bims-mitrat 2024-08-25 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒08‒25
twelve papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Inner membrane turns inside out to exit mitochondrial organelles.
Melatonin-loaded bioactive microspheres accelerate aged bone regeneration by formation of tunneling nanotubes to enhance mitochondrial transfer.
Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.
Emerging role and translational potential of small extracellular vesicles in neuroscience.
BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.
Extracellular vesicles may provide an alternative detoxification pathway during skeletal muscle myoblast ageing.
Muscle Mitochondrial Capacity Is Impaired Immediately Following Maximal Exercise.
Muscle-derived IL-1β regulates EcSOD expression via the NBR1-p62-Nrf2 pathway in muscle during cancer cachexia.
Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.
YAP activation in Müller cells protects against NMDA-induced retinal ganglion cell injury by regulating Bcl-xL expression.
Skeletal muscle adaptations following eccentric contractions are not mediated by keratin 18.
Sarcopenia is attenuated by mairin in SAMP8 mice via the inhibition of FAPs fibrosis through the AMPK-TGF-β-SMAD axis.

Nature. 2024 Aug;632(8027): 987-988

Inner membrane turns inside out to exit mitochondrial organelles.

David Pla-Martín, Andreas S Reichert.



Keywords:  Biochemistry; Cell biology

DOI:  https://doi.org/10.1038/d41586-024-02528-w
Mater Today Bio. 2024 Oct;28 101175

Melatonin-loaded bioactive microspheres accelerate aged bone regeneration by formation of tunneling nanotubes to enhance mitochondrial transfer.

Huacui Xiong, Huanhuan Qiu, Chunhui Wang, Yonghao Qiu, Shuyi Tan, Ke Chen, Fujian Zhao, Jinlin Song.

  The repair of bone defects in the elderly individuals is significantly delayed due to cellular senescence and dysfunction, which presents a challenge in clinical settings. Furthermore, there are limited effective methods available to promote bone repair in older individuals. Herein, melatonin-loaded mesoporous bioactive glasses microspheres (MTBG) were successfully prepared based on their mesoporous properties. The repair of bone defects in aged rats was significantly accelerated by enhancing mitochondrial function through the sustained release of melatonin and bioactive ions. MTBG effectively rejuvenated senescent bone marrow mesenchymal stem cells (BMSCs) by scavenging excessive reactive oxygen species (ROS), stabilizing the mitochondrial membrane potential (ΔΨm), and increasing ATP synthesis. Analysis of the underlying mechanism revealed that the formation of tunneling nanotubes (TNTs) facilitated the intercellular transfer of mitochondria, thereby resulting in the recovery of mitochondrial function. This study provides critical insights into the design of new biomaterials for the elderly individuals and the biological mechanism involved in aged bone regeneration.

Keywords:  Aged bone regeneration; Mesoporous bioactive glasses; Mitochondrial function; Mitochondrial transfer; Tunneling nanotubes

DOI:  https://doi.org/10.1016/j.mtbio.2024.101175
PLoS Biol. 2024 Aug;22(8): e3002753

Adenosine diphosphate released from stressed cells triggers mitochondrial transfer to achieve tissue homeostasis.

Hao Li, Hongping Yu, Delin Liu, Peng Liao, Chuan Gao, Jian Zhou, Jialun Mei, Yao Zong, Peng Ding, Meng Yao, Bingqi Wang, Yafei Lu, Yigang Huang, Youshui Gao, Changqing Zhang, Minghao Zheng, Junjie Gao.

Cell-to-cell mitochondrial transfer has recently been shown to play a role in maintaining physiological functions of cell. We previously illustrated that mitochondrial transfer within osteocyte dendritic network regulates bone tissue homeostasis. However, the mechanism of triggering this process has not been explored. Here, we showed that stressed osteocytes in mice release adenosine diphosphate (ADP), resulting in triggering mitochondrial transfer from healthy osteocytes to restore the oxygen consumption rate (OCR) and to alleviate reactive oxygen species accumulation. Furthermore, we identified that P2Y2 and P2Y6 transduced the ADP signal to regulate osteocyte mitochondrial transfer. We showed that mitochondrial metabolism is impaired in aged osteocytes, and there were more extracellular nucleotides release into the matrix in aged cortical bone due to compromised membrane integrity. Conditioned medium from aged osteocytes triggered mitochondrial transfer between osteocytes to enhance the energy metabolism. Together, using osteocyte as an example, this study showed new insights into how extracellular ADP triggers healthy cells to rescue energy metabolism crisis in stressed cells via mitochondrial transfer in tissue homeostasis.

DOI: https://doi.org/10.1371/journal.pbio.3002753
Life Sci. 2024 Aug 14. pii: S0024-3205(24)00577-0. [Epub ahead of print]355 122987

Emerging role and translational potential of small extracellular vesicles in neuroscience.

Iswarya Shanmugam, Sivani Radhakrishnan, Shradha Santosh, Akansha Ramnath, Meghna Anil, Yogesh Devarajan, Saravanakumar Maheswaran, Vaibav Narayanan, Arunkumar Pitchaimani.

  Small extracellular vesicles (sEV) are endogenous lipid-bound membrane vesicles secreted by both prokaryotic and eukaryotic cells into the extracellular environment, performs several biological functions such as cell-cell communication, transfer of proteins, mRNA, and ncRNA to target cells in distant sites. Due to their role in molecular pathogenesis and its potential to deliver biological cargo to target cells, it has become a prominent area of interest in recent research in the field of Neuroscience. However, their role in neurological disorders, like neurodegenerative diseases is more complex and still unaddressed. Thus, this review focuses on the role of sEV in neurodegenerative and neurodevelopmental diseases, including their biogenesis, classification, and pathogenesis, with translational advantages and limitations in the area of neurobiology.

Keywords:  Alzheimer's disease; Neurodegenerative diseases; Neuroscience; Parkinson's disease; Small extracellular vesicles

DOI:  https://doi.org/10.1016/j.lfs.2024.122987
iScience. 2024 Aug 16. 27(8): 110510

BCL2L13 at endoplasmic reticulum-mitochondria contact sites regulates calcium homeostasis to maintain skeletal muscle function.

Dogan Grepper, Cassandra Tabasso, Nadège Zanou, Axel K F Aguettaz, Mauricio Castro-Sepulveda, Dorian V Ziegler, Sylviane Lagarrigue, Yoan Arribat, Adrien Martinotti, Ammar Ebrahimi, Jean Daraspe, Lluis Fajas, Francesca Amati.

  The physical connection between mitochondria and endoplasmic reticulum (ER) is an essential signaling hub to ensure organelle and cellular functions. In skeletal muscle, ER-mitochondria calcium (Ca2+) signaling is crucial to maintain cellular homeostasis during physical activity. High expression of BCL2L13, a member of the BCL-2 family, was suggested as an adaptive response in endurance-trained human subjects. In adult zebrafish, we found that the loss of Bcl2l13 impairs skeletal muscle structure and function. Ca2+ signaling is altered in Bcl2l13 knockout animals and mitochondrial complexes activity is decreased. Organelle fractioning in mammalian cells shows BCL2L13 at mitochondria, ER, and mitochondria-associated membranes. ER-mitochondria contact sites number is not modified by BCL2L13 modulation, but knockdown of BCL2L13 in C2C12 cells changes cytosolic Ca2+ release and mitochondrial Ca2+ uptake. This suggests that BCL2L13 interaction with mitochondria and ER, and its role in Ca2+ signaling, contributes to proper skeletal muscle function.

Keywords:  cell biology; pharmacology

DOI:  https://doi.org/10.1016/j.isci.2024.110510
J Extracell Biol. 2024 Aug;3(8): e171

Extracellular vesicles may provide an alternative detoxification pathway during skeletal muscle myoblast ageing.

María Fernández-Rhodes, Emma Buchan, Stephanie D Gagnon, Jiani Qian, Lee Gethings, Rebecca Lees, Ben Peacock, Andrew J Capel, Neil R W Martin, Pola Goldberg Oppenheimer, Mark P Lewis, Owen G Davies.

  Skeletal muscle (SM) acts as a secretory organ, capable of releasing myokines and extracellular vesicles (SM-EVs) that impact myogenesis and homeostasis. While age-related changes have been previously reported in murine SM-EVs, no study has comprehensively profiled SM-EV in human models. To this end, we provide the first comprehensive comparison of SM-EVs from young and old human primary skeletal muscle cells (HPMCs) to map changes associated with SM ageing. HPMCs, isolated from young (24 ± 1.7 years old) and older (69 ± 2.6 years old) participants, were immunomagnetically sorted based on the presence of the myogenic marker CD56 (N-CAM) and cultured as pure (100% CD56+) or mixed populations (MP: 90% CD56+). SM-EVs were isolated using an optimised protocol combining ultrafiltration and size exclusion chromatography (UF + SEC) and their biological content was extensively characterised using Raman spectroscopy (RS) and liquid chromatography mass spectrometry (LC-MS). Minimal variations in basic EV parameters (particle number, size, protein markers) were observed between young and old populations. However, biochemical fingerprinting by RS highlighted increased protein (amide I), lipid (phospholipids and phosphatidylcholine) and hypoxanthine signatures for older SM-EVs. Through LC-MS, we identified 84 shared proteins with functions principally related to cell homeostasis, muscle maintenance and transcriptional regulation. Significantly, SM-EVs from older participants were comparatively enriched in proteins involved in oxidative stress and DNA/RNA mutagenesis, such as E3 ubiquitin-protein ligase TTC3 (TTC3), little elongation complex subunit 1 (ICE1) and Acetyl-CoA carboxylase 1 (ACACA). These data suggest SM-EVs could provide an alternative pathway for homeostasis and detoxification during SM ageing.

Keywords:  LC‐MS/MS; Raman spectroscopy; ageing; extracellular vesicles; human primary cells; skeletal muscle

DOI:  https://doi.org/10.1002/jex2.171
Med Sci Sports Exerc. 2024 Aug 20.

Muscle Mitochondrial Capacity Is Impaired Immediately Following Maximal Exercise.

Callie G Dickinson, Kristin M Mendez, Makayla D Holyfield, Nicholas T Batchelor, Kevin K McCully.

PURPOSE: This study measured the time course mVO2max following both maximal and submaximal exercise.METHODS: Healthy male and female participants were tested (n = 12 maximal and n = 8 submaximal exercise). A NIRS device was placed on the left medial gastrocnemius. Participants performed either one minute of maximal, rapid (~2 Hz), or submaximal (~0.37 Hz) plantar flexion exercise on a custom pneumatic ergometer. mVO2max was measured before and immediately after exercise. mVO2max measurements consisted of four incomplete recovery curves of muscle metabolism taken after 30 seconds of electrical muscle stimulation except in the first post-exercise trial. The four recovery curves were collected 50-, 156-, 260-, and 366-seconds post-exercise, each producing a mVO2max rate constant.
RESULTS: After maximal exercise muscle acceleration decreased to 52 + 18% (p = 0.001) of pre-values. mVO2max was reduced from the pre-exercise mean at the first post-trial (2.16 + 0.44 min-1 to 1.21 + 0.52 min -1, p < 0.001). The fourth trial showed recovery from the first (2.2 + 0.46 min-1 vs 1.21 + 0.52 min-1, p < 0.001) and was not significantly different from pre-exercise values (2.2 + 0.46 min-1 vs 2.16 + 0.44 min-1, p = 0.41). No change in acceleration or mVO2max was seen after submaximal exercise (p > 0.05).
CONCLUSIONS: The 56.7% reduction in mVO2max supports the hypothesis that in young, healthy individuals a minute of maximal exercise transiently impairs mVO2max which then recovers within six minutes. The NIRS method shows promise in tracking time course changes in mVO2max and warrants further investigation of the transient effects of exercise on mVO2max.

DOI: https://doi.org/10.1249/MSS.0000000000003533
J Physiol. 2024 Aug 21.

Muscle-derived IL-1β regulates EcSOD expression via the NBR1-p62-Nrf2 pathway in muscle during cancer cachexia.

Mami Yamada, Eiji Warabi, Hisashi Oishi, Vitor A Lira, Mitsuharu Okutsu.

  Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well-established oxidative stress-inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13-week-old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia-prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin-1β (IL-1β) expression and release from extensor digitorum longus muscle fibres. Moreover, IL-1β treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL-1β injection is sufficient to stimulate EcSOD expression, which is prevented by muscle-specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL-1β may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2-dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle-derived IL-1β-induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia-induced muscle atrophy. KEY POINTS: Oxidative stress plays an important role in muscle atrophy during cancer cachexia. EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13-week-old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia. Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle-derived IL-1β-dependent stimulation of the NBR1-p62-Nrf2 signalling pathway. These results provide further evidence for the potential therapeutic targeting of the NBR1-p62-Nrf2 signalling pathway downstream of IL-1β to mitigate cancer cachexia-induced muscle atrophy.

Keywords:  NBR1; Nrf2; SQSTM1/p62; extracellular superoxide dismutase; interleukin‐1β; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.1113/JP286460
Biochim Biophys Acta Mol Basis Dis. 2024 Aug 15. pii: S0925-4439(24)00463-0. [Epub ahead of print]1870(8): 167470

Accumulation of damaged mitochondria in aging astrocytes due to mitophagy dysfunction: Implications for susceptibility to mitochondrial stress.

Luan Pereira Diniz, Ana Paula Bergamo Araujo, Clara Fernandes Carvalho, Isadora Matias, Lívia de Sá Hayashide, Mariana Marques, Bruna Pessoa, Cherley Borba Vieira Andrade, Gabriele Vargas, Daniela Dias Queiroz, Jorge José de Carvalho, Antonio Galina, Flávia Carvalho Alcantara Gomes.

  Aging disrupts brain function, leading to cognitive decline and neurodegenerative diseases. Senescent astrocytes, a hallmark of aging, contribute to this process through unknown mechanisms. This study investigates how senescence impacts astrocytic mitochondrial dynamics, which are critical for brain health. Our research, conducted using aged mouse brains, represents the first evidence of morphologically damaged mitochondria in astrocytes, along with functional alterations in mitochondrial respiration. In vitro experiments revealed that senescent astrocytes exhibit an increase in mitochondrial fragmentation and impaired mitophagy. Concurrently, there was an upregulation of mitochondrial biogenesis, indicating a compensatory response to mitochondrial damage. Importantly, these senescent astrocytes were more susceptible to mitochondrial stress, a vulnerability reversed by rapamycin treatment. These findings suggest a potential link between senescence, impaired mitochondrial quality control, and increased susceptibility to mitochondrial stress in astrocytes. Overall, our study highlights the importance of addressing mitochondrial dysfunction and senescence-related changes in astrocytes as a promising approach for developing therapies to counter age-related neurodegeneration and improve brain health.

Keywords:  Aging; Astrocytes; Mitochondria and senescence

DOI:  https://doi.org/10.1016/j.bbadis.2024.167470
Front Pharmacol. 2024 ;15 1446521

YAP activation in Müller cells protects against NMDA-induced retinal ganglion cell injury by regulating Bcl-xL expression.

Toshihide Kashihara, Yui Morita, Misaki Hatta, Sae Inoue, Yume Suzuki, Akane Morita, Tsutomu Nakahara.

  Retinal neurodegeneration, characterized by retinal ganglion cell (RGC) death, is a leading cause of vision impairment and loss in blind diseases, such as glaucoma. Müller cells play crucial roles in maintaining retinal homeostasis. Thus, dysfunction of Müller cells has been implicated as one of the causes of retinal diseases. Yes-associated protein 1 (YAP), a nuclear effector of the Hippo pathway, regulates mammalian cell survival. In this study, we investigated the role of YAP in Müller cells during N-methyl-D-aspartic acid (NMDA)-induced excitotoxic RGC injury in rats. We found that YAP expression increased and was activated in Müller cells after NMDA-induced RGC injury. This YAP response was partly due to an increase in Yap mRNA levels, although it may be independent of the Hippo pathway and β-TrCP-mediated YAP degradation. Morphological analysis revealed that verteporfin, a selective YAP inhibitor, exacerbated NMDA-induced RGC degeneration, suggesting that YAP activation in Müller cells contributes to RGC survival in NMDA-treated retinas. Studies in the rat Müller cell line (rMC-1) demonstrated that overexpression of YAP increased the levels of Bcl-xL, while verteporfin decreased the levels of Bcl-xL and cell viability and increased the levels of cytochrome c released from mitochondria and cleaved caspase-3. Finally, we found that Bcl-xL expression increased slightly in NMDA-treated retinas, whereas intravitreal injection of verteporfin suppressed this increase. Our findings suggest that activated YAP in Müller cells protects against NMDA-induced RGC injury by upregulating Bcl-xL expression.

Keywords:  Bcl-XL; Müller cell; NMDA; YAP; mitochondrial dysfunction; retina; retinal ganglion cell

DOI:  https://doi.org/10.3389/fphar.2024.1446521
J Appl Physiol (1985). 2024 Aug 22.

Skeletal muscle adaptations following eccentric contractions are not mediated by keratin 18.

Muni Swamy Ganjayi, Samuel W Frank, Thomas A Krauss, Michael L York, Robert J Bloch, Cory W Baumann.

  The molecular mechanisms that drive muscle adaptations after eccentric exercise training are multifaceted and likely impacted by age. Previous studies have reported that many genes and proteins respond differently in young and older muscles following training. Keratin 18 (Krt18), a cytoskeletal protein involved in force transduction and organization, was found to be upregulated after muscles performed repeated bouts of eccentric contractions, with higher levels observed in young muscle compared to older muscle. Therefore, the purpose of this study was to determine if Krt18 mediates skeletal muscle adaptations following eccentric exercise training. The anterior crural muscles of Krt18 knockout (KO) and wild-type (WT) mice were subjected to either a single bout or repeated bouts of eccentric contractions, with isometric torque assessed across the initial and final bouts. Functionally, Krt18 KO and WT mice did not differ prior to performing any eccentric contractions (p≥0.100). Muscle strength (tetanic isometric torques) and the ability to adapt to eccentric exercise training were also consistent across strains at all time points (p≥0.169). Stated differently, immediate strength deficits and the recovery of strength following a single or multiple bouts of eccentric contractions were similar between Krt18 KO and WT mice. In summary, the absence of Krt18 does not impede the muscle's ability to adapt to repeated eccentric contractions, suggesting it is not essential for exercise-induced remodeling.

Keywords:  damage; exercise; injury; intermediate filaments; strength

DOI:  https://doi.org/10.1152/japplphysiol.00496.2024
Gene. 2024 Aug 17. pii: S0378-1119(24)00754-6. [Epub ahead of print]931 148873

Sarcopenia is attenuated by mairin in SAMP8 mice via the inhibition of FAPs fibrosis through the AMPK-TGF-β-SMAD axis.

Wen Zhong, Huanan Jia, Haiyan Zhu, Yuan Tian, Wei Huang, Qiyue Yang.

  Sarcopenia has become a prominent health problem among the elderly because of its adverse consequence, including physical disabilities and death. Fibro-adipogenic progenitors (FAPs) exhibit adipogenic and fibrogenic potencies and regulate skeletal muscle development, which plays important role in sarcopenia. Mairin, as an ingredient of Astragalus membranaceus, has the effect of anti-fibrosis. Therefore, we predicted that mairin targeted the fibrosis of FAPs and then affected sarcopenia. To verify our ideas, mairin (30 mg/kg/day or 60 mg/kg/day) was given to senescence accelerated mouse-prone 8 (SAMP8) mice by oral administration. Aging led to loss of weight, skeletal muscle mass, strength, and function, and an increase in muscle atrophy and fibrosis, while mairin administration inhibited physiological decline caused by aging. Similarly, mairin (20 μM or 40 μM) treatment enhanced FAP proliferation but blocked the differentiation into fibroblasts. Mechanically, mairin played an anti-fibrotic role via AMP-activated protein kinase-transforming growth factor beta-drosophila mothers against decapentaplegic protein (AMPK-TGF-β-SMAD) axis, as evidenced by increased phosphorylation of AMPKα and decreased TGF-β and phosphorylated-SMAD2/3. In addition, the potential target genes of mairin were explored by mRNA sequencing in our study. In conclusion, mairin may interfere with the AMPK/TGF-β/SMAD pathway to repress the fibrosis of FAPs and eventually ameliorate sarcopenia.

Keywords:  AMPK-TGF-β-SMAD; FAPs; Fibrosis; Mairin; Sarcopenia

DOI:  https://doi.org/10.1016/j.gene.2024.148873