bims-mitrat 2024-10-20 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒10‒20
thirteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitophagy as a guardian against cellular aging.
Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.
Mitochondrial transfer in the progression and treatment of cardiac disease.
What causes cardiac mitochondrial failure at high environmental temperatures?
Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.
Luteolin alleviates muscle atrophy, mitochondrial dysfunction and abnormal FNDC5 expression in high fat diet-induced obese rats and palmitic acid-treated C2C12 myotubes.
Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4.
Molecular mechanisms of mitochondrial dynamics.
Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.
Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model.
The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.
Nose-to-brain delivery of stem cells in stroke: the role of extracellular vesicles.
Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.

Autophagy. 2024 Oct 14. 1-3

Mitophagy as a guardian against cellular aging.

Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.

  Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.

Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence

DOI:  https://doi.org/10.1080/15548627.2024.2414461
J Transl Med. 2024 Oct 15. 22(1): 941

Mitochondrial transplantation: a promising strategy for treating degenerative joint diseases.

Hong Luo, Yue Lai, Weili Tang, Guoyou Wang, Jianlin Shen, Huan Liu.

  The prevalence of age-related degenerative joint diseases, particularly intervertebral disc degeneration and osteoarthritis, is increasing, thereby posing significant challenges for the elderly population. Mitochondrial dysfunction is a critical factor in the etiology and progression of these disorders. Therapeutic interventions that incorporate mitochondrial transplantation exhibit considerable promise by increasing mitochondrial numbers and improving their functionality. Existing evidence suggests that exogenous mitochondrial therapy improves clinical outcomes for patients with degenerative joint diseases. This review elucidates the mitochondrial abnormalities associated with degenerative joint diseases and examines the mechanisms of mitochondrial intercellular transfer and artificial mitochondrial transplantation. Furthermore, therapeutic strategies for mitochondrial transplantation in degenerative joint diseases are synthesized, and the concept of engineered mitochondrial transplantation is proposed.

Keywords:  Degenerative joint diseases; Engineered mitochondria; Intervertebral disc degeneration; Mitochondrial transplantation; Osteoarthritis

DOI:  https://doi.org/10.1186/s12967-024-05752-0
Life Sci. 2024 Oct 10. pii: S0024-3205(24)00709-4. [Epub ahead of print]358 123119

Mitochondrial transfer in the progression and treatment of cardiac disease.

Yaqing Huang, Wanling Li, Hongyu Sun, Xin Guo, Yue Zhou, Jun Liu, Feila Liu, Yonghong Fan.

  Mitochondria are the primary site for energy production and play a crucial role in supporting normal physiological functions of the human body. In cardiomyocytes (CMs), mitochondria can occupy up to 30 % of the cell volume, providing sufficient energy for CMs contraction and relaxation. However, some pathological conditions such as ischemia, hypoxia, infection, and the side effect of drugs, can cause mitochondrial dysfunction in CMs, leading to various myocardial injury-related diseases including myocardial infarction (MI), myocardial hypertrophy, and heart failure. Self-control of mitochondria quality and conversion of metabolism pathway in energy production can serve as the self-rescue measure to avoid autologous mitochondrial damage. Particularly, mitochondrial transfer from the neighboring or extraneous cells enables to mitigate mitochondrial dysfunction and restore their biological functions in CMs. Here, we described the homeostatic control strategies and related mechanisms of mitochondria in injured CMs, including autologous mitochondrial quality control, mitochondrial energy conversion, and especially the exogenetic mitochondrial donation. Additionally, this review emphasizes on the therapeutic effects and potential application of utilizing mitochondrial transfer in reducing myocardial injury. We hope that this review can provide theoretical clues for the developing of advanced therapeutics to treat cardiac diseases.

Keywords:  Cardiac diseases; Cardiomyocyte; Mitochondrial quality control; Mitochondrial therapy; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.lfs.2024.123119
J Exp Biol. 2024 Oct 15. pii: jeb247432. [Epub ahead of print]227(20):

What causes cardiac mitochondrial failure at high environmental temperatures?

Anthony J R Hickey, Alice R Harford, Pierre U Blier, Jules B Devaux.

  Although a mechanism accounting for hyperthermic death at critical temperatures remains elusive, the mitochondria of crucial active excitable tissues (i.e. heart and brain) may well be key to this process. Mitochondria produce ∼90% of the ATP required by cells to maintain cellular integrity and function. They also integrate into biosynthetic pathways that support metabolism as a whole, allow communication within the cell, and regulate cellular health and death pathways. We have previously shown that cardiac and brain mitochondria demonstrate decreases in the efficiency of, and absolute capacity for ATP synthesis as temperatures rise, until ultimately there is too little ATP to support cellular demands, and organ failure follows. Importantly, substantial decreases in ATP synthesis occur at temperatures immediately below the temperature of heart failure, and this suggests a causal role of mitochondria in hyperthermic death. However, what causes mitochondria to fail? Here, we consider the answers to this question. Mitochondrial dysfunction at high temperature has classically been attributed to elevated leak respiration suspected to result from increased movement of protons (H+) through the inner mitochondrial membrane (IMM), thereby bypassing the ATP synthases. In this Commentary, we introduce some alternative explanations for elevated leak respiration. We first consider respiratory complex I and then propose that a loss of IMM structure occurs as temperatures rise. The loss of the cristae folds of the IMM may affect the efficiency of H+ transport, increasing H+ conductance either through the IMM or into the bulk water phases of mitochondria. In either case, O2 consumption increases while ATP synthesis decreases.

Keywords:  ATP; Cristae; Hyperthermic death; Leak respiration; Mitochondria; Proton gradient; Proton motive force; ROS; Temperature; Ultrastructure

DOI:  https://doi.org/10.1242/jeb.247432
J Physiol Biochem. 2024 Oct 18.

Normobaric hypoxia accelerates high-intensity intermittent training-induced mitochondrial biogenesis (PGC-1α)- and dynamics (OPA1)-related protein expressions in rat gastrocnemius muscle.

Shohei Dobashi, Toshinori Yoshihara, Yuji Ogura, Hisashi Naito.

  High-intensity intermittent training (HIIT) in a normobaric hypoxic environment enhances exercise capacity, possibly by increasing the mitochondrial content in skeletal muscle; however, the molecular mechanisms underlying these adaptations are not well understood. Therefore, we investigated whether HIIT under normobaric hypoxia can enhance the expression of proteins involved in mitochondrial biogenesis and dynamics in rat gastrocnemius muscle. Five-week-old male Wistar rats (n = 24) were randomly assigned to the following four groups: (1) sedentary under normoxia (20.9% O2) (NS), (2) training under normoxia (NT), (3) sedentary under normobaric hypoxia (14.5% O2) (HS), and (4) training under normobaric hypoxia (HT). The training groups in both conditions were engaged in HIIT on a treadmill five to six days per week for nine weeks. From the fourth week of the training period, the group assigned to hypoxic conditions was exposed to normobaric hypoxia. Forty-eight hours after completing the final training session, gastrocnemius muscles were surgically removed, and mitochondrial enzyme activity and mitochondrial biogenesis and dynamics regulatory protein levels were determined. Citrate synthase (CS) activity and mitochondrial oxygen phosphorylation (OXPHOS) subunits in the gastrocnemius muscle in the HT significantly exceeded those in the other three groups. Moreover, the levels of a master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and a mitochondrial fusion-related protein, optic atrophy 1 (OPA1), were significantly increased by HIIT under normobaric hypoxia. Our data indicates that HIIT and normobaric hypoxia increase the expression of mitochondrial biogenesis- and dynamics-related proteins in skeletal muscles.

Keywords:  Autophagy; Hind limb muscle; Mitochondrial fusion and fission; Mitochondrial synthesis; Moderate hypoxia; Treadmill running

DOI:  https://doi.org/10.1007/s13105-024-01052-9
J Nutr Biochem. 2024 Oct 10. pii: S0955-2863(24)00211-0. [Epub ahead of print] 109780

Luteolin alleviates muscle atrophy, mitochondrial dysfunction and abnormal FNDC5 expression in high fat diet-induced obese rats and palmitic acid-treated C2C12 myotubes.

Yiyuan Zhang, Chunyun Luo, Puxin Huang, Yahong Cheng, Yufang Ma, Jiefang Gao, Hong Ding.

  Obesity is associated with a series of skeletal muscle impairments and dysfunctions, which are characterized by metabolic disturbances and muscle atrophy. Luteolin is a phenolic phytochemical with broad pharmacological activities. The present study aimed to evaluate the protective effects of Luteolin on muscle function and explore the potential mechanisms in high-fat diet (HFD)-induced obese rats and palmitic acid (PA)-treated C2C12 myotubes. Male Sprague-Dawley (SD) rats were fed with a control diet or HFD and orally administrated 0.5% sodium carboxymethyl cellulose (vehicle) or Luteolin (25, 50 and 100 mg/kg, respectively) for 12 weeks. The results showed that Luteolin ameliorated HFD-induced body weight gain, glucose intolerance and hyperlipidemia. Luteolin also alleviated muscle atrophy, decreased ectopic lipid deposition and prompted muscle-fiber-type conversion in the skeletal muscle. Meanwhile, we observed an evident improvement in mitochondrial quality control and respiratory capacity, accompanied by reduced oxidative stress. Mechanistic studies indicated that AMPK/SIRT1/PGC-1α signaling pathway plays a key role in the protective effects of Luteolin on skeletal muscle in the obese states, which was further verified by using specific inhibitors of AMPK and SIRT1. Moreover, the mRNA expression levels of markers in brown adipocyte formation were significantly up-regulated post Luteolin supplementation in different adipose depots. Taken together, these results revealed that Luteolin supplementation might be a promising strategy to prevent obesity-induced loss of mass and biological dysfunctions of skeletal muscle.

Keywords:  Luteolin; high fat diet; irisin; mitochondrial dysfunction; muscle atrophy

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109780
J Appl Physiol (1985). 2024 Oct 17.

Acute contractile activity induces the activation of the mitochondrial integrated stress response and the transcription factor ATF4.

Victoria C Sanfrancesco, David A Hood.

  Skeletal muscle relies on mitochondria to produce energy and support its metabolic flexibility. The function of the mitochondrial pool is regulated by quality control (MQC) processes. The integrated stress response (ISR), a MQC pathway, is activated in response to various cellular stressors. The transcription factor ATF4, the main effector of the ISR, ameliorates cellular stress by upregulating protective genes, such as CHOP and ATF5. Recent literature has shown that the ISR is activated upon mitochondrial stress, however, whether this includes acute exercise-induced stress is poorly defined. To investigate this, a mouse in situ hindlimb protocol was utilized to acutely stimulate muscles at 0.25, 0.5 and 1 tetanic contraction/per second for 9 mins, followed by a 1-hour recovery period. CAMKII and JNK2 were robustly activated 6-fold immediately following the protocol. ISR activation, denoted as the ratio of phosphorylated to total-eIF2a protein levels, was also elevated following recovery. Downstream, contractile activity induced an increase in the nuclear localization of ATF4. Robust 2-fold increases in the mRNA expression of ATF4 and CHOP were also observed following the recovery period. Changes in ATF4 mRNA were independent of transcriptional activation, as assessed using an ATF4 promoter-reporter plasmid. Instead, mRNA decay assays revealed an increase in ATF4 mRNA stability post-contractile activity, as a result of enhanced stabilization by the RNA binding protein, HuR. Thus, acute contractile activity is sufficient to induce mitochondrial stress and activate the ISR, corresponding to the induction of ATF4 with potential consequences for mitochondrial phenotype adaptations in response to repeated exercise.

Keywords:  Adaptations; Exercise; Mitochondrial Biogenesis; Skeletal Muscle; eIF2α

DOI:  https://doi.org/10.1152/japplphysiol.00307.2024
Nat Rev Mol Cell Biol. 2024 Oct 17.

Molecular mechanisms of mitochondrial dynamics.

Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.

Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.

DOI: https://doi.org/10.1038/s41580-024-00785-1
Methods Mol Biol. 2025 ;2861 155-164

Analyzing Mitochondrial Calcium Influx in Isolated Mitochondria.

Nasab Ghazal, Jennifer Q Kwong.

  Mitochondria play a crucial role in Ca2+ signaling and homeostasis and can contribute to shaping the cytosolic Ca2+ landscape as well as regulate a variety of pathways including energy production and cell death. Dysregulation of mitochondrial Ca2+ homeostasis promotes pathologies including neurodegenerative diseases, cardiovascular disorders, and metabolic syndromes. The significance of mitochondria to Ca2+ signaling and regulation underscores the value of methods to assess mitochondrial Ca2+ import. Here we present a plate reader-based method using the Ca2+-sensitive fluorescent probe calcium green-5 N to measure mitochondrial Ca2+ import in isolated cardiac mitochondria. This technique can be expanded to measure Ca2+ uptake in mitochondria isolated from other tissue types and from cultured cells.

Keywords:  Calcium; Heart; Mitochondria; Mitochondrial permeability transition pore; Signaling; Uniporter

DOI:  https://doi.org/10.1007/978-1-0716-4164-4_12
Skelet Muscle. 2024 Oct 14. 14(1): 23

Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model.

Gareth Hazell, Eve McCallion, Nina Ahlskog, Emma R Sutton, Magnus Okoh, Emad I H Shaqoura, Joseph M Hoolachan, Taylor Scaife, Sara Iqbal, Amarjit Bhomra, Anna J Kordala, Frederique Scamps, Cedric Raoul, Matthew J A Wood, Melissa Bowerman.

  BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits.METHODS: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14-/- mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14-/-, SOD1G93A and SOD1G93A;Fn14-/-).
RESULTS: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size.
CONCLUSIONS: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.

Keywords:  Amyotrophic lateral sclerosis; Exercise; Fn14; Metabolism; Sex; Skeletal muscle; TWEAK

DOI:  https://doi.org/10.1186/s13395-024-00356-0
EMBO J. 2024 Oct 18.

The mitochondrial long non-coding RNA lncMtloop regulates mitochondrial transcription and suppresses Alzheimer's disease.

Wandi Xiong, Kaiyu Xu, Jacquelyne Ka-Li Sun, Siling Liu, Baizhen Zhao, Jie Shi, Karl Herrup, Hei-Man Chow, Lin Lu, Jiali Li.

  Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3'UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer's pathogenesis.

Keywords:   lncMtDloop ; Alzheimer’s Disease; Mitochondrial Homeostasis; TFAM; mtDNA

DOI:  https://doi.org/10.1038/s44318-024-00270-7
Stem Cells Transl Med. 2024 Oct 14. pii: szae072. [Epub ahead of print]

Nose-to-brain delivery of stem cells in stroke: the role of extracellular vesicles.

Cesar V Borlongan, Jea-Young Lee, Francesco D'Egidio, Matthieu de Kalbermatten, Ibon Garitaonandia, Raphael Guzman.

  Stem cell transplantation offers a promising therapy that can be administered days, weeks, or months after a stroke. We recognize 2 major mitigating factors that remain unresolved in cell therapy for stroke, notably: (1) well-defined donor stem cells and (2) mechanism of action. To this end, we advance the use of ProtheraCytes, a population of non-adherent CD34+ cells derived from human peripheral blood and umbilical cord blood, which have been processed under good manufacturing practice, with testing completed in a phase 2 clinical trial in post-acute myocardial infarction (NCT02669810). We also reveal a novel mechanism whereby ProtheraCytes secrete growth factors and extracellular vesicles (EVs) that are associated with angiogenesis and vasculogenesis. Our recent data revealed that intranasal transplantation of ProtheraCytes at 3 days after experimentally induced stroke in adult rats reduced stroke-induced behavioral deficits and histological damage up to 28 days post-stroke. Moreover, we detected upregulation of human CD63+ EVs in the ischemic brains of stroke animals that were transplanted with ProtheraCytes, which correlated with increased levels of DCX-labeled neurogenesis and VEGFR1-associated angiogenesis and vasculogenesis, as well as reduced Iba1-marked inflammation. Altogether, these findings overcome key laboratory-to-clinic translational hurdles, namely the identification of well-characterized, clinical grade ProtheraCytes and the elucidation of a potential CD63+ EV-mediated regenerative mechanism of action. We envision that additional translational studies will guide the development of clinical trials for intranasal ProtheraCytes allografts in stroke patients, with CD63 serving as a critical biomarker.

Keywords:  angiogenesis; cell transplantation; cerebral ischemia; exosomes; functional recovery; inflammation; neurogenesis

DOI:  https://doi.org/10.1093/stcltm/szae072
Nat Commun. 2024 Oct 18. 15(1): 9008

Post-transcriptional methylation of mitochondrial-tRNA differentially contributes to mitochondrial pathology.

Sunita Maharjan, Howard Gamper, Yuka Yamaki, Thomas Christian, Robert Y Henley, Nan-Sheng Li, Takeo Suzuki, Tsutomu Suzuki, Joseph A Piccirilli, Meni Wanunu, Erin Seifert, Douglas C Wallace, Ya-Ming Hou.

Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases.

DOI: https://doi.org/10.1038/s41467-024-53318-x