skeletal muscle (sampled pre-HIIE, post-HIIE, +3 h, +8 h, +24 h) was analyzed for whole-muscle glycogen and mRNA content, plus signaling proteins in cytoplasmic- and nuclear-enriched fractions. After 24 h, participants repeated the HIIE protocol until failure, to test subsequent HIIE capacity; blood lactate, heart rate, and ratings of perceived effort (RPE) were measured throughout.
RESULTS: Muscle glycogen concentrations, and relative changes, were similar between conditions throughout (p > 0.05). Muscle glycogen was reduced from baseline (mean ± SD mmol/kg dm; IC: 409 ± 166; DC: 352 ± 76) at post-HIIE (IC: 253 ± 96; DC: 214 ± 82), +3 h (IC: 276 ± 62; DC: 269 ± 116) and + 8 h (IC: 321 ± 56; DC: 269 ± 116), returning to near-baseline by +24 h. Several genes (PGC-1ɑ, p53) and proteins (p-ACCSer79, p-P38 MAPKThr180/Tyr182) elicited typical exercise-induced changes irrespective of condition. Delaying carbohydrate intake reduced next-day HIIE capacity (5 ± 3 intervals) and increased RPE (~2 ratings), despite similar physiological responses between conditions.
CONCLUSION: Molecular responses to HIIE (performed in the fed state) were not enhanced by delayed post-exercise carbohydrate intake. Our findings support immediate post-exercise refueling if the goal is to maximize next-day HIIE capacity and recovery time is ≤24 h.

Keywords:  carbohydrates; exercise; mRNA; muscle glycogen; nutrition; signaling

DOI:  https://doi.org/10.1111/apha.14215
Int Immunopharmacol. 2024 Sep 12. pii: S1567-5769(24)01625-4. [Epub ahead of print]142(Pt A): 113104

A promising therapeutic: Exosome-mediated mitochondrial transplantation.

Meiling Cao, Jiahui Zou, Mingyue Shi, Danyang Zhao, Chang Liu, Yanshan Liu, Lei Li, Hongkun Jiang.

  Mitochondrial dysfunction has been identified as a trigger for cellular autophagy dysfunction and programmed cell death. Emerging studies have revealed that, in pathological contexts, intercellular transfer of mitochondria takes place, facilitating the restoration of mitochondrial function, energy metabolism, and immune homeostasis. Extracellular vesicles, membranous structures released by cells, exhibit reduced immunogenicity and enhanced stability during the transfer of mitochondria. Thus, this review provides a concise overview of mitochondrial dysfunction related diseases and the mechanism of mitochondrial dysfunction in diseases progression, and the composition and functions of the extracellular vesicles, along with elucidating the principal mechanisms underlying intercellular mitochondrial transfer. In this article, we will focus on the advancements in both animal models and clinical trials concerning the therapeutic efficacy of extracellular vesicle-mediated mitochondrial transplantation across various systemic diseases in neurodegenerative diseases and cardiovascular diseases. Additionally, the review delves into the multifaceted roles of extracellular vesicle-transplanted mitochondria, encompassing anti-inflammatory actions, promotion of tissue repair, enhancement of cellular function, and modulation of metabolic and immune homeostasis within diverse pathological contexts, aiming to provide novel perspectives for extracellular vesicle transplantation of mitochondria in the treatment of various diseases.

Keywords:  Extracellular vesicles; Mitochondria; Mitochondrial transfer; Mitochondrial transplantation; Organ damage; Therapy

DOI:  https://doi.org/10.1016/j.intimp.2024.113104
Adv Sci (Weinh). 2024 Sep 11. e2406287

An Engineered Hierarchical Hydrogel with Immune Responsiveness and Targeted Mitochondrial Transfer to Augmented Bone Regeneration.

Wenjin Cai, Shihua Mao, Ying Wang, Bicong Gao, Jiaying Zhao, Yongzheng Li, Yani Chen, Dong Zhang, Jintao Yang, Guoli Yang.

  Coordinating the immune response and bioenergy metabolism in bone defect environments is essential for promoting bone regeneration. Mitochondria are important organelles that control internal balance and metabolism. Repairing dysfunctional mitochondria has been proposed as a therapeutic approach for disease intervention. Here, an engineered hierarchical hydrogel with immune responsiveness can adapt to the bone regeneration environment and mediate the targeted mitochondria transfer between cells. The continuous supply of mitochondria by macrophages can restore the mitochondrial bioenergy of bone marrow mesenchymal stem cells (BMSC). Fundamentally solving the problem of insufficient energy support of BMSCs caused by local inflammation during bone repair and regeneration. This discovery provides a new therapeutic strategy for promoting bone regeneration and repair, which has research value and practical application prospects in the treatment of various diseases caused by mitochondrial dysfunction.

Keywords:  bioenergy metabolism; bone mesenchymal stem cells; bone regeneration; mitochondrial transfer

DOI:  https://doi.org/10.1002/advs.202406287
J Vis Exp. 2024 Aug 23.

Robust Mitochondrial Isolation from Rodent Cardiac Tissue.

Alyssa C Vadovsky, Melissa Quinn, Tianyi Xia, Yan Levitsky, Jason N Bazil.

Mitochondrial isolation has been practiced for decades, following procedures established by pioneers in the fields of molecular biology and biochemistry to study metabolic impairments and disease. Consistent mitochondrial quality is necessary to properly investigate mitochondrial physiology and bioenergetics; however, many different published isolation methods are available for researchers. Although different experimental strategies require different isolation methods, the basic principles and procedures are similar. This protocol details a method capable of extracting well-coupled mitochondria from a variety of tissue sources, including small animals and cells. The steps outlined include organ dissection, mitochondrial purification, protein quantification, and various quality control checks. The primary quality control metric used to identify high-quality mitochondria is the respiratory control ratio (RCR). The RCR is the ratio of the respiratory rate during oxidative phosphorylation to the rate in the absence of ADP. Alternative metrics are discussed. While high RCR values relative to their tissue source are obtained using this protocol, several steps can be optimized to suit the individual needs of researchers. This procedure is robust and has consistently resulted in isolated mitochondria with above-average RCR values across animal models and tissue sources.

DOI: https://doi.org/10.3791/67093
Transl Neurodegener. 2024 Sep 06. 13(1): 46

Neurodegenerative disorders, metabolic icebergs, and mitohormesis.

Matthew C L Phillips, Martin Picard.

  Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Hormesis; Huntington’s disease; Lumping; Mitochondria; Mitohormesis; Mitotypes; Parkinson’s disease; Splitting

DOI:  https://doi.org/10.1186/s40035-024-00435-8
Physiol Rep. 2024 Sep;12(17): e70048

Akt1 deficiency does not affect fiber type composition or mitochondrial protein expression in skeletal muscle of male mice.

Tatsuya Miyaji, Ryuichi Kasuya, Atsushi Sawada, Daisuke Sawamura, Yu Kitaoka, Mitsunori Miyazaki.

  Insulin-like growth factor-1-induced activation of ATP citrate lyase (ACLY) improves muscle mitochondrial function through an Akt-dependent mechanism. In this study, we examined whether Akt1 deficiency alters skeletal muscle fiber type and mitochondrial function by regulating ACLY-dependent signaling in male Akt1 knockout (KO) mice (12-16 weeks old). Akt1 KO mice exhibited decreased body weight and muscle wet weight, with reduced cross-sectional areas of slow- and fast-type muscle fibers. Loss of Akt1 did not affect the phosphorylation status of ACLY in skeletal muscle. The skeletal muscle fiber type and expression of mitochondrial oxidative phosphorylation complex proteins were unchanged in Akt1 KO mice compared with the wild-type control. These observations indicate that Akt1 is important for the regulation of skeletal muscle fiber size, whereas the regulation of muscle fiber type and muscle mitochondrial content occurs independently of Akt1 activity.

Keywords:  Akt1; glycolysis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70048
Biochem Biophys Res Commun. 2024 Sep 03. pii: S0006-291X(24)01186-0. [Epub ahead of print]733 150650

Long-term effects of the chronic administration of doxorubicin on aged skeletal muscle: An exploratory study in mice.

Alexandra Moreira-Pais, Rita Ferreira, Telmo Baltazar, Maria João Neuparth, Rui Vitorino, Ana Reis-Mendes, Vera Marisa Costa, Paula A Oliveira, José A Duarte.

  The widely used chemotherapeutic drug doxorubicin (DOX) has been associated with adverse effects on the skeletal muscle, which can persist for years after the end of the treatment. These adverse effects may be exacerbated in older patients, whose skeletal muscle might already be impaired by aging. Nonetheless, the mediators responsible for DOX-induced myotoxicity are still largely unidentified, particularly the ones involved in the long-term effects that negatively affect the quality of life of the patients. Therefore, this study aimed to investigate the long-term effects of the chronic administration of DOX on the soleus muscle of aged mice. For that and to mimic the clinical regimen, a dose of 1.5 mg kg-1 of DOX was administered two times per week for three consecutive weeks in a cumulative dose of 9 mg kg-1 to 19-month-old male mice, which were sacrificed two months after the last administration. Body wasting and the atrophy of the soleus muscle, as measured by a decrease in the cross-sectional area of the soleus muscle fibers, were identified as long-term effects of DOX administration. The atrophy observed was correlated with increased reactive oxygen species production and caspase-3 activity. An impaired skeletal muscle regeneration was also suggested due to the correlation between satellite cells activation and the soleus muscle fibers atrophy. Systemic inflammation, skeletal muscle energy metabolism and neuromuscular junction-related markers do not appear to be involved in the long-term DOX-induced skeletal muscle atrophy. The data provided by this study shed light on the mediators involved in the overlooked long-term DOX-induced myotoxicity, paving the way to the improvement of the quality of life and survival rates of older cancer patients.

Keywords:  Aging; Chemotherapy; Muscle wasting; Oxidative stress; Sarcopenia

DOI:  https://doi.org/10.1016/j.bbrc.2024.150650
Results Probl Cell Differ. 2024 ;73 203-227

Tunneling Nanotubes in the Brain.

Dimitri Budinger, Vivian Baker, Michael T Heneka.

Tunneling nanotubes (TNTs) have emerged as intriguing structures facilitating intercellular communications across diverse cell types, which are integral to several biological processes, as well as participating in various disease progression. This review provides an in-depth analysis of TNTs, elucidating their structural characteristics and functional roles, with a particular focus on their significance within the brain environment and their implications in neurological and neurodegenerative disorders. We explore the interplay between TNTs and neurological diseases, offering potential mechanistic insights into disease progression, while also highlighting their potential as viable therapeutic targets. Additionally, we address the significant challenges associated with studying TNTs, from technical limitations to their investigation in complex biological systems. By addressing some of these challenges, this review aims to pave the way for further exploration into TNTs, establishing them as a central focus in advancing our understanding of neurodegenerative disorders.

DOI: https://doi.org/10.1007/978-3-031-62036-2_10
Neural Regen Res. 2024 Sep 06.

Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction.

Said Hashemolhosseini, Lea Gessler.

Skeletal muscles are essential for locomotion, posture, and metabolic regulation. To understand physiological processes, exercise adaptation, and muscle-related disorders, it is critical to understand the molecular pathways that underlie skeletal muscle function. The process of muscle contraction, orchestrated by a complex interplay of molecular events, is at the core of skeletal muscle function. Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction. Within muscle fibers, calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force. Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling. The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis. Myogenic regulators coordinate the differentiation of myoblasts into mature muscle fibers. Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability. Several muscle-related diseases, including congenital myasthenic disorders, sarcopenia, muscular dystrophies, and metabolic myopathies, are underpinned by dysregulated molecular pathways in skeletal muscle. Therapeutic interventions aimed at preserving muscle mass and function, enhancing regeneration, and improving metabolic health hold promise by targeting specific molecular pathways. Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway, a critical regulator of myogenesis, muscle regeneration, and metabolic function, and the Hippo signaling pathway. In recent years, more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers, and at the neuromuscular junction. In fact, research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers. In this review, we will summarize and discuss the data on these two pathways, focusing on their concerted action next to their contribution to skeletal muscle biology. However, an in-depth discussion of the non-canonical Wnt pathway, the fibro/adipogenic precursors, or the mechanosensory aspects of these pathways is not the focus of this review.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00417
Results Probl Cell Differ. 2024 ;73 3-23

Organelle Communication with the Nucleus.

Sourabh Sengupta, Daniel L Levy.

  Compartmentalization of cellular components is critical to the spatiotemporal and environmental regulation of biochemical activities inside a cell, ensures the proper division of cellular labor and resources, and increases the efficiency of metabolic processes. However, compartmentalization also poses a challenge as organelles often need to communicate across these compartments to complete reaction pathways. These communication signals are often critical aspects of the cellular response to changing environmental conditions. A central signaling hub in the cell, the nucleus communicates with mitochondria, lysosomes, the endoplasmic reticulum, and the Golgi body to ensure optimal organellar and cellular performance. Here we review different mechanisms by which these organelles communicate with the nucleus, focusing on anterograde and retrograde signaling of mitochondria, localization-based signaling of lysosomes, the unfolded protein response of the endoplasmic reticulum, and evidence for nucleus-Golgi signaling. We also include a brief overview of some less well-characterized mechanisms of communication between non-nuclear organelles.

Keywords:  Endoplasmic reticulum; Golgi; Inter-organellar communication; Lysosomes; Mitochondria; Nucleus

DOI:  https://doi.org/10.1007/978-3-031-62036-2_1
EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

Hilda Delgado de la Herran, Denis Vecellio Reane, Yiming Cheng, Máté Katona, Fabian Hosp, Elisa Greotti, Jennifer Wettmarshausen, Maria Patron, Hermine Mohr, Natalia Prudente de Mello, Margarita Chudenkova, Matteo Gorza, Safal Walia, Michael Sheng-Fu Feng, Anja Leimpek, Dirk Mielenz, Natalia S Pellegata, Thomas Langer, György Hajnóczky, Matthias Mann, Marta Murgia, Fabiana Perocchi.

  The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords:  Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI:  https://doi.org/10.1038/s44318-024-00219-w
Sci Rep. 2024 09 10. 14(1): 21154

Endurance exercise-induced histone methylation modification involved in skeletal muscle fiber type transition and mitochondrial biogenesis.

Jialin Li, Sheng Zhang, Can Li, Xiaoxia Zhang, Yuhui Shan, Ziyi Zhang, Hai Bo, Yong Zhang.

  Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Keywords:  AMPK; Endurance exercise; Histone methylation; Mitochondrial biogenesis; ROS; Skeletal muscle fiber type

DOI:  https://doi.org/10.1038/s41598-024-72088-6