bims-mitrat 2024-11-10 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–11–10
twelve papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mechanisms Regulating Mitochondrial Transfer in Human Corneal Epithelial Cells.
The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells.
Impact of autologous mitochondrial transfer on obstetric and neonatal health of offspring: A small single-center case series.
Methods to analyze the mitochondrial unfolded protein response (UPRmt).
Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks.
Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.
The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
Alterations in the transcriptome and microRNAs of adipose-derived mesenchymal stem cells from different sites in rats during aging.
Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement.
Comparative analysis of acute eccentric contraction-induced changes to the skeletal muscle transcriptome in young and aged mice and humans.
TOM-TIM23 supercomplex formation.

Invest Ophthalmol Vis Sci. 2024 Nov 04. 65(13): 10

Mechanisms Regulating Mitochondrial Transfer in Human Corneal Epithelial Cells.

Sonali Pal-Ghosh, Beverly A Karpinski, Himani Datta-Majumdar, Soneha Datta, Shelly Dimri, Jordan Hally, Hugo Wehmeyer, Mary Ann Stepp.

Purpose: The intraepithelial corneal nerves (ICNs) innervating the cornea are essential to corneal epithelial cell homeostasis. Rho-associated kinase (ROCK) inhibitors (RIs) have been reported to play roles in neuron survival after injury and in mitochondrial transfer between corneal epithelial cells. In this study, the mechanisms human corneal limbal epithelial (HCLE) cells use to control intercellular mitochondrial transfer are assessed.
Methods: Mitotracker and AAV1 mitotag eGFPmCherry were used to allow us to study mitochondrial transfer between HCLE cells and neurons in co-cultures and in HCLE cultures. A mitochondrial transfer assay was developed using HCLE cells to quantify the impact of cell stress and inhibition of phagocytosis, gap junctions, and ROCK on mitochondrial transfer, cell adhesion, migration, matrix deposition, and mitochondrial content.
Results: Bidirectional mitochondrial transfer occurs between HCLE cells and neurons. Mitochondrial transfer among HCLE cells is inhibited when gap junction function is reduced and enhanced by acid stress and by inhibition of either phagocytosis or ROCK. Media conditioned by RI-treated cells stimulates cell adhesion and mitochondrial transfer.
Conclusions: Maximal mitochondrial transfer takes place when gap junctions are functional, when ROCK and phagocytosis are inhibited, and when cells are stressed by low pH media. Treatments that reduce mitochondrial content increase HCLE cell mitochondrial transfer. ROCK inhibition in co-cultures causes the release and adhesion of mitochondria to substrates where they can be engulfed by migrating HCLE cells and growing axons and their growth cones.

DOI: https://doi.org/10.1167/iovs.65.13.10
Stem Cell Res Ther. 2024 Nov 04. 15(1): 394

The role of mitochondrial transfer in the suppression of CD8+ T cell responses by Mesenchymal stem cells.

Loic Vaillant, Waseem Akhter, Jean Nakhle, Matthieu Simon, Martin Villalba, Christian Jorgensen, Marie-Luce Vignais, Javier Hernandez.

   BACKGROUND: . CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown.
METHODS AND RESULTS: . We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells.
CONCLUSION: . In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells.

Keywords:  Autoimmunity; CD8+ T cells; Immunotherapy; Mesenchymal stem/stromal cells; Mitochondrial transfer

DOI:  https://doi.org/10.1186/s13287-024-03980-1
Placenta. 2024 Oct 15. pii: S0143-4004(24)00677-5. [Epub ahead of print]158 217-222

Impact of autologous mitochondrial transfer on obstetric and neonatal health of offspring: A small single-center case series.

Julia Gil, Mar Nohales, David Ortega-Jaen, Angel Martin, M L Pardiñas, Vicente Serra, Elena Labarta, Maria José de Los Santos.

   INTRODUCTION: A pilot study was carried out to test the efficacy of the autologous mitochondrial transfer therapy (AUGMENT) technique. No improvements in pregnancy rate, development, or embryo quality were observed in the AUGMENT-treated group versus the Control group in this study. The main objective of this research is to analyze whether AUGMENT technology did have any impact on the obstetric and perinatal outcomes of pregnancies and children resulting from treated oocytes.
METHODS: Follow up study of women with a livebirth who participated in a pilot randomized controlled trial in which sibling MII oocytes were randomly allocated to AUGMENT + intracytoplasmic sperm injection (ICSI) (AUGMENT group) or ICSI alone (control group). Preimplantation genetic testing for aneuploidy was performed in both groups. Pregnancy and neonatal outcomes of 14 women (15 pregnancies) and their 18 children were analyzed. The information was retrieved by reviewing the medical records or through questionnaires sent to the patients.
RESULTS: No differences were found in this small case series between the AUGMENT and control groups regarding the rate of gestational complications, birth defects, gestational age at delivery (271.4 ± 12.56 vs 278 ± 10.4 days), birthweight (3.1 ± 0.6 kg vs. 3.1 ± 0.4 kg) and neonatal outcome.
DISCUSSION: The few pregnancies achieved using AUGMENT oocyte therapy had similar outcomes than controls in this very small series. Our very preliminary data need to be confirmed in larger samples. The long term follow up of these children also needs to be analyzed.

Keywords:  AUGMENT; Mitochondrial transfer; Pregnancy

DOI:  https://doi.org/10.1016/j.placenta.2024.10.007
Methods Enzymol. 2024 ;pii: S0076-6879(24)00365-3. [Epub ahead of print]707 543-564

Methods to analyze the mitochondrial unfolded protein response (UPRmt).

Avijit Mallick, Cole M Haynes.

  The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nuclear signaling pathway that mediates the transcription of genes required to maintain mitochondrial function during development as well as during aging. In this chapter, we describe the approaches and techniques that we and others have used to elucidate the mechanism(s) by which cells detect mitochondrial stress or dysfunction and communicate with the nucleus to induce transcription of a protective stress response. We also describe approaches to evaluate the impact of UPRmt activation on mitochondrial function and mitochondrial biogenesis including imaging-based approaches as well as approaches to evaluate mitochondrial genome (mtDNA) copy number.

Keywords:  Deleterious mtDNA heteroplasmy; Mito-nuclear communication; Mitochondrial biogenesis; Mitochondrial unfolded protein response; Molecular chaperones; MtDNA replication

DOI:  https://doi.org/10.1016/bs.mie.2024.07.029
Nat Commun. 2024 Nov 01. 15(1): 9438

Transfer of mitochondrial DNA into the nuclear genome during induced DNA breaks.

Jinchun Wu, Yang Liu, Liqiong Ou, Tingting Gan, Zhengrong Zhangding, Shaopeng Yuan, Xinyi Liu, Mengzhu Liu, Jiasheng Li, Jianhang Yin, Changchang Xin, Ye Tian, Jiazhi Hu.

Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.

DOI: https://doi.org/10.1038/s41467-024-53806-0
Mitochondrion. 2023 Oct 28. pii: S1567-7249(23)00087-9. [Epub ahead of print]

Mitochondrial dysfunction and inflammasome activation in neurodegenerative diseases: Mechanisms and therapeutic implications.

Olia Hamzeh, Fatemeh Rabiei, Mahdi Shakeri, Hadi Parsian, Payam Saadat, Sahar Rostami-Mansoor.

  Impaired mitochondrial function is crucial to the pathogenesis of several neurodegenerative diseases. It causes the release of mitochondrial DNA (mtDNA), mitochondrial reactive oxygen species (mtROS), ATP, and cardiolipin, which activate the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome. NLRP3 inflammasome is an important innate immune system element contributing to neuroinflammation and neurodegeneration. Therefore, targeting the NLRP3 inflammasome has become an interesting therapeutic approach for treating neurodegenerative diseases. This review describes the role of mitochondrial abnormalities and over-activated inflammasomes in the progression of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Friedrich ataxia (FRDA). We also discuss the therapeutic strategies focusing on signaling pathways associated with inflammasome activation, which potentially alleviate neurodegenerative symptoms and impede disease progression.

Keywords:  Inflammasome; Mitochondrial dysfunction; NLRP3; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.mito.2023.10.003
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977

The multifaceted modulation of mitochondrial metabolism in tumorigenesis.

Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.

  Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Keywords:  EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis

DOI:  https://doi.org/10.1016/j.mito.2024.101977
Nature. 2024 Nov 06.

Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.

Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.

Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.

DOI: https://doi.org/10.1038/s41586-024-08146-w
Am J Physiol Cell Physiol. 2024 Nov 04.

Alterations in the transcriptome and microRNAs of adipose-derived mesenchymal stem cells from different sites in rats during aging.

Zhenyang Su, Tianhua Xu, Jin-Yu Sun, Wei Sun, Xiangqing Kong.

  Aging is an intricate and gradual process characterized by tissue and cellular dysfunction. Adipose-derived mesenchymal stem cells (ADMSCs) experience a functional decline as part of systemic aging. However, the alterations in ADMSCs across various anatomical sites throughout an individual's lifespan remain unclear. To shed light on these changes, we collected white adipose tissue and brown adipose tissue samples from the epididymis, perirenal, inguinal, and scapular regions of young, adult, and aged rats and subsequently isolated ADMSCs for RNA sequencing. As aging progressed, we observed a reduction in the number of ADMSCs at all anatomical sites. Marker genes of ADMSCs from different sites were identified. Aging triggered notable activation of inflammatory and immune responses while diminishing the ADMSC differentiation capacity and ability to maintain normal tissue morphology. Furthermore, miR-195-5p and miR-497-3p, which promoted cell senescence and apoptosis while inhibiting proliferation and differentiation, were positively correlated with aging. These findings increase our understanding of ADMSC senescence and underscore the unique physiological changes and functions of ADMSCs across different anatomical sites during aging.

Keywords:  adipose-derived mesenchymal stem cell; aging; microRNA; transcriptome

DOI:  https://doi.org/10.1152/ajpcell.00044.2024
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00137-5. [Epub ahead of print] 101979

Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement.

Vaibhav Patange, Kailash Ahirwar, Tripti Tripathi, Pratima Tripathi, Rahul Shukla.

  Genetic control is vital for the growth of cells and tissues, and it also helps living things, from single-celled organisms to complex creatures, maintain a stable internal environment. Within cells, structures called mitochondria act like tiny power plants, producing energy and keeping the cell balanced. The two primary categories of RNA are messenger RNA (mRNA) and non-coding RNA (ncRNA). mRNA carries the instructions for building proteins, while ncRNA does various jobs at the RNA level. There are different kinds of ncRNA, each with a specific role. Some help put RNA molecules together correctly, while others modify other RNAs or cut them into smaller pieces. Still others control how much protein is made from a gene. Scientists have recently discovered many more ncRNAs than previously known, and their functions are still being explored. This article analyzes the RNA molecules present within mitochondria, which have a crucial purpose in the operation of mitochondria. We'll also discuss how genes can be turned on and off without changing their DNA code, and how this process might be linked to mitochondrial RNA. Finally, we'll explore how scientists are using engineered particles to silence genes and develop new treatments based on manipulating ncRNA.

Keywords:  Mitochondrial epigenetics; Neurodegeneration; Non-coding RNA; Transcriptomics; lnc-RNA; miRNA

DOI:  https://doi.org/10.1016/j.mito.2024.101979
Am J Physiol Regul Integr Comp Physiol. 2024 Nov 04.

Comparative analysis of acute eccentric contraction-induced changes to the skeletal muscle transcriptome in young and aged mice and humans.

Jake R Boykin, Jennifer L Steiner, Grant R Laskin, Michael D Roberts, Cynthia Vied, Craig Rg Willis, Timothy Etheridge, Bradley S Gordon.

  Adaptations to skeletal muscle following resistance exercise are due in part to changes to the skeletal muscle transcriptome. While transcriptional changes in response to resistance exercise occur in young and aged muscle, aging alters this response. Rodent models have served great utility in defining regulatory factors that underscore the influence of mechanical load and aging on changes to skeletal muscle phenotype. Unilateral eccentric contractions in young and aged rodents are widely used to model resistance exercise in humans. However, the extent to which unilateral eccentric contractions in young and aged rodents mimics the transcriptional response in humans remains unknown. We re-analyzed two publicly available RNA sequencing datasets from young and aged mice and humans that were subjected to acute eccentric contractions to define key similarities and differences to the muscle transcriptional response following this exercise modality. The effect of aging on the number of contraction-sensitive genes, the distribution patterns of those genes into unique/common categories, and the cellular pathways associated with the differentially expressed genes (DEGs) were similar in mice and humans. However, there was little overlap between species when comparing specific contraction-sensitive DEGs within the same age group. There were strong intraspecies relationships for the common transcription factors predicted to influence the contraction-sensitive gene sets, whereas interspecies relationships were weak. Overall, these data demonstrate key similarities between mice and humans for the contraction-induced changes to the muscle transcriptome, but we posit species-specific responses exist and should be taken into consideration when attempting to translate rodent eccentric exercise models.

Keywords:  aging; gene expression; resistance exercise; transcription factors

DOI:  https://doi.org/10.1152/ajpregu.00224.2024
Methods Enzymol. 2024 ;pii: S0076-6879(24)00382-3. [Epub ahead of print]707 3-22

TOM-TIM23 supercomplex formation.

Naintara Jain, Ridhima Gomkale, Peter Rehling.

  Mitochondria import the vast majority of proteins from the cytosol. Protein translocation machineries in outer and inner membranes facilitate precursor recognition and transport. Most mitochondrial proteins utilize N-terminal presequences as targeting signals that eventually direct them across the inner mitochondrial membrane. These precursors are transported by the TOM complex across the outer-, and subsequently by the TIM23 complex across the inner membrane. During this process the translocases align and the polypeptide chain is translocated across both membranes in a coupled manner. A transient precursor-containing TOM-TIM23 supercomplex is formed. This TOM-TIM23 supercomplex provides a fascinating import intermediate which can be stabilized if the precursor contains a tightly folded moiety at the C-terminus that is not able to pass through the TOM complex. Such a supercomplex can be generated during in vitro import, and in vivo. The stabilized TOM-TIM23 supercomplex can be purified for downstream analysis. The possibility of pausing translocation at this step provides a means to understand the mechanisms underlying precursor translocation.

Keywords:  Import; Mitochondria; Supercomplex; TIM23; TOM

DOI:  https://doi.org/10.1016/bs.mie.2024.07.042