bims-mitrat 2024-12-08 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–12–08
eleven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Autologous mitochondrial transplant for acute cerebral ischemia: Phase 1 trial results and review.
CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.
Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.
Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.
OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.
Enhancement of Mitochondrial Homeostasis: A Novel Approach to Attenuate Hypoxic Myocardial Injury.
Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.
Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.
Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.

J Cereb Blood Flow Metab. 2024 Dec 04. 271678X241305230

Autologous mitochondrial transplant for acute cerebral ischemia: Phase 1 trial results and review.

Melanie Walker, Michael R Levitt, Emma M Federico, Francisco Javier Miralles, Sam Hs Levy, Keiko Lynne Prijoles, Ashtyn Winter, Jennifer K Swicord, Yasemin Sancak.

  The results of a Phase 1 trial of autologous mitochondrial transplantation for the treatment of acute ischemic stroke during mechanical thrombectomy are presented. Standardized methods were used to isolate viable autologous mitochondria in the acute clinical setting, allowing for timely transplantation within the ischemic window. No significant adverse events were observed with the endovascular approach during reperfusion therapy. Safety outcomes in study participants were comparable to those of matched controls who did not undergo transplantation. This study represents the first use of mitochondrial transplantation in the human brain, highlighting specific logistical challenges related to the acute clinical setting, such as limited tissue samples and constrained time for isolation and transplantation. We also review the opportunities and challenges associated with further clinical translation of mitochondrial transplantation in the context of acute cerebral ischemia and beyond.

Keywords:  Clinical; ischemia; mitochondria; stroke; transplant; trial

DOI:  https://doi.org/10.1177/0271678X241305230
Stem Cell Res Ther. 2024 Dec 02. 15(1): 460

CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.

Huihui Fu, Xiaoqing Xie, Liuyue Zhai, Yi Liu, Yifeng Tang, Sanxiu He, Jun Li, Qing Xiao, Guofa Xu, Zailin Yang, Xiaomei Zhang, Yao Liu.

   BACKGROUND: Acute myeloid leukemia (AML) is characterized by abundant immature myeloid cells, relapse and refractory due to leukemia stem cells (LSCs). Bone marrow mesenchymal stem/ stromal cells (BMSCs) supported LSCs survival, meanwhile, chemotherapy improved connexin43 (CX43) expression. CX43, as the most intercellular gap junction, facilitated transmit mitochondria from BMSCs into AML. We hypothesized that increased mitochondria transferred from BMSCs supported metabolic remodeling in LSCs to sustain their stemness.
METHODS: Primary BMSCs from AML patients were isolated. CX43-BMSCs, overexpressing CX43, were cocultured with KG-1a cells. Fluorescence and confocal microscopy observed mitochondrial transfer. Flow cytometry, EdU assay, and clonogenicity evaluated cell cycle, proliferation, and clonogenic potential. Xenograft mouse models were used to evaluate the tumorigenicity of KG-1a in vivo. Seahorse, RNA-seq, and LC-MS assessed mitochondrial function, transcriptomes, and metabolites post-coculture.
RESULTS: CX43-BMSCs promoted unidirectional mitochondrial transfer, enhancing KG-1a adhesion and proliferation to maintain LSCs stemness in vitro and vivo. RNA-seq revealed coculture with CX43-BMSCs upregulated genes related to adhesion, proliferation, and migration in KG-1a cells. Elevated CX43 expression strengthened BMSCs-KG-1a interaction, facilitating mitochondrial transfer and nucleoside metabolism, fueling KG-1a cells. This enhanced mitochondrial energy metabolism, promoting metabolic reprogramming and clonogenicity.
CONCLUSION: CX43-mediated mitochondrial transfer from BMSCs to KG-1a enhances LSCs adhesion, proliferation, clonogenicity, and metabolic reprogramming. CX43 emerges as a potential therapeutic target for AML by sustaining LSCs stemness through metabolic remodeling.

Keywords:  Adhesion; Bone marrow microenvironment; Connexin; Leukemia stem cells; Metabolic remodeling; Mitochondrial transfer

DOI:  https://doi.org/10.1186/s13287-024-04079-3
Neurosci Biobehav Rev. 2024 Dec 03. pii: S0149-7634(24)00440-8. [Epub ahead of print] 105971

Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.

Aurélien Riou, Aline Broeglin, Amandine Grimm.

  Mitochondrial transplantation is a new treatment strategy aimed at repairing cellular damage by introducing healthy mitochondria into injured cells. The approach shows promise in protecting brain function in various neurological disorders such as traumatic brain injury/ischemia, neurodegenerative diseases, cognitive disorders, and cancer. These conditions are often characterized by mitochondrial dysfunction, leading to impaired energy production and neuronal death. The review highlights promising preclinical studies where mitochondrial transplantation has been shown to restore mitochondrial function, reduce inflammation, and improve cognitive and motor functions in several animal models. It also addresses significant challenges that must be overcome before this therapy can be clinically applied. Current efforts to overcome these challenges, including advancements in isolation techniques, cryopreservation methods, finding an appropriate mitochondria source, and potential delivery routes, are discussed. Considering the rising incidence of neurological disorders and the limited effectiveness of current treatments, this review offers a comprehensive overview of the current state of mitochondrial transplantation research and critically assesses the remaining obstacles. It provides valuable insights that could steer future studies and potentially lead to more effective treatments for various brain disorders.

Keywords:  Cognitive disorders; ischemia; mitochondrial transplantation; neurodegenerative diseases; traumatic brain injury

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105971
Aging Cell. 2024 Dec 04. e14386

Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.

Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Brent Appelman, Michèle van Vugt, Anita E Grootemaat, Nicole N van der Wel, Jos J de Koning, Frank W Bloemers, Rob C I Wüst.

  Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals. Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2.s-1.mg-1, p = 0.95) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%, p = 0.25), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U., p < 0.0001), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%, p = 0.002) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%, p = 0.005). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density. Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.

Keywords:  ageing; maximal oxygen uptake; mitochondrial morphology; mitochondrial respiration; skeletal muscle

DOI:  https://doi.org/10.1111/acel.14386
J Cachexia Sarcopenia Muscle. 2024 Dec 02.

Skeletal Muscle mRNA Splicing Variants Association With Four Different Fitness and Energetic Measures in the GESTALT Study.

Stefano Donega, Nirad Banskota, Esha Gupta, Marta Gonzalez-Freire, Ann Zenobia Moore, Ceereena Ubaida-Mohien, Rachel Munk, Linda Zukley, Yulan Piao, Chris Bergeron, Jan Bergeron, Arsun Bektas, Marta Zampino, Carole Stagg, Fred Indig, Lisa M Hartnell, Mary Kaileh, Kenneth Fishbein, Richard G Spencer, Myriam Gorospe, Supriyo De, Josephine M Egan, Ranjan Sen, Luigi Ferrucci.

   BACKGROUND: Physical activity is essential for maintaining muscle mitochondrial function and aerobic capacity. The molecular mechanisms underlying such protective effects are incompletely understood, in part because it is difficult to separate the effects of disease status and physical activity. We explored the association of human skeletal muscle transcriptomic with four measures of energetics and mitochondria oxidative capacity in healthy individuals.
METHODS: Using RNA sequencing of vastus lateralis muscle biopsies from 82 GESTALT participants (52 males, aged 22-89 years), we explored gene and splicing variant expression profiles associated with self-reported physical activity, peak oxygen consumption (VO2 peak), muscle oxidative capacity (kPCr) and mitochondrial respiration (Mit-O2 flux). The effect of aging on gene expression was examined in participants with low and high VO2 peak.
RESULTS: The four measures of energetics were negative correlated with age and generally intercorrelated. We identified protein-coding genes associated with four energetic measures adjusting for age, muscle fiber-ratio, sex and batch effect. Mitochondrial pathways were overrepresented across all energetic variables, albeit with little overlap at the gene level. Alternative spliced transcript isoforms associated with energetics were primarily enriched for cytoplasmic ribonucleoprotein granules. The splicing pathway was up-regulated with aging in low but not in high fitness participants, and transcript isoforms detected in the low fitness group pertain to processes such as cell cycle regulation, RNA/protein localization, nuclear transport and catabolism.
CONCLUSIONS: A consistent mitochondrial signature emerged across all energetic measures. Alternative splicing was enhanced in older, low fitness participants supporting the energy-splicing axis hypothesis. The identified splicing variants were enriched in pathways involving the accumulation of ribonucleoproteins in cytoplasmic granules, whose function remains unclear. Further research is needed to understand the function of these proteoforms in promoting adaptation to low energy availability.

Keywords:  VO2; aging; alternative splicing; energy; exercise; kPCr; mitochondria respirometry; muscle; physical activity

DOI:  https://doi.org/10.1002/jcsm.13603
Cell Death Dis. 2024 Nov 30. 15(11): 870

OPA1 and disease-causing mutants perturb mitochondrial nucleoid distribution.

J Macuada, I Molina-Riquelme, G Vidal, N Pérez-Bravo, C Vásquez-Trincado, G Aedo, D Lagos, P Yu-Wai-Man, R Horvath, T J Rudge, B Cartes-Saavedra, V Eisner.

Optic atrophy protein 1 (OPA1) mediates inner mitochondrial membrane (IMM) fusion and cristae organization. Mutations in OPA1 cause autosomal dominant optic atrophy (ADOA), a leading cause of blindness. Cells from ADOA patients show impaired mitochondrial fusion, cristae structure, bioenergetic function, and mitochondrial DNA (mtDNA) integrity. The mtDNA encodes electron transport chain subunits and is packaged into nucleoids spread within the mitochondrial population. Nucleoids interact with the IMM, and their distribution is tightly linked to mitochondrial fusion and cristae shaping. Yet, little is known about the physio-pathological relevance of nucleoid distribution. We studied the effect of OPA1 and ADOA-associated mutants on nucleoid distribution using high-resolution confocal microscopy. We applied a novel model incorporating the mitochondrial context, separating nucleoid distribution into the array in the mitochondrial population and intramitochondrial longitudinal distribution. Opa1-null cells showed decreased mtDNA levels and nucleoid abundance. Also, loss of Opa1 led to an altered distribution of nucleoids in the mitochondrial population, loss of cristae periodicity, and altered nucleoids to cristae proximity partly rescued by OPA1 isoform 1. Overexpression of WT OPA1 or ADOA-causing mutants c.870+5 G > A or c.2713 C > T in WT cells, showed perturbed nucleoid array in the mitochondria population associated with cristae disorganization, which was partly reproduced in Skeletal muscle-derived fibroblasts from ADOA patients harboring the same mutants. Opa1-null and cells overexpressing ADOA mutants accumulated mitochondria without nucleoids. Interestingly, intramitochondrial nucleoid distribution was only altered in Opa1-null cells. Altogether, our results highlight the relevance of OPA1 in nucleoid distribution in the mitochondrial landscape and at a single-organelle level and shed light on new components of ADOA etiology.

DOI: https://doi.org/10.1038/s41419-024-07165-9
Int J Med Sci. 2024 ;21(15): 2897-2911

Enhancement of Mitochondrial Homeostasis: A Novel Approach to Attenuate Hypoxic Myocardial Injury.

Zhijiang Guo, Yingjie Tian, Jing Gao, Bei Zhou, XiuTeng Zhou, Xing Chang, Hao Zhou.

  Cardiomyocytes are highly oxygen-dependent cells, relying on oxygen-driven oxidative phosphorylation to maintain their function. During hypoxia, mitochondrial ATP production decreases, leading to calcium overload, acidosis, and oxidative stress, which collectively trigger myocardial injury. Ischemic heart disease, caused by coronary atherosclerosis, results in myocardial ischemia and hypoxia, leading to ischemia-reperfusion (I/R) injury. Early myocardial injury is attributed to ischemia and hypoxia, but even after thrombolytic therapy, interventional surgery, or coronary artery bypass grafting (CABG) restores local blood flow and oxygen supply, myocardial reperfusion injury (I/R) may still occur. Mitochondria, often referred to as the "powerhouses" of the cell, play a crucial role in cellular energy production. In the early stages of ischemia and hypoxia, mitochondrial dysfunction disrupts mitochondrial homeostasis, causing the accumulation of unfolded or misfolded proteins in the mitochondria. This activates the mitochondrial unfolded protein response (mtUPR) and mitophagy, which work to clear damaged proteins and mitochondria, playing a key role during this period. This review focuses on mitochondrial mechanisms during the ischemic phase of ischemia-reperfusion injury, aiming to provide new theoretical foundations and potential therapeutic strategies to reduce myocardial damage.

Keywords:  hypoxic myocardial injury; mitophagy; unfolded protein response (UPR)

DOI:  https://doi.org/10.7150/ijms.103986
Nat Commun. 2024 Dec 04. 15(1): 10582

Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation.

Yating Liu, Qian Li, Guojing Tian, Xinyi Zhou, Panpan Chen, Bo Chen, Zhao Shan, Bin Qi.

All organisms depend on food digestion for survival, yet the brain-gut signaling mechanisms that regulate this process are not fully understood. Here, using an established C. elegans digestion model, we uncover a pathway in which neuronal ROS (free radicals) signal the intestine to suppress digestion. Genetic screening reveals that reducing genes responsible for maintaining ROS balance increases free radicals and decreases digestion. PRDX-2 knockout in olfactory neurons (AWC) elevates ROS and reduces digestive capacity, mediated by the neuropeptide NLP-1 and activation of the mitochondrial unfolded protein response (UPRmt) in the intestine. Additionally, over-expressing nlp-1 or ablating AWC neurons both trigger UPRmt and inhibit digestion. These findings reveal a brain-gut connection in which neuronal PRDX-2-mediated ROS signaling modulates food digestion, highlighting a critical role of free radicals in shutting down digestion to alleviate stress and reduce food consumption.

DOI: https://doi.org/10.1038/s41467-024-55013-3
Cell Metab. 2024 Dec 03. pii: S1550-4131(24)00418-2. [Epub ahead of print]36(12): 2491-2492

Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.

Andreas Carlström, Martin Ott.

Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.

DOI: https://doi.org/10.1016/j.cmet.2024.10.022
J Drug Target. 2024 Dec 02. 1-22

Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.

Lissette Sanchez-Aranguren, Mohamad Anas Al Tahan, Muhammad Uppal, Parag Juvale, Mandeep Kaur Marwah.

  Liposomes, as nanocarriers for therapeutics, are a prominent focus in translational medicine. Given their biocompatibility, liposomes are suitable drug delivery systems rendering highly efficient therapeutic outcomes with minimal off-site toxicity. In different scenarios of human disease, it is essential not only to maintain therapeutic drug levels but also to target them to the appropriate intracellular compartment. Mitochondria regulate cellular signalling, calcium balance, and energy production, playing a crucial role in various human diseases. The notion of focusing on mitochondria for targeted drug delivery was proposed several decades ago, yet the practical application of this idea and its translation to clinical use is still in development. Mitochondrial-targeted liposomes offer an alternative to standard drug delivery systems, potentially reducing off-target interactions, side effects, and drug dosage or frequency. . To advance this field, it is imperative to integrate various disciplines such as efficient chemical design, pharmacology, pharmaceutics, and cell biology. This review summarises scientific advances in the design, development and characterisation of novel liposome-based drug delivery systems targeting the mitochondria while revisiting their translational potential.

Keywords:  liposomes; mitochondria; mitochondrial dysfunction; nanocarriers; targeted drug delivery

DOI:  https://doi.org/10.1080/1061186X.2024.2437440
Biochim Biophys Acta Bioenerg. 2024 Nov 29. pii: S0005-2728(24)00498-5. [Epub ahead of print]1866(1): 149528

Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.

Cristina Algieri, Antonia Cugliari, Patrycja Anna Glogowski, Silvia Granata, Micaela Fabbri, Fabiana Trombetti, Maria Laura Bacci, Salvatore Nesci.

  The inside-out submitochondrial particles (IO-SMPs) showed a strong protective effect against mitochondrial permeability transition pore (mPTP) opening in mitochondria isolated from swine hearts 3 h after explantation. The latter condition was used to emulate situation of mitochondrial damage. We identified that the protective effect of IO-SMPs cannot be attributed to a functional modulation of the enzymatic complexes involved in mPTP formation. Indeed, oxidative phosphorylation and F1FO-ATPase activity were not affected. Conversely, mPTP desensitization might be caused by structural modification. IO-SMP incorporation into the mitochondria can modulate the membrane-bound enzyme complexes' functionality, inducing F1FO-ATPase to be unable to carry out the conformational changes useful for mPTP opening. Thus, the data are a valid starting point for IO-SMP application in the treatment of impaired cardiovascular conditions supported by mPTP opening.

Keywords:  F(1)F(O)-ATPase; Inside-out submitochondrial particles; Mitochondrial dysfunction; Mitochondrial permeability transition pore

DOI:  https://doi.org/10.1016/j.bbabio.2024.149528