bims-mitrat 2024-03-03 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–03–03
eleven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Considerations for developing mitochondrial transplantation techniques for individualized medicine.
Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.
Chrysophanol accelerates astrocytic mitochondria transfer to neurons and attenuates the cerebral ischemia-reperfusion injury in rats.
The role of mitochondrial transfer via tunneling nanotubes in the central nervous system: A review.
Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.
Human Platelet Derived Mitochondrial OPA-1 Isoforms and Interaction With TDP-43 in Neurodegenerative Diseases.
Miro1 improves the exogenous engraftment efficiency and therapeutic potential of mitochondria transfer using Wharton's jelly mesenchymal stem cells.
ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.
Cell adhesion and actin dynamics factors promote axonal extension and synapse formation in transplanted Drosophila photoreceptor cells.
Mitochondria in biology and medicine - 2023.
Mechanical overload-induced release of extracellular mitochondrial particles from tendon cells leads to inflammation in tendinopathy.

Biotechniques. 2024 Feb 29.

Considerations for developing mitochondrial transplantation techniques for individualized medicine.

Kit Neikirk, Dominique C Stephens, Heather K Beasley, Andrea G Marshall, Jennifer A Gaddy, Steven M Damo, Antentor O Hinton.

  Tweetable abstract Mitochondrial transplantation has been used to treat various diseases associated with mitochondrial dysfunction. Here, we highlight the considerations in quality control mechanisms that should be considered in the context of mitochondrial transplantation.

Keywords:  individualized medicine; mitochondria diseases; mitochondria transfer; mitochondria transplantation

DOI:  https://doi.org/10.2144/btn-2023-0072
Brain Res. 2024 Feb 23. pii: S0006-8993(24)00080-5. [Epub ahead of print] 148826

Hypothermia promotes tunneling nanotube formation and the transfer of astrocytic mitochondria into oxygen-glucose deprivation/reoxygenation-injured neurons.

Xiao-Rui Xi, Zhi-Qiang Zhang, Yan-Li Li, Zheng Liu, Dong-Yang Ma, Zan Gao, Shan Zhang.

  Mitochondrial transfer occurs between cells, and it is important for damaged cells to receive healthy mitochondria to maintain their normal function and protect against cell death. Accumulating evidence suggests that the functional mitochondria of astrocytes are released and transferred to oxygen-glucose deprivation/reoxygenation (OGD/R)-injured neurons. Mild hypothermia (33 °C) is capable of promoting this process, which partially restores the function of damaged neurons. However, the pathways and mechanisms by which mild hypothermia facilitates mitochondrial transfer remain unclear. We are committed to studying the role of mild hypothermia in neuroprotection to provide reliable evidence and insights for the clinical application of mild hypothermia in brain protection. Tunneling nanotubes (TNTs) are considered to be one of the routes through which mitochondria are transferred between cells. In this study, an OGD/R-injured neuronal model was successfully established, and TNTs, mitochondria, neurons and astrocytes were double labeled using immunofluorescent probes. Our results showed that TNTs were present and involved in the transfer of mitochondria between cells in the mixed-culture system of neurons and astrocytes. When neurons were subjected to OGD/R exposure, TNT formation and mitochondrial transportation from astrocytes to injured neurons were facilitated. Further analysis revealed that mild hypothermia increased the quantity of astrocytic mitochondria transferred into damaged neurons through TNTs, raised the mitochondrial membrane potential (MMP), and decreased the neuronal damage and death during OGD/R. Altogether, our data indicate that TNTs play an important role in the endogenous neuroprotection of astrocytic mitochondrial transfer. Furthermore, mild hypothermia enhances astrocytic mitochondrial transfer into OGD/R-injured neurons via TNTs, thereby promoting neuroprotection and neuronal recovery.

Keywords:  Hypothermia; Mitochondrial transfer; Oxygen–glucose deprivation/reoxygenation (OGD/R); Tunneling nanotubes (TNTs)

DOI:  https://doi.org/10.1016/j.brainres.2024.148826
Biochem Biophys Res Commun. 2024 Feb 23. pii: S0006-291X(24)00248-1. [Epub ahead of print]704 149712

Chrysophanol accelerates astrocytic mitochondria transfer to neurons and attenuates the cerebral ischemia-reperfusion injury in rats.

Xiao-Mei Su, Dan-Shen Zhang, Nan Zhang.

  Astrocytes transfer extracellular functional mitochondria into neurons to rescue injured neurons after a stroke. However, there are no reports on drugs that interfere with intercellular mitochondrial transfer. Chrysophanol (CHR) was an effective drug for the treatment of cerebral ischemia-reperfusion injury (CIRI) and was selected as the test drug. The oxygen-glucose deprivation/reoxygenation (OGD/R) cell model and the middle cerebral artery occlusion animal model were established to investigate the effect of CHR on CIRI. The result showed that astrocytes could act as mitochondrial donors to ameliorate neuronal injury. Additionally, the neuroprotective effect of astrocytes was enhanced by CHR, the CHR improved the neuronal mitochondrial function, decreased the neurological deficit score and infarction volume, recovered cell morphology in ischemic penumbra. The mitochondrial fluorescence probe labeling technique has shown that the protective effect of CHR is associated with accelerated astrocytic mitochondrial transfer to neurons. The intercellular mitochondrial transfer may be an important way to ameliorate ischemic brain injury and be used as a key target for drug treatment.

Keywords:  Astrocyte-neuron co-culture model; Cerebral ischemia/reperfusion injury; Chrysophanol; Mitochondrial transfer; Oxygen glucose deprivation/reoxygenation model

DOI:  https://doi.org/10.1016/j.bbrc.2024.149712
Medicine (Baltimore). 2024 Mar 01. 103(9): e37352

The role of mitochondrial transfer via tunneling nanotubes in the central nervous system: A review.

Ye Chen, Dongqiong Xiao, Xihong Li.

Tumour necrosis factor alpha-induced protein 2 (TNFAIP2) is a gene induced by tumor necrosis factor in endothelial cells. TNFAIP2 has important functions in physiological and pathological processes, including cell proliferation, adhesion, migration, angiogenesis, inflammation, tunneling nanotube (TNT) formation and tumorigenesis. Moreover, TNFAIP2 is the key factor in the formation of TNTs. TNTs are related to signal transduction between different cell types and are considered a novel means of cell-to-cell communication. Mesenchymal stem cells (MSCs) are pluripotent cells that exhibit self-renewal, multidirectional differentiation, paracrine function and immune-regulating ability. MSCs can transfer mitochondria through TNTs to improve the functions of target cells. This review revealed that TNFAIP2 promotes the formation of TNTs and that MSCs rely on TNTs for mitochondrial transfer to ameliorate cell dysfunction.

DOI: https://doi.org/10.1097/MD.0000000000037352
J Physiol. 2024 Mar 01.

Reorganization of mitochondria-organelle interactions during postnatal development in skeletal muscle.

Yuho Kim, Hailey A Parry, T Bradley Willingham, Greg Alspaugh, Eric Lindberg, Christian A Combs, Jay R Knutson, Christopher K E Bleck, Brian Glancy.

  Skeletal muscle cellular development requires the integrated assembly of mitochondria and other organelles adjacent to the sarcomere in support of muscle contractile performance. However, it remains unclear how interactions among organelles and with the sarcomere relates to the development of muscle cell function. Here, we combine 3D volume electron microscopy, proteomic analyses, and live cell functional imaging to investigate the postnatal reorganization of mitochondria-organelle interactions in skeletal muscle. We show that while mitochondrial networks are disorganized and loosely associated with the contractile apparatus at birth, contact sites among mitochondria, lipid droplets and the sarcoplasmic reticulum are highly abundant in neonatal muscles. The maturation process is characterized by a transition to highly organized mitochondrial networks wrapped tightly around the muscle sarcomere but also to less frequent interactions with both lipid droplets and the sarcoplasmic reticulum. Concomitantly, expression of proteins involved in mitochondria-organelle membrane contact sites decreases during postnatal development in tandem with a decrease in abundance of proteins associated with sarcomere assembly despite an overall increase in contractile protein abundance. Functionally, parallel measures of mitochondrial membrane potential, NADH redox status, and NADH flux within intact cells revealed that mitochondria in adult skeletal muscle fibres maintain a more activated electron transport chain compared with neonatal muscle mitochondria. These data demonstrate a developmental redesign reflecting a shift from muscle cell assembly and frequent inter-organelle communication toward a muscle fibre with mitochondrial structure, interactions, composition and function specialized to support contractile function. KEY POINTS: Mitochondrial network organization is remodelled during skeletal muscle postnatal development. The mitochondrial outer membrane is in frequent contact with other organelles at birth and transitions to more close associations with the contractile apparatus in mature muscles. Mitochondrial energy metabolism becomes more activated during postnatal development. Understanding the developmental redesign process within skeletal muscle cells may help pinpoint specific areas of deficit in muscles with developmental disorders.

Keywords:  3D mitochondrial structure; functional cellular imaging; organelle interactions; postnatal muscle development; volume electron microscopy

DOI:  https://doi.org/10.1113/JP285014
Mo Med. 2024 Jan-Feb;121(1):121(1): 87-92

Human Platelet Derived Mitochondrial OPA-1 Isoforms and Interaction With TDP-43 in Neurodegenerative Diseases.

Su Han Lee, Duyen Pham, Edina Kosa, Abdulbaki Agbas.

Optic atrophy 1(OPA1) is a GTPase protein that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), the mitochondrial network morphology is compromised. Studies on TAR-DNA binding protein 43 (TDP-43) has been the focus in our lab. OPA1 and TDP-43 interaction may shed a light on how aberrant TDP-43 interacts with OPA1, which will lead to mitochondrial dysfunction. The preliminary study tested the idea of whether OPA1 and TDP-43 are physically interacting in human platelet derived mitochondria obtained from healthy human subjects.
Mitochondrion. 2024 Feb 24. pii: S1567-7249(24)00014-X. [Epub ahead of print] 101856

Miro1 improves the exogenous engraftment efficiency and therapeutic potential of mitochondria transfer using Wharton's jelly mesenchymal stem cells.

Yu-Han Lin, Kai-Lieh Lin, Xiao-Wen Wang, Jong-Jer Lee, Feng-Sheng Wang, Pei-Wen Wang, Min-Yu Lan, Chia-Wei Liou, Tsu-Kung Lin.

  Mitochondria are important for maintaining cellular energy metabolism and regulating cellular senescence. Mitochondrial DNA (mtDNA) encodes subunits of the OXPHOS complexes which are essential for cellular respiration and energy production. Meanwhile, mtDNA variants have been associated with the pathogenesis of neurodegenerative diseases, including MELAS, for which no effective treatment has been developed. To alleviate the pathological conditions involved in mitochondrial disorders, mitochondria transfer therapy has shown promise. Wharton's jelly mesenchymal stem cells (WJMSCs) have been identified as suitable mitochondria donors for mitochondria-defective cells, wherein mitochondrial functions can be rescued. Miro1 participates in mitochondria trafficking by anchoring mitochondria to microtubules. In this study, we identified Miro1 over-expression as a factor that could help to enhance the efficiency of mitochondrial delivery. More specifically, we reveal that Miro1 over-expressed WJMSCs significantly improved intercellular communications, cell proliferation rates, and mitochondrial membrane potential, while restoring mitochondrial bioenergetics in mitochondria-defective fibroblasts. Furthermore, Miro1 over-expressed WJMSCs decreased rates of induced apoptosis and ROS production in MELAS fibroblasts; although, Miro1 over-expression did not rescue mtDNA mutation ratios nor mitochondrial biogenesis. This study presents a potentially novel therapeutic strategy for treating mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and other diseases associated with dysfunctional mitochondria, while the pathophysiological relevance of our results should be further verified by animal models and clinical studies.

Keywords:  MELAS; Miro1; Mitochondria; Mitochondrial bioenergetics; WJMSCs

DOI:  https://doi.org/10.1016/j.mito.2024.101856
J Cell Physiol. 2024 Feb 28.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Antentor Hinton, Prasanna Katti, Margaret Mungai, Duane D Hall, Olha Koval, Jianqiang Shao, Zer Vue, Edgar Garza Lopez, Rahmati Rostami, Kit Neikirk, Jessica Ponce, Jennifer Streeter, Brandon Schickling, Serif Bacevac, Chad Grueter, Andrea Marshall, Heather K Beasley, Young Do Koo, Sue C Bodine, Nayeli G Reyes Nava, Anita M Quintana, Long-Sheng Song, Isabella M Grumbach, Renata O Pereira, Brian Glancy, E Dale Abel.

  Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+ , lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Keywords:  activating transcription factor 4; endoplasmic reticulum; integrated stress response; interorganelle communication; mitochondria

DOI:  https://doi.org/10.1002/jcp.31204
Dev Growth Differ. 2024 Feb 25.

Cell adhesion and actin dynamics factors promote axonal extension and synapse formation in transplanted Drosophila photoreceptor cells.

Riku Iwanaga, Nagisa Yahagi, Satoko Hakeda-Suzuki, Takashi Suzuki.

  Vision is formed by the transmission of light stimuli to the brain through axons extending from photoreceptor cells. Damage to these axons leads to loss of vision. Despite research on neural circuit regeneration through transplantation, achieving precise axon projection remains challenging. To achieve optic nerve regeneration by transplantation, we employed the Drosophila visual system. We previously established a transplantation method for Drosophila utilizing photoreceptor precursor cells extracted from the eye disc. However, little axonal elongation of transplanted cells into the brain, the lamina, was observed. We verified axonal elongation to the lamina by modifying the selection process for transplanted cells. Moreover, we focused on N-cadherin (Ncad), a cell adhesion factor, and Twinstar (Tsr), which has been shown to promote actin reorganization and induce axon elongation in damaged nerves. Overexpression of Ncad and tsr promoted axon elongation to the lamina, along with presynaptic structure formation in the elongating axons. Furthermore, overexpression of Neurexin-1 (Nrx-1), encoding a protein identified as a synaptic organizer, was found to not only promote presynapse formation but also enhance axon elongation. By introducing Ncad, tsr, and Nrx-1, we not only successfully achieved axonal projection of transplanted cells to the brain beyond the retina, but also confirmed the projection of transplanted cells into a deeper ganglion, the medulla. The present study offers valuable insights to realize regeneration through transplantation in a more complex nervous system.

Keywords:  Drosophila; actin dynamics; axon growth; transplantation; visual system

DOI:  https://doi.org/10.1111/dgd.12916
Mitochondrion. 2024 Feb 27. pii: S1567-7249(24)00011-4. [Epub ahead of print] 101853

Mitochondria in biology and medicine - 2023.

B Disha, Rohan Peter Mathew, Ashwin B Dalal, Ajay K Mahato, Kapaettu Satyamoorthy, Keshav K Singh, Kumarasamy Thangaraj, Periyasamy Govindaraj.

  Mitochondria are an indispensable part of the cell that plays a crucial role in regulating various signaling pathways, energy metabolism, cell differentiation, proliferation, and cell death. Since mitochondria have their own genetic material, they differ from their nuclear counterparts, and dysregulation is responsible for a broad spectrum of diseases. Mitochondrial dysfunction is associated with several disorders, including neuro-muscular disorders, cancer, and premature aging, among others. The intricacy of the field is due to the cross-talk between nuclear and mitochondrial genes, which has also improved our knowledge of mitochondrial functions and their pathogenesis. Therefore, interdisciplinary research and communication are crucial for mitochondrial biology and medicine due to the challenges they pose for diagnosis and treatment. The ninth annual conference of the Society for Mitochondria Research and Medicine (SMRM)- India, titled "Mitochondria in Biology and Medicine" was organized at the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India, on June 21-23, 2023. The latest advancements in the field of mitochondrial biology and medicine were discussed at the conference. In this article, we summarize the entire event for the benefit of researchers working in the field of mitochondrial biology and medicine.

Keywords:  Disease; Genetics; Metabolism; Mitochondria

DOI:  https://doi.org/10.1016/j.mito.2024.101853
Exp Mol Med. 2024 Mar 01.

Mechanical overload-induced release of extracellular mitochondrial particles from tendon cells leads to inflammation in tendinopathy.

Ziming Chen, Mengyuan Li, Peilin Chen, Andrew Tai, Jiayue Li, Euphemie Landao Bassonga, Junjie Gao, Delin Liu, David Wood, Brendan F Kennedy, Qiujian Zheng, Ming H Zheng.

Tendinopathy is one of the most common musculoskeletal diseases, and mechanical overload is considered its primary cause. However, the underlying mechanism through which mechanical overload induces tendinopathy has not been determined. In this study, we identified for the first time that tendon cells can release extracellular mitochondria (ExtraMito) particles, a subtype of medium extracellular particles (mEPs), into the environment through a process regulated by mechanical loading. RNA sequencing systematically revealed that oxygen-related reactions, extracellular particles, and inflammation were present in diseased human tendons, suggesting that these factors play a role in the pathogenesis of tendinopathy. We simulated the disease condition by imposing a 9% strain overload on three-dimensional mouse tendon constructs in our cyclic uniaxial stretching bioreactor. The three-dimensional mouse tendon constructs under normal loading with 6% strain exhibited an extended mitochondrial network, as observed through live-cell confocal laser scanning microscopy. In contrast, mechanical overload led to a fragmented mitochondrial network. Our microscopic and immunoblot results demonstrated that mechanical loading induced tendon cells to release ExtraMito particles. Furthermore, we showed that mEPs released from tendon cells overloaded with a 9% strain (mEP9%) induced macrophage chemotaxis and increased the production of proinflammatory cytokines, including IL-6, CXCL1, and IL-18, from macrophages compared to mEP0%, mEP3%, and mEP6%. Partial depletion of the ExtraMito particles from mEP9% by magnetic-activated cell sorting significantly reduced macrophage chemotaxis. N-acetyl-L-cysteine treatment preserved the mitochondrial network in overloaded tendon cells, diminishing overload-induced macrophage chemotaxis toward mEP9%. These findings revealed a novel mechanism of tendinopathy; in an overloaded environment, ExtraMito particles convey mechanical response signals from tendon cells to the immune microenvironment, culminating in tendinopathy.

DOI: https://doi.org/10.1038/s12276-024-01183-5