bims-mitrat 2024-08-11 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒08‒11
ten papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondrial Transfer Between Mesenchymal Stem Cells and Cancer Cells.
Artificial mitochondrial transplantation (AMT) reverses aging of mesenchymal stromal cells and improves their immunomodulatory properties in LPS-induced synoviocytes inflammation.
Mitochondrial Transplantation Alleviates Doxorubicin-Induced Toxicity in Rat Renal Cells.
Activation of Mitochondria in Mesenchymal Stem Cells by Mitochondrial Delivery of Coenzyme Q10.
ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.
Mitigating disuse-induced skeletal muscle atrophy in ageing: Resistance exercise as a critical countermeasure.
Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart.
The interplay of mitochondrial dysfunction in oral diseases: Recent updates in pathogenesis and therapeutic implications.
Disease-associated mutations in C-terminus of HSP70 interacting protein (CHIP) impair its ability to negatively regulate mitophagy.
Telomerase and mitochondria inhibition promote apoptosis and TET2 and ANMT3a expression in triple negative breast cancer cell lines.

Methods Mol Biol. 2024 ;2835 39-48

Mitochondrial Transfer Between Mesenchymal Stem Cells and Cancer Cells.

S Kumar Panda, M Torsiello, A Rehman, Vincenzo Desiderio, V Del Vecchio.

  Mitochondrial transfer (MT) is a biological process that allows a donor cell to horizontally share its own mitochondria with a recipient cell. Mitochondria are highly dynamic membrane-bound sub-cellular organelles prominently involved in the regulation of the cell energy balance, calcium homeostasis, and apoptotic machinery activation. They physiologically undergo fusion and fission processes in response to the cell requirement, with a continuous morphological re-arrangement. This structural and functional plasticity is at the basis of the MT, described in tissue regeneration, cardiac and neurological diseases, as well as in cancer. Here, the MT has been observed in the tumor micro-environment (TME) from the adipose-derived stem cells (ASCs) to the cancer cells, eventually reverting the lack of the mitochondria respiration function, or enhancing their motility and drug resistance. In this chapter, we outline some key protocols for evaluating this exciting phenomenon of MT. These methodological and technical approaches are very important, considering all the limitations that scientists constantly face, especially in this field of the research.

Keywords:  Mitochondrial transfer; Stromal cells; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/978-1-0716-3995-5_4
Biochim Biophys Acta Mol Cell Res. 2024 Aug 03. pii: S0167-4889(24)00149-6. [Epub ahead of print]1871(7): 119806

Artificial mitochondrial transplantation (AMT) reverses aging of mesenchymal stromal cells and improves their immunomodulatory properties in LPS-induced synoviocytes inflammation.

Lynda Bourebaba, Nabila Bourebaba, Larry Galuppo, Krzysztof Marycz.

  Nowadays, regenerative medicine techniques are usually based on the application of mesenchymal stromal cells (MSCs) for the repair or restoration of injured damaged tissues. However, the effectiveness of autologous therapy is limited as therapeutic potential of MSCs declines due to patient's age, health condition and prolonged in vitro cultivation as a result of decreased growth rate. For that reason, there is an urgent need to develop strategies enabling the in vitro rejuvenation of MSCs prior transplantation in order to enhance their in vivo therapeutic efficiency. In presented study, we attempted to mimic the naturally occurring mitochondrial transfer (MT) between neighbouring cells and verify whether artificial MT (AMT) could reverse MSCs aging and improve their biological properties. For that reason, mitochondria were isolated from healthy donor equine adipose-derived stromal cells (ASCs) and transferred into metabolically impaired recipient ASCs derived from equine metabolic syndrome (EMS) affected horses, which were subsequently subjected to various analytical methods in order to verify the cellular and molecular outcomes of the applied AMT. Mitochondria recipient cells were characterized by decreased apoptosis, senescence and endoplasmic reticulum stress while insulin sensitivity was enhanced. Furthermore, we observed increased mitochondrial fragmentation and associated PARKIN protein accumulation, which indicates on the elimination of dysfunctional organelles via mitophagy. AMT further promoted physioxia and regulated autophagy fluxes. Additionally, rejuvenated ASCs displayed an improved anti-inflammatory activity toward LPS-stimulated synoviocytes. The presented findings highlight AMT as a promising alternative and effective method for MSCs rejuvenation, for potential application in autologous therapies in which MSCs properties are being strongly deteriorated due to patients' condition.

Keywords:  AMT; ASCs; Aging; EMS; Immunomodulation; Senescence

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119806
Iran J Pharm Res. 2024 Jan-Dec;23(1):23(1): e146033

Mitochondrial Transplantation Alleviates Doxorubicin-Induced Toxicity in Rat Renal Cells.

Enayatollah Seydi, Mahsa Andalib, Sana Yaghoubi, Amir Fakhri, Jale Yuzugulen, Abdollah Arjmand, Jalal Pourahmad.

  Background: Doxorubicin (DOX) is used in the treatment of various cancers and has good effectiveness. However, its therapeutic use is limited due to its effects on various organs and healthy cells. Doxorubicin can affect the kidneys and cause toxicity. Evidence shows that DOX induces nephrotoxicity through oxidative stress.Objectives: In this research, we examined the effect of mitochondrial transplantation on improving mitochondrial and cellular toxicity caused by DOX on renal proximal tubular cells (RPTCs).
Methods: The research measured 7 toxicity parameters, including cell lysis, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) decline, GSH and GSSG content, lipid peroxidation (LPO), adenosine triphosphate (ATP) content, and Caspase-3 activity (the final mediator of apoptosis). Active fresh mitochondria were prepared from Wistar rat kidney.
Results: The findings indicated that DOX caused cytotoxicity in RPTCs. Additionally, DOX induced oxidative stress by increasing the level of reactive oxygen species, reducing glutathione content, and elevating lipid peroxidation. Moreover, it led to damage to the mitochondrial membrane, increased caspase-3 activity, and decreased ATP content. Mitochondrial transplantation, as a new therapeutic approach, reduced oxidative stress, mitochondrial membrane damage, and apoptosis caused by DOX in RPTCs. Furthermore, this therapeutic approach increased the ATP content in RPTCs.
Conclusions: Our study suggests that this therapeutic approach could be helpful in the treatment of drug-induced nephrotoxicity.

Keywords:  Doxorubicin; Mitochondria Transplantation; Nephrotoxicity; Oxidative Stress; Renal Proximal Tubular Cells

DOI:  https://doi.org/10.5812/ijpr-146033
Biol Pharm Bull. 2024 ;47(8): 1415-1421

Activation of Mitochondria in Mesenchymal Stem Cells by Mitochondrial Delivery of Coenzyme Q10.

Yuji Maruo, Masahiro Shiraishi, Mitsue Hibino, Jiro Abe, Atsuhito Takeda, Yuma Yamada.

  The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using a microfluidic device to encapsulate Coenzyme Q10 (CoQ10) on a large scale. The current study aimed to confirm if treatment with CoQ10 encapsulated by MITO-Porter enhanced mitochondrial functions in MSCs, with the potential to improve MSC transplantation therapy. We used highly purified human bone marrow-derived MSCs, described as rapidly expanding clones (RECs), and attempted to control and increase the amount of CoQ10 encapsulated in the MITO-Porter using microfluidic device system. We treated these RECs with CoQ10 encapsulated MITO-Porter, and evaluated its cellular uptake, co-localization with mitochondria, changes in mitochondrial respiratory capacity, and cellular toxicity. There was no significant change in mitochondrial respiratory capacity following treatment with the previous CoQ10 encapsulated MITO-Porter; however, mitochondrial respiratory capacity in RECs was significantly increased by treatment with CoQ10-rich MITO-Porter. Utilization of a microfluidic device enabled the amount of CoQ10 encapsulated in MITO-Porter to be controlled, and treatment with CoQ10-rich MITO-Porter successfully activated mitochondrial functions in MSCs. The MITO-Porter system thus provides a promising tool to improve MSC cell transplantation therapy.

Keywords:  Coenzyme Q10; drug delivery system; lipid nanoparticle; mesenchymal stem cell; microfluidics; mitochondrial delivery

DOI:  https://doi.org/10.1248/bpb.b24-00284
Free Radic Biol Med. 2024 Aug 04. pii: S0891-5849(24)00586-0. [Epub ahead of print]223 172-183

ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.

Ying Shen, Yimei Hong, Xinran Huang, Jiaqi Chen, Ziqi Li, Jie Qiu, Xiaoting Liang, Cong Mai, Weifeng Li, Xin Li, Yuelin Zhang.

  Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated β-galactosidase (SA-β-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.

Keywords:  Aldehyde dehydrogenase 2; Interferon regulatory factor 7; Mesenchymal stem cells; Mitochondria; Senescence

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.07.040
Exp Physiol. 2024 Aug 06.

Mitigating disuse-induced skeletal muscle atrophy in ageing: Resistance exercise as a critical countermeasure.

James McKendry, Giulia Coletta, Everson A Nunes, Changhyun Lim, Stuart M Phillips.

  The gradual deterioration of physiological systems with ageing makes it difficult to maintain skeletal muscle mass (sarcopenia), at least partly due to the presence of 'anabolic resistance', resulting in muscle loss. Sarcopenia can be transiently but markedly accelerated through periods of muscle disuse-induced (i.e., unloading) atrophy due to reduced physical activity, sickness, immobilisation or hospitalisation. Periods of disuse are detrimental to older adults' overall quality of life and substantially increase their risk of falls, physical and social dependence, and early mortality. Disuse events induce skeletal muscle atrophy through various mechanisms, including anabolic resistance, inflammation, disturbed proteostasis and mitochondrial dysfunction, all of which tip the scales in favour of a negative net protein balance and subsequent muscle loss. Concerningly, recovery from disuse atrophy is more difficult for older adults than their younger counterparts. Resistance training (RT) is a potent anabolic stimulus that can robustly stimulate muscle protein synthesis and mitigate muscle losses in older adults when implemented before, during and following unloading. RT may take the form of traditional weightlifting-focused RT, bodyweight training and lower- and higher-load RT. When combined with sufficient dietary protein, RT can accelerate older adults' recovery from a disuse event, mitigate frailty and improve mobility; however, few older adults regularly participate in RT. A feasible and practical approach to improving the accessibility and acceptability of RT is through the use of resistance bands. Moving forward, RT must be prescribed to older adults to mitigate the negative consequences of disuse atrophy.

Keywords:  anabolism; catabolism; muscle unloading; physical activity; sarcopenia

DOI:  https://doi.org/10.1113/EP091937
J Cardiovasc Aging. 2024 Apr;pii: 18. [Epub ahead of print]4(2):

Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart.

Peiyong Zhai, Junichi Sadoshima.

  Cellular senescence in cardiomyocytes, characterized by cell cycle arrest, resistance to apoptosis, and the senescence-associated secretory phenotype, occurs during aging and in response to various stresses, such as hypoxia/reoxygenation, ischemia/reperfusion, myocardial infarction (MI), pressure overload, doxorubicin treatment, angiotensin II, diabetes, and thoracic irradiation. Senescence in the heart has both beneficial and detrimental effects. Premature senescence of myofibroblasts has salutary effects during MI and pressure overload. On the other hand, persistent activation of senescence in cardiomyocytes precipitates cardiac dysfunction and adverse remodeling through paracrine mechanisms during MI, myocardial ischemia/reperfusion, aging, and doxorubicin-induced cardiomyopathy. Given the adverse roles of senescence in many conditions, specific removal of senescent cells, i.e., senolysis, is of great interest. Senolysis can be achieved using senolytic drugs (such as Navitoclax, Dasatinib, and Quercetin), pharmacogenetic approaches (including INK-ATTAC and AP20187, p16-3MR and Ganciclovir, p16 ablation, and p16-LOX-ATTAC and Cre), and immunogenetic interventions (CAR T cells or senolytic vaccination). In order to enhance the specificity and decrease the off-target effects of senolytic approaches, investigation into the mechanisms through which cardiomyocytes develop and/or maintain the senescent state is needed.

Keywords:  Aging; senescence; senescence-associated secretory phenotype; senolysis

DOI:  https://doi.org/10.20517/jca.2024.06
Mitochondrion. 2024 Aug 05. pii: S1567-7249(24)00100-4. [Epub ahead of print] 101942

The interplay of mitochondrial dysfunction in oral diseases: Recent updates in pathogenesis and therapeutic implications.

Al-Hassan Soliman Wadan, Mohamed Abdelsattar Ahmed, Abdelnaser Hussein Ahmed, Doha El-Sayed Ellakwa, Nourhan Hamed Elmoghazy, Abeer Gawish.

  Mitochondrial dysfunction is linked to various systemic and localized diseases, including oral diseases like periodontitis, oral cancer, and temporomandibular joint disorders. This paper explores the intricate mechanisms underlying mitochondrial dysfunction in oral pathologies, encompassing oxidative stress, inflammation, and impaired energy metabolism. Furthermore, it elucidates the bidirectional relationship between mitochondrial dysfunction and oral diseases, wherein the compromised mitochondrial function exacerbates disease progression, while oral pathologies, in turn, exacerbate mitochondrial dysfunction. Understanding these intricate interactions offers insights into novel therapeutic strategies targeting mitochondrial function for managing oral diseases. This paper pertains to the mechanisms underlying mitochondrial dysfunction, its implications in various oral pathological and inflammatory conditions, and emerging versatile treatment approaches. It reviews current therapeutic strategies to mitigate mitochondrial dysfunction, including antioxidants, mitochondrial-targeted agents, and metabolic modulators.

Keywords:  Cancer; Mitochondrial dysfunction; Periodontitis; Pulpitis; Sjogren’s syndrome

DOI:  https://doi.org/10.1016/j.mito.2024.101942
Neurobiol Dis. 2024 Aug 06. pii: S0969-9961(24)00225-0. [Epub ahead of print] 106625

Disease-associated mutations in C-terminus of HSP70 interacting protein (CHIP) impair its ability to negatively regulate mitophagy.

Rebecca Earnshaw, Yu Tong Zhang, Gregory Heymann, Kazuko Fujisawa, Sarah Hui, Minesh Kapadia, Lorraine V Kalia, Suneil K Kalia.

  C-terminus of HSP70 interacting protein (CHIP) is an E3 ubiquitin ligase and HSP70 cochaperone. Mutations in the CHIP encoding gene are the cause of two forms of neurodegenerative conditions: spinocerebellar ataxia autosomal dominant type 48 (SCA48) and autosomal recessive type 16 (SCAR16). The mechanisms underlying CHIP-associated diseases are currently unknown. Mitochondrial dysfunction, specifically dysfunction in mitochondrial autophagy (mitophagy), is increasingly being implicated in neurodegenerative diseases and loss of CHIP has been demonstrated to result in mitochondrial dysfunction in multiple animal models, although how CHIP is involved in mitophagy regulation has been previously unknown. Here, we demonstrate that CHIP acts as a negative regulator of the PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy pathway, promoting the degradation of PINK, impairing Parkin translocation to the mitochondria, and suppressing mitophagy in response to mitochondrial stress. We also show that loss of CHIP enhances neuronal mitophagy in a PINK1 and Parkin dependent manner in Caenorhabditis elegans. Furthermore, we find that multiple disease-associated mutations in CHIP dysregulate mitophagy both in vitro and in vivo in C. elegans neurons, a finding which could implicate mitophagy dysregulation in CHIP-associated diseases.

Keywords:  Ataxia; Mitophagy; Neurodegeneration; SCA48; STUB1

DOI:  https://doi.org/10.1016/j.nbd.2024.106625
Bioimpacts. 2024 ;14(4): 27640

Telomerase and mitochondria inhibition promote apoptosis and TET2 and ANMT3a expression in triple negative breast cancer cell lines.

Zeinab Mazloumi, Ali Rafat, Khadijeh Dizaji Asl, Mohammad Karimipour, Dariush Shanehbandi, Mehdi Talebi, Majid Montazer, Ali Akbar Movassaghpour, Alireza Dehnad, Raheleh Farahzadi, Hojjatollah Nozad Charoudeh.

  Introduction: High metastasis, resistance to common treatments, and high mortality rate, has made triple-negative breast cancer (TNBC) to be the most invasive type of breast cancer. High telomerase activity and mitochondrial biogenesis are involved in breast cancer tumorigenesis. The catalytic subunit of telomerase, telomerase reverse transcriptase (hTERT), plays a role in telomere lengthening and extra-biological functions such as gene expression, mitochondria function, and apoptosis. In this study, it has been aimed to evaluate intrinsic-, extrinsic-apoptosis and DNMT3a and TET2 expression following the inhibition of telomerase and mitochondria respiration in TNBC cell lines.
Methods: TNBC cells were treated with IC50 levels of BIBR1532, tigecycline, and also their combination. Then, telomere length, and DNMT3a, TET2, and hTERT expression were evaluated. Finally, apoptosis rate, apoptosis-related proteins, and genes were analyzed.
Results: The present results showed that IC50 level of telomerase and inhibition of mitochondria respiration induced apoptosis but did not leave any significant effect on telomere length. The results also indicated that telomerase inhibition induced extrinsic-apoptosis in MDA-MB-231 and caused intrinsic- apoptosis in MDA-MB-468 cells. Furthermore, it was found that the expression of p53 decreased and was ineffective in cell apoptosis. The expressions of DNMT3a and TET2 increased in cells. In addition, combination treatment was better than BIBR1532 and tigecycline alone.
Conclusion: The inhibition of telomerase and mitochondria respiration caused intrinsic- and extrinsic- apoptosis and increased DNMT3a and TET2 expression and it could be utilized in breast cancer treatment.

Keywords:  Apoptosis; Cancer stem cell; DNMT3a; Mitochondria; TET2; Telomerase; Triple negative breast ‎cancer

DOI:  https://doi.org/10.34172/bi.2023.27640