bims-mitrat 2024-12-15 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–12–15
eleven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondrial transplantation rescues Ca2+ homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy.
Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.
Myonuclear and satellite cell content of the vastus lateralis and soleus with70 days of simulated microgravity and the NASA SPRINT exercise program.
Rubicon regulates exosome secretion via the non-autophagic pathway.
Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective.
Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.
Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.
Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischemic injury involves direct activation of mitochondrial sirtuin 3.
Mitochondrial Fitness Science Communication for Aging Adults: Prospective Formative Pilot Study.
Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.
Mitochondrial Dysfunction and Calcium Homeostasis in Heart Failure: Exploring the Interplay Between Oxidative Stress and Cardiac Remodeling for Future Therapeutic Innovations.

Cell Rep. 2024 Dec 12. pii: S2211-1247(24)01416-5. [Epub ahead of print]43(12): 115065

Mitochondrial transplantation rescues Ca2+ homeostasis imbalance and myocardial hypertrophy in SLC25A3-related hypertrophic cardiomyopathy.

Shuang Li, Jianchao Zhang, Wanrong Fu, Jinhua Cao, Zhonggen Li, Xiaoxu Tian, Meng Yang, Jing Zhao, Chuchu Wang, Yangyang Liu, Mengduan Liu, Xiaoyan Zhao, Xiaowei Li, Jianzeng Dong, Yuanming Qi.

  SLC25A3 encodes mitochondrial phosphate carrier (PiC), which is involved in inorganic phosphate transport. Clinical reports have found that most patients with homozygous or complex heterozygous mutations in SLC25A3 exhibit lactic acidosis, cardiac hypertrophy, and premature death. However, the potential molecular mechanisms underlying these associations remain unclear. Using CRISPR-Cas9 technology, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying SLC25A3-knockout (KO) or missense mutations (c.C544T, c.A547G, c.C349T) to elucidate the pathogenic mechanisms of SLC25A3-related hypertrophic cardiomyopathy (HCM) and evaluate potential therapeutic interventions. These SLC25A3-KO or missense mutation hiPSC-CMs recapitulated the disease phenotype associated with myocardial hypertrophy, including diastolic dysfunction, Ca2+ homeostasis imbalance, and mitochondrial energy metabolism dysfunction. Further studies suggested the potential link between the accumulation of glycolytic byproducts and Ca2+ homeostasis imbalance in SLC25A3-KO hiPSC-CMs. Finally, we explored the prospective therapeutic implications of mitochondrial transplantation in rescuing SLC25A3-related HCM.

Keywords:  CP: Metabolism; Ca(2+) homeostasis imbalance; SLC25A3; glycolysis; mitochondrial transplantation; myocardial hypertrophy

DOI:  https://doi.org/10.1016/j.celrep.2024.115065
J Cereb Blood Flow Metab. 2024 Dec 12. 271678X241306054

Astrocytic mitochondrial transfer to brain endothelial cells and pericytes in vivo increases with aging.

Gopal V Velmurugan, Hemendra J Vekaria, Samir P Patel, Patrick G Sullivan, W Brad Hubbard.

  Intercellular mitochondrial transfer (IMT) is an intriguing biological phenomenon where mitochondria are transferred between different cells and notably, cell types. IMT is physiological, occurring in normal conditions, but also is utilized to deliver healthy mitochondria to cells in distress. Transferred mitochondria can be integrated to improve cellular metabolism, and mitochondrial function. Research on the mitochondrial transfer axis between astrocytes and brain capillaries in vivo is limited by the cellular heterogeneity of the neurovascular unit. To this end, we developed an inducible mouse model that expresses mitochondrial Dendra2 only in astrocytes and then isolated brain capillaries to remove all intact astrocytes. This method allows the visualization of in vivo astrocyte- endothelial cell (EC) and astrocyte-pericyte IMT. We demonstrate evidence of astrocyte-EC and astrocyte-pericyte mitochondrial transfer within brain capillaries. We also show that healthy aging enhances mitochondrial transfer from astrocytes to brain capillaries, revealing a potential link between brain aging and cellular mitochondrial dynamics. Finally, we observe that astrocyte-derived extracellular vesicles transfer mitochondria to brain microvascular endothelial cells, showing the potential route of in vivo IMT. These results represent a breakthrough in our understanding of IMT in the brain and a new target in brain aging and neurovascular metabolism.

Keywords:  Mitochondrial transfer; aging; astrocyte EV-mito; brain capillaries; capillary isolation

DOI:  https://doi.org/10.1177/0271678X241306054
J Appl Physiol (1985). 2024 Dec 10.

Myonuclear and satellite cell content of the vastus lateralis and soleus with70 days of simulated microgravity and the NASA SPRINT exercise program.

Chad M Skiles, Gerard Boyd, Aaron Gouw, Ethan Robbins, Kiril Minchev, Jeffrey Ryder, Lori Ploutz-Snyder, Todd A Trappe, Scott Trappe.

  We previously observed a range of whole muscle and individual slow and fast myofiber size responses (mean: +4 to -24%) in quadriceps (vastus lateralis) and triceps surae (soleus) muscles of individuals undergoing 70 days of simulated microgravity with or without the NASA SPRINT exercise countermeasures program. The purpose of the current investigation was to further explore, in these same individuals, the content of myonuclei and satellite cells, both of which are key regulators of skeletal muscle mass. Individuals completed 6° head-down-tilt bedrest (BR, n=9), bedrest with resistance and aerobic exercise (BRE, n=9), or bedrest with resistance and aerobic exercise and low-dose testosterone (BRE+T, n=8). The number of myonuclei and satellite cells associated with each slow (myosin heavy chain (MHC) I) and fast (MHC IIa) myofiber in the vastus lateralis was not changed (P>0.05) pre- to post-bedrest within the BR, BRE, or BRE+T groups. Similarly, in the soleus the number of myonuclei associated with each slow and fast myofiber, and the number of satellite cells associated with each slow myofiber were not changed (P>0.05) pre- to post-bedrest within the BR, BRE, or BRE+T groups. It appears that even with relatively large perturbations in muscle mass over a few months of simulated microgravity, or with partially or completely effective exercise countermeasures, human skeletal muscle tightly regulates the abundance of myonuclei and satellite cells. Thus, exercise countermeasures efficacy for skeletal muscle atrophy appears to be independent of myonuclei and satellite cell abundance.

Keywords:  bedrest; exercise; microgravity; myonuclei; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00468.2024
Autophagy. 2024 Dec 12. 1-3

Rubicon regulates exosome secretion via the non-autophagic pathway.

Kyosuke Yanagawa, Tamotsu Yoshimori.

  Exosomes are small extracellular vesicles (EVs), which have the diameter of 50-150 nm and originate from intralumenal vesicles in multivesicular endosomes (MVBs). Exosomes secreted from donor cells are delivered to recipient cells for transferring of exosome cargos, such as proteins, lipids and nucleic acids. The cargo transfer by exosomes has a pivotal role in cell-to-cell communication for many cellular processes; however, the detailed mechanism remains largely elusive. In our recent study, we found that RUBCN/rubicon regulates exosome secretion through endosomal recruitment of WIPI2, which promotes ESCRT-dependent MVB formation. We further showed that this pathway is essential for age-dependent increasing of exosomes, which transfer the pro-senescent microRNAs, including Mir26a and Mir486a, and accelerate cellular senescence in the recipient cells. Our findings highlight RUBCN's key role in exosome secretion and its impact on cellular senescence, providing insights into its potential contributions to aging.

Keywords:  Aging; autophagy; exosome; extracellular vesicle; microRNA; senescence

DOI:  https://doi.org/10.1080/15548627.2024.2437653
Biochim Biophys Acta Mol Basis Dis. 2024 Dec 07. pii: S0925-4439(24)00611-2. [Epub ahead of print]1871(3): 167617

Mitochondria-targeting by small molecules against Alzheimer's disease: A mechanistic perspective.

Chinmay Pal.

  Alzheimer's disease (AD) poses a considerable worldwide health obstacle, marked by gradual cognitive deterioration and neuronal loss. While the molecular mechanisms underlying AD pathology have been elucidated to some extent, therapeutic options remain limited. Mitochondrial dysfunction has become recognized as a significant factor in the development of AD, with oxidative stress and disrupted energy metabolism being critical elements. This review explores the mechanistic aspects of small molecule targeting of mitochondria as a potential therapeutic approach for AD. The review explores the role of mitochondrial dysfunction in AD, including its involvement in the accumulation of β-amyloid plaques and neurofibrillary tangles, synaptic dysfunction, and neuronal death. Furthermore, the effects of oxidative stress on mitochondrial function were investigated, including the resulting damage to mitochondrial components. Mitochondrial-targeted therapies have attracted attention for their potential to restore mitochondrial function and reduce AD pathology. The review outlines the latest preclinical and clinical evidence supporting the effectiveness of small molecules in targeting mitochondrial dysfunction in AD. Additionally, it discusses the molecular pathways involved in mitochondrial dysfunction and examines how small molecules can intervene to address these abnormalities. By providing a comprehensive overview of the latest research in this field, this review aims to shed light on the therapeutic potential of small molecule targeting of mitochondria in AD and stimulate further research in this promising area of drug development.

Keywords:  Alzheimer's disease; Mitochondrial dysfunction; Oxidative stress; Reactive oxygen species; Small molecule

DOI:  https://doi.org/10.1016/j.bbadis.2024.167617
Am J Physiol Cell Physiol. 2024 Dec 13.

Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.

Sabrina Champsi, David A Hood.

  Mitochondria are metabolic hubs that govern skeletal muscle health. While exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined Sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial ROS emission. Signaling towards biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggests that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.

Keywords:  Nrf-2; PGC-1α; exercise; mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00669.2024
Mitochondrion. 2024 Dec 09. pii: S1567-7249(24)00158-2. [Epub ahead of print] 102000

Mitochondria-targeted nanotherapeutics: A new Frontier in neurodegenerative disease treatment.

Nishad Keethedeth, Rajesh Anantha Shenoi.

  Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.

Keywords:  Blood brain barrier; Mitochondria targeting; Nanotherapeutics; Neurodegenerative diseases; Triphenyl Phosphonium

DOI:  https://doi.org/10.1016/j.mito.2024.102000
Cardiovasc Res. 2024 Dec 10. pii: cvae252. [Epub ahead of print]

Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischemic injury involves direct activation of mitochondrial sirtuin 3.

Ahmed M Darwesh, Liye Fang, Tariq R Altamimi, K Lockhart Jamieson, Wesam Bassiouni, Robert Valencia, Andy Huang, Faqi Wang, Hao Zhang, Marawan Ahmed, Keshav Gopal, Yongneng Zhang, Evangelos D Michelakis, John R Ussher, Matthew L Edin, Darryl C Zeldin, Khaled Barakat, Gavin Y Oudit, Zamaneh Kassiri, Gary D Lopaschuk, John M Seubert.

AIMS: Although current clinical therapies following myocardial infarction have improved patient outcomes, morbidity, and mortality rates secondary to ischemic and ischemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism. In the current study, we hypothesize that 19,20-epoxydocosapentaenoic acid (19,20-EDP) attenuates cardiac IR injury via stimulating mitochondrial SIRT3.
METHODS AND RESULTS: Ex vivo models of isolated heart perfusions were performed in C57BL/6 mice to assess the effect of 19,20-EDP on cardiac function and energy metabolism following IR injury. In vivo permanent occlusion of the left anterior descending coronary artery (LAD) was performed to induce myocardial infarction (MI), mice were administered 19,20-EDP with or without the SIRT3 selective inhibitor 3-TYP. Mitochondrial SIRT3 targets and respiration were assessed in human left ventricular (LV) tissues obtained from individuals with ischemic heart disease (IHD) and compared to non-failing controls (NFC). Binding affinity of 19,20-EDP to human SIRT3 was assessed using molecular modeling and fluorescence thermal shift assay. Results demonstrated hearts treated with 19,20-EDP had improved post-ischemic cardiac function, better glucose oxidation rates and enhanced cardiac efficiency. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity. Interestingly, treatment with 19,20-EDP markedly improved mitochondrial respiration and SIRT3 activity in human left ventricle (LV) fibers with IHD compared to NFC. Moreover, 19,20-EDP was found to bind to the human SIRT3 protein enhancing the NAD+ -complex stabilization leading to improved SIRT3 activity. Importantly, the beneficial effects of 19,20-EDP were abolished by SIRT3 inhibition or using the S149A mutant SIRT3.
CONCLUSION: These data demonstrate that 19,20-EDP-mediated cardioprotective mechanisms against ischemia and IR injury involve mitochondrial SIRT3, resulting in improved cardiac efficiency.

DOI: https://doi.org/10.1093/cvr/cvae252
JMIR Form Res. 2024 Dec 13. 8 e64437

Mitochondrial Fitness Science Communication for Aging Adults: Prospective Formative Pilot Study.

Cathy A Maxwell, Brandon Grubbs, Mary S Dietrich, Jeffrey T Boon, John Dunavan, Kelly J Knickerbocker, Maulik R Patel.

   BACKGROUND: A key driver that leads to age-associated decline and chronic disease is mitochondrial dysfunction. Our previous work revealed strong community interest in the concept of mitochondrial fitness, which led to the development of a video-based science communication intervention to prompt behavior change in adults aged 50 years and older.
OBJECTIVE: This study aimed to conduct formative and summative evaluations of MitoFit, an instructional, biologically based communication intervention aimed at improving physical activity in older adults aged 50 years and older.
METHODS: In the phase-1 formative evaluation, community-dwelling older adults (N=101) rated the acceptability, appropriateness, and helpfulness of our MitoFit video series, titled "How to Slow Down Aging Through Mitochondrial Fitness." In the phase-2 summative evaluation, a subgroup of phase-1 participants (n=19) participated in a 1-month MitoFit intervention prototype to evaluate the intervention and data collection feasibility.
RESULTS: In phase 1, participants (mean age 67.8, SD 8.9 y; 75/100, 75% female) rated the MitoFit videos as acceptable (≥4 out of 5 on a Likert-scale survey; from 97/101, 96% to 100/101, 99%), appropriate (101/101, 100%), and helpful (from 95/101, 94% to 100/101, 99%) to support adaptation and continued work on our novel approach. Previous knowledge of mitochondria ranged from 52% (50/97; What are mitochondria?) to 80% (78/97; What are the primary functions of mitochondria?). In phase 2, participants (mean age 71.4, SD 7.9 y; 13/19, 72% female) scored better than the national average (50) on the Patient-Reported Outcomes Measurement Information System-19 for physical function (57), social activities (55.5), depression (41), fatigue (48.6), and sleep disturbance (49.6) but worse for anxiety (55.3) and pain interference (52.4). Additionally, 95% (18/19) of participants demonstrated MitoFit competencies within 2 attempts (obtaining pulse: 19/19, 100%; calculating maximum and zone 2 heart rate: 18/19, 95%; and demonstration of exercises: 19/19, 100%). At 1 month after instruction, 68% (13/19) had completed a self-initiated daily walking/exercise plan and submitted a daily activity log. A walking pulse was documented by 85% (11/13) of participants. The time needed to walk 1 mile ranged from 17.4 to 27.1 minutes. The number of miles walked in 1 month was documented by 62% (8/13) of participants and ranged from 10 miles to 31 miles. The number of days of strength training ranged from 2 to 31 days/month. Intervention feasibility scores ranged from 89% (17/19; seems easy to follow) to 95% (18/19; seems implementable, possible, and doable). Overall, 79% (15/19) stated an intention to continue the MitoFit intervention. Furthermore, 4 weeks after delivery of the prototype intervention, the percentage of participants doing aerobic activity for regular moderate activity increased from 35% (6/17) to 59% (10/17; P=.03).
CONCLUSIONS: MitoFit was enthusiastically embraced and is a cost-effective, scalable, and potentially efficacious intervention to advance with community-dwelling older adults.

Keywords:  behavior change; community dwelling; digital health; evaluation; exercise; feasibility study; fitness; gerontology; health intervention; mitochondria; older adults; physical activity; science communication; usability

DOI:  https://doi.org/10.2196/64437
Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101372

Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo.

David V Begelman, Bhavna Dixit, Carly Truong, Christina D King, Mark A Watson, Birgit Schilling, Martin D Brand, Amutha Boominathan.

  Replicative errors, inefficient repair, and proximity to sites of reactive oxygen species production make mitochondrial DNA (mtDNA) susceptible to damage with time. We explore in vivo allotopic expression (re-engineering mitochondrial genes and expressing them from the nucleus) as an approach to rescue defects arising from mtDNA mutations. We used a mouse strain C57BL/6J(mtFVB) with a natural polymorphism (m.7778 G>T) in the mitochondrial ATP8 gene that encodes a protein subunit of the ATP synthase. We generated a transgenic mouse with an epitope-tagged recoded mitochondrial-targeted ATP8 gene expressed from the ROSA26 locus in the nucleus and used the C57BL/6J(mtFVB) strain to verify successful incorporation. The allotopically expressed ATP8 protein in transgenic mice was constitutively expressed across all tested tissues, successfully transported into the mitochondria, and incorporated into ATP synthase. The ATP synthase with transgene had similar activity to non-transgenic control, suggesting successful integration and function. Exogenous ATP8 protein had no negative impact on measured mitochondrial function, metabolism, or behavior. Successful allotopic expression of a mitochondrially encoded protein in vivo in a mammal is a step toward utilizing allotopic expression as a gene therapy in humans to repair physiological consequences of mtDNA defects that may accumulate in congenital mitochondrial diseases or with age.

Keywords:  ATP8 gene; allotopic expression; in vivo gene therapy; mitochondrial DNA mutation; mtDNA; safe harbor expression; transgenic mouse

DOI:  https://doi.org/10.1016/j.omtm.2024.101372
Curr Probl Cardiol. 2024 Dec 07. pii: S0146-2806(24)00603-0. [Epub ahead of print] 102968

Mitochondrial Dysfunction and Calcium Homeostasis in Heart Failure: Exploring the Interplay Between Oxidative Stress and Cardiac Remodeling for Future Therapeutic Innovations.

Emily Johnson, Liam Nguyen, Jameela Shukri Albakri, Oliver Smith.

  Heart failure (HF) is a multifaceted clinical syndrome characterized by the heart's inability to pump sufficient blood to meet the body's metabolic demands. It arises from various etiologies, including myocardial injury, hypertension, and valvular heart disease. A critical aspect of HF pathophysiology involves mitochondrial dysfunction, particularly concerning calcium (Ca2+) homeostasis and oxidative stress. This review highlights the pivotal role of excess mitochondrial Ca2+ in exacerbating oxidative stress, contributing significantly to HF progression. Novel insights are provided regarding the mechanisms by which mitochondrial Ca2+ overload leads to increased production of reactive oxygen species (ROS) and impaired cellular function. Despite this understanding, key gaps in research remain, particularly in elucidating the complex interplay between mitochondrial dynamics and oxidative stress across different HF phenotypes. Furthermore, therapeutic strategies targeting mitochondrial dysfunction are still in their infancy, with limited applications in clinical practice. By summarizing recent findings and identifying these critical research gaps, this review aims to pave the way for innovative therapeutic approaches that improve the management of heart failure, ultimately enhancing patient outcomes through targeted interventions.

Keywords:  Calcium Homeostasis; Cardiac Remodeling; Cardiomyocyte Function; Heart Failure; Mitochondrial Ca2+; Mitochondrial Dysfunction; Oxidative Stress

DOI:  https://doi.org/10.1016/j.cpcardiol.2024.102968