bims-mitmed 2025-01-05 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–01–05
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Reduced ATP turnover during hibernation in relaxed skeletal muscle.
Mitochondrial transplantation normalizes transcriptomic and proteomic shift associated with ischemia reperfusion injury in neonatal hearts donated after circulatory death.
Molecular basis of human nuclear and mitochondrial tRNA 3' processing.
E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development.
Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.
Loss of Mfn1 but not Mfn2 enhances adipogenesis.
Mitochondrial epigenetics brings new perspectives on doubly uniparental inheritance in bivalves.
The relationship between mitochondrial health, telomerase activity and longitudinal telomere attrition, considering the role of chronic stress.
Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review.
Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.
Pantothenate kinase 4 controls skeletal muscle substrate metabolism.
Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis.
Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.
DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.
Basic Science and Pathogenesis.
Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
Basic Science and Pathogenesis.
Mitochondrial transplantation reconstructs the oxidative microenvironment within fibroblasts to reverse photoaging.
CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.

Nat Commun. 2025 Jan 02. 16(1): 80

Reduced ATP turnover during hibernation in relaxed skeletal muscle.

Cosimo De Napoli, Luisa Schmidt, Mauro Montesel, Laura Cussonneau, Samuele Sanniti, Lorenzo Marcucci, Elena Germinario, Jonas Kindberg, Alina Lynn Evans, Guillemette Gauquelin-Koch, Marco Narici, Fabrice Bertile, Etienne Lefai, Marcus Krüger, Leonardo Nogara, Bert Blaauw.

Hibernating brown bears, due to a drastic reduction in metabolic rate, show only moderate muscle wasting. Here, we evaluate if ATPase activity of resting skeletal muscle myosin can contribute to this energy sparing. By analyzing single muscle fibers taken from the same bears, either during hibernation or in summer, we find that fibers from hibernating bears have a mild decline in force production and a significant reduction in ATPase activity. Single fiber proteomics, western blotting, and immunohistochemical analyses reveal major remodeling of the mitochondrial proteome during hibernation. Furthermore, using bioinformatical approaches and western blotting we find that phosphorylated myosin light chain, a known stimulator of basal myosin ATPase activity, is decreased in hibernating and disused muscles. These results suggest that skeletal muscle limits energy loss by reducing myosin ATPase activity, indicating a possible role for myosin ATPase activity modulation in multiple muscle wasting conditions.

DOI: https://doi.org/10.1038/s41467-024-55565-4
Sci Rep. 2024 12 28. 14(1): 31236

Mitochondrial transplantation normalizes transcriptomic and proteomic shift associated with ischemia reperfusion injury in neonatal hearts donated after circulatory death.

Ilias P Doulamis, Aspasia Tzani, Victor S Alemany, Rio S Nomoto, Aybuke Celik, Dominic P Recco, Mossab Y Saeed, Alvise Guariento, Jorge Plutzky, Sitaram M Emani, Pedro J Del Nido, James D McCully.

  Heart transplantation remains the ultimate treatment strategy for neonates and children with medically refractory end-stage heart failure and utilization of donors after circulatory death (DCD) can expand th donor pool. We have previously shown that mitochondrial transplantation preserves myocardial function and viability in neonatal swine DCD hearts to levels similar to that observed in donation after brain death (DBD). Herein, we sought to investigate the transcriptomic and proteomic pathways implicated in these phenotypic changes using ex situ perfused swine hearts. Pathway analysis showed that ATP binding, voltage-gated K channel activity involved in cardiac cell muscle contraction and ribosomal RNA biogenesis were upregulated in the mitochondrial transplantation group, while mitochondria were the predicted source. Promotion of ribosome biogenesis and downregulation of apoptosis were the overlapping mechanisms between transcriptomic and proteomic alterations. Moreover, we showed that mitochondrial transplantation modulates ischemic transcriptomic and proteomic profiles to that of non-ischemia through the mitochondria. Replication of these findings in human in vivo experiments is warranted.

Keywords:  Donation after cardiac death; Ex situ heart perfusion; Mitochondrial transplantation; Neonatal; Proteomic; RNA sequencing

DOI:  https://doi.org/10.1038/s41598-024-82578-2
Nat Struct Mol Biol. 2025 Jan 02.

Molecular basis of human nuclear and mitochondrial tRNA 3' processing.

Arjun Bhatta, Bernhard Kuhle, Ryan D Yu, Lucas Spanaus, Katja Ditter, Katherine E Bohnsack, Hauke S Hillen.

Eukaryotic transfer RNA (tRNA) precursors undergo sequential processing steps to become mature tRNAs. In humans, ELAC2 carries out 3' end processing of both nucleus-encoded (nu-tRNAs) and mitochondria-encoded (mt-tRNAs) tRNAs. ELAC2 is self-sufficient for processing of nu-tRNAs but requires TRMT10C and SDR5C1 to process most mt-tRNAs. Here we show that TRMT10C and SDR5C1 specifically facilitate processing of structurally degenerate mt-tRNAs lacking the canonical elbow. Structures of ELAC2 in complex with TRMT10C, SDR5C1 and two divergent mt-tRNA substrates reveal two distinct mechanisms of pre-tRNA recognition. While canonical nu-tRNAs and mt-tRNAs are recognized by direct ELAC2-RNA interactions, processing of noncanonical mt-tRNAs depends on protein-protein interactions between ELAC2 and TRMT10C. These results provide the molecular basis for tRNA 3' processing in both the nucleus and the mitochondria and explain the organelle-specific requirement for additional factors. Moreover, they suggest that TRMT10C-SDR5C1 evolved as a mitochondrial tRNA maturation platform to compensate for the structural erosion of mt-tRNAs in bilaterian animals.

DOI: https://doi.org/10.1038/s41594-024-01445-w
Nat Commun. 2025 Jan 02. 16(1): 67

E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development.

Michela Di Michele, Aurore Attina, Pierre-François Roux, Imène Tabet, Sophie Laguesse, Javier Florido, Morane Houdeville, Armelle Choquet, Betty Encislai, Giuseppe Arena, Carlo De Blasio, Olivia Wendling, François-Xavier Frenois, Laura Papon, Lucille Stuani, Maryse Fuentes, Céline Jahannault Talignani, Mélanie Rousseau, Justine Guégan, Yoan Buscail, Pierrick Dupré, Henri-Alexandre Michaud, Geneviève Rodier, Floriant Bellvert, Hanna Kulyk, Carole Ferraro Peyret, Hugo Mathieu, Pierre Close, Francesca Rapino, Cédric Chaveroux, Nelly Pirot, Lucie Rubio, Adeline Torro, Tania Sorg, Fabrice Ango, Christophe Hirtz, Vincent Compan, Elise Lebigot, Andrea Legati, Daniele Ghezzi, Laurent Nguyen, Alexandre David, Claude Sardet, Matthieu Lacroix, Laurent Le Cam.

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

DOI: https://doi.org/10.1038/s41467-024-55444-y
Nat Commun. 2024 Dec 30. 15(1): 10815

Structural insights into GrpEL1-mediated nucleotide and substrate release of human mitochondrial Hsp70.

Marc A Morizono, Kelly L McGuire, Natalie I Birouty, Mark A Herzik.

Maintenance of protein homeostasis is necessary for cell viability and depends on a complex network of chaperones and co-chaperones, including the heat-shock protein 70 (Hsp70) system. In human mitochondria, mitochondrial Hsp70 (mortalin) and the nucleotide exchange factor (GrpEL1) work synergistically to stabilize proteins, assemble protein complexes, and facilitate protein import. However, our understanding of the molecular mechanisms guiding these processes is hampered by limited structural information. To elucidate these mechanistic details, we used cryoEM to determine structures of full-length human mortalin-GrpEL1 complexes in previously unobserved states. Our structures and molecular dynamics simulations allow us to delineate specific roles for mortalin-GrpEL1 interfaces and to identify steps in GrpEL1-mediated nucleotide and substrate release by mortalin. Subsequent analyses reveal conserved mechanisms across bacteria and mammals and facilitate a complete understanding of sequential nucleotide and substrate release for the Hsp70 chaperone system.

DOI: https://doi.org/10.1038/s41467-024-54499-1
PLoS One. 2024 ;19(12): e0306243

Loss of Mfn1 but not Mfn2 enhances adipogenesis.

Jake P Mann, Luis Carlos Tábara, Satish Patel, Pushpa Pushpa, Anna Alvarez-Guaita, Liang Dong, Afreen Haider, Koini Lim, Panna Tandon, Fabio Scurria, James E N Minchin, Stephen O'Rahilly S, Daniel J Fazakerley, Julien Prudent, Robert K Semple, David B Savage.

OBJECTIVE: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells.
METHODS: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.
RESULTS: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.
CONCLUSIONS: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.

DOI: https://doi.org/10.1371/journal.pone.0306243
Sci Rep. 2024 Dec 28. 14(1): 31544

Mitochondrial epigenetics brings new perspectives on doubly uniparental inheritance in bivalves.

Émélie Leroux, Hajar Hosseini Khorami, Annie Angers, Bernard Angers, Sophie Breton.

  Mitochondrial epigenetics, particularly mtDNA methylation, is a flourishing field of research. MtDNA methylation appears to play multiple roles, including regulating mitochondrial transcription, cell metabolism and mitochondrial inheritance. In animals, bivalves with doubly uniparental inheritance (DUI) of mitochondria are the exception to the rule of maternal mitochondrial inheritance since DUI also involve a paternal mtDNA transmitted from the father to sons. The mechanisms underlying DUI are still unknown, but mtDNA methylation could play a role in its regulation. Here, we investigated mtDNA methylation levels and machinery in gonads of the mussel Mytilus edulis using methods based on antibodies, enzymatic cleavage and methylome sequencing. Our results confirm the presence in mitochondria of methylated cytosines and adenines and methyltransferases and unveil a more variable cytosine methylation state among males than females. Also, spermatid mtDNA is always methylated, while only few spermatozoa present methylated mtDNA suggesting a relation between cytosine methylation and development stage of male gametes. We propose that mtDNA methylation could play a role in the different fates of the parental mtDNAs in male and female embryos in M. edulis. Our study provides novel insights into the epigenetic landscape of bivalve mtDNA and highlights the multiple roles of mtDNA methylation in animals.

Keywords:  Bivalves; Gametes; Methyltransferases; Mitochondria; Mitochondrial inheritance; MtDNA methylation

DOI:  https://doi.org/10.1038/s41598-024-83368-6
Sci Rep. 2024 Dec 30. 14(1): 31589

The relationship between mitochondrial health, telomerase activity and longitudinal telomere attrition, considering the role of chronic stress.

Mauricio Guillen-Parra, Jue Lin, Aric A Prather, Owen M Wolkowitz, Martin Picard, Elissa S Epel.

  Telomere attrition is a hallmark of biological aging, contributing to cellular replicative senescence. However, few studies have examined the determinants of telomere attrition in vivo in humans. Mitochondrial Health Index (MHI), a composite marker integrating mitochondrial energy-transformation capacity and content, may be one important mediator of telomere attrition, as it could impact telomerase activity, a direct regulator of telomere maintenance. In this observational longitudinal study, we examined in peripheral blood mononuclear cells (PBMCs), whether MHI predicted changes in telomerase activity over a 9-month period, thus impacting telomere maintenance over this same period of time. We secondarily examined the role of chronic stress, by comparing these relationships in mothers of children with an autism spectrum disorder (caregivers) vs. mothers of a neurotypical child (controls). Here we show that both chronic stress exposure and lower MHI independently predicted decreases in telomerase activity over the subsequent 9 months. Finally, changes in telomere length were directly related with changes in telomerase activity, and indirectly with MHI and chronic stress, as revealed by a path analysis. These results highlight the potential role of chronic stress and MHI as drivers of telomere attrition in human PBMCs, through an impairment of both energy-transformation capacity and telomerase production.

Keywords:  Chronic stress; Mitochondrial health; Telomerase activity; Telomere attrition

DOI:  https://doi.org/10.1038/s41598-024-77279-9
Orphanet J Rare Dis. 2024 Dec 30. 19(1): 495

Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review.

Ankita Umrao, Monika Pahuja, Nabendu Sekhar Chatterjee.

   BACKGROUND: Friedreich's ataxia (FA) is a rare genetic disorder caused by silencing of the frataxin gene (FXN), which leads to multiorgan damage. Nrf2 is a regulator of FXN, which is a modulator of oxidative stress in animals and humans. Omaveloxolone (Omav) is an Nrf2 activator and has been reported to have antioxidative potential in various disease conditions. The present review was conducted to determine the use of Omav, the only FDA-approved treatment for FA.
METHODS: Three electronic databases, Cochrane, PubMed and Google Scholar, were searched with terms such as 'Omaveloxolone', 'Friedreich ataxia', 'genetic diseases', 'autosomal recessive', and 'rare disorders' using various advanced search filters. Articles were screened, extracted, and assessed for quality, and a qualitative synthesis of the data was performed. The study protocol was registered in PROSPERO (CRD42024531449).
RESULTS: A total of 201 records were found, with very few published research articles on the topic. Only two randomized clinical trials published in a series of three research articles were included in the current systematic review. Peak load exercise and modified Friedreich's Ataxia Rating Scale (mFARS) values were considered the major outcome measures for determining the efficacy of 150 mg Omav capsules/day in FA. Exploratory outcome measures, such as low-contrast letter visual acuity test, exercise test, T25-FW, 9-HPT, health-related quality of life, and biochemical tests, were also assessed along with adverse events in all the studies.
CONCLUSION: Although, the quality of the articles demonstrated low bias. However, the short duration, small sample size, and missing data, including the values of different measures of mFARS scores in patients, limit the generalizability of the results. Further studies with longer durations and in severe patients with foot deformities are needed to clearly define the efficacy of Omav in FA and to determine the optimal drug for FA patients in India.

Keywords:  Friedreich’s ataxia; Omaveloxolone; Randomized clinical trials; Rare disease; Systematic review; mFARS

DOI:  https://doi.org/10.1186/s13023-024-03474-6
J Transl Med. 2024 Dec 31. 22(1): 1160

Targeting mitochondrial transfer: a new horizon in cardiovascular disease treatment.

Baile Zuo, Xiaoyan Li, Dawei Xu, Liping Zhao, Yang Yang, Yi Luan, Bi Zhang.

  Cardiovascular diseases (CVDs) are the leading cause of mortality among individuals with noncommunicable diseases worldwide. Obesity is associated with an increased risk of developing cardiovascular disease (CVD). Mitochondria are integral to the cardiovascular system, and it has been reported that mitochondrial transfer is associated with the pathogenesis of multiple CVDs and obesity. This review offers a comprehensive examination of the relevance of mitochondrial transfer to cardiovascular health and disease, emphasizing the critical functions of mitochondria in energy metabolism and signal transduction within the cardiovascular system. This highlights how disruptions in mitochondrial transfer contribute to various CVDs, such as myocardial infarction, cardiomyopathies, and hypertension. Additionally, we provide an overview of the molecular mechanisms governing mitochondrial transfer and its potential implications for CVD treatment. This finding underscores the therapeutic potential of mitochondrial transfer and addresses the various mechanisms and challenges in its implementation. By delving into mitochondrial transfer and its targeted modulation, this review aims to advance our understanding of cardiovascular disease treatment, presenting new insights and potential therapeutic strategies in this evolving field.

Keywords:  Cardiomyopathies; Cardiovascular diseases; Mitochondrial transfer; Myocardial infarction; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12967-024-05979-x
Nat Commun. 2025 Jan 02. 16(1): 345

Pantothenate kinase 4 controls skeletal muscle substrate metabolism.

Adriana Miranda-Cervantes, Andreas M Fritzen, Steffen H Raun, Ondřej Hodek, Lisbeth L V Møller, Kornelia Johann, Luisa Deisen, Paul Gregorevic, Anders Gudiksen, Anna Artati, Jerzy Adamski, Nicoline R Andersen, Casper M Sigvardsen, Christian S Carl, Christian T Voldstedlund, Rasmus Kjøbsted, Stefanie M Hauck, Peter Schjerling, Thomas E Jensen, Alberto Cebrian-Serrano, Markus Jähnert, Pascal Gottmann, Ingo Burtscher, Heiko Lickert, Henriette Pilegaard, Annette Schürmann, Matthias H Tschöp, Thomas Moritz, Timo D Müller, Lykke Sylow, Bente Kiens, Erik A Richter, Maximilian Kleinert.

Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.

DOI: https://doi.org/10.1038/s41467-024-55036-w
Nat Metab. 2025 Jan 02.

Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis.

Ying Peng, Liangjie Jia, Xiao Hu, Xiaoliu Shi, Xinlei Fang, Yifu Qiu, Zhenji Gan, Yiguo Wang.

Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity. Mechanistically, we found that AMP-activated protein kinase (AMPK) phosphorylates cFeimin and facilitates its translocation into the cell nucleus during exercise. Within the nucleus, cFeimin binds to the forkhead transcription factor FOXC2, leading to the suppressed expression of sarcolipin (Sln), which is a key regulator of muscle thermogenesis. In addition, our results further reveal that short-term AMPK agonist treatments can enhance exercise performance through the activation of the AMPK-cFeimin signalling pathway. In summary, these results underscore the crucial role of cFeimin in enhancing exercise performance by modulating SLN-mediated thermogenesis.

DOI: https://doi.org/10.1038/s42255-024-01176-8
Front Aging Neurosci. 2024 ;16 1517965

Mitochondrial dysfunction and Alzheimer's disease: pathogenesis of mitochondrial transfer.

Yun Wei, Xinlei Du, Hongling Guo, Jingjing Han, Meixia Liu.

  In recent years, mitochondrial transfer has emerged as a universal phenomenon intertwined with various systemic physiological and pathological processes. Alzheimer's disease (AD) is a multifactorial disease, with mitochondrial dysfunction at its core. Although numerous studies have found evidence of mitochondrial transfer in AD models, the precise mechanisms remain unclear. Recent studies have revealed the dynamic transfer of mitochondria in Alzheimer's disease, not only between nerve cells and glial cells, but also between nerve cells and glial cells. In this review, we explore the pathways and mechanisms of mitochondrial transfer in Alzheimer's disease and how these transfer activities contribute to disease progression.

Keywords:  AD treatment; Alzheimer’s disease; mitochondrial dysfunction; mitochondrial transfer; neuroprotection

DOI:  https://doi.org/10.3389/fnagi.2024.1517965
Nat Commun. 2024 Dec 30. 15(1): 10806

DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.

Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-54982-9
Alzheimers Dement. 2024 Dec;20 Suppl 1 e091641

Basic Science and Pathogenesis.

Keith P Smith, Taylor A Strope, Brittany M Hauger, Colton R Lysaker, Cynthia Shaddy-Gouvion, Mohammad Haeri, Elizabeth Head, Russell H Swerdlow, Heather M Wilkins.

BACKGROUND: Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). However, the role of these pathologies in Down Syndrome associated Alzheimer's Disease (DSAD) is unknown. Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), from which Aβ is generated, is found in mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. How these interactions contribute to DSAD pathology and progression are unknown. Here we interrogated the association of full-length APP with mitochondria, mitochondrial function, and AD pathological hallmarks.
METHOD: ND (n = 10, without DS) and DS associated Alzheimer's Disease (DSAD, n = 10) postmortem brain tissue was obtained from the University of California Irvine. A human iPSC line was purchased from WiCell with Trisomy 21 and a isogenic control line which underwent Crispr/Cas9 genome editing to remove the extra chromosome 21 copy. iPSC models were differentiated into neurons, astrocytes, and cerebral organoids using StemCell Technologies reagents and protocols. We examined mitochondrial function using a Seahorse XF analyzer. We measured full-length APP protein levels in whole cell extracts and mitochondrial fractions via Western Blotting. We measured Aβ levels with ELISA kits from ThermoFisher.
RESULT: DSAD postmortem brain tissue had reduced mitochondrial function regardless of sex. Full-length APP levels were significantly higher in mitochondrial fractions in DSAD brain tissue. Full-length APP levels in mitochondrial fractions correlated with mitochondrial function. Higher mitochondrial APP (full-length) levels associated with lower mitochondrial function. iPSC derived models showed similar phenotypes to postmortem brain tissues, including increased mitochondrial APP levels, and decreased mitochondrial function.
CONCLUSION: We describe a relationship between mitochondrial APP accumulation, and mitochondrial function. These data support a centralized role for mitochondrial function in APP physiology and APP may play a role in modulating mitochondrial function. Further, DSAD postmortem tissue and iPSC models show significant mitochondrial dysfunction.

DOI: https://doi.org/10.1002/alz.091641
Nat Commun. 2024 Dec 30. 15(1): 10786

Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.

Qu Tian, Erin E Greig, Christos Davatzikos, Bennett A Landman, Susan M Resnick, Luigi Ferrucci.

Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, kPCr) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher kPCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration.

DOI: https://doi.org/10.1038/s41467-024-55009-z
Alzheimers Dement. 2024 Dec;20 Suppl 1 e087688

Basic Science and Pathogenesis.

Sara Bermudez, Junghyun Choi, Sunghoon Kim, Jacob W Vogel, Niaz Mahmood, Vivian Yuchan Zhu, Moein L Yaqubi, Jo Anne Stratton, Oskar Hansson, Argel Aguilar Valles, Luke M Healy, Nahum Sonenberg.

BACKGROUND: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022). mTOR complex 1 (mTORC1) inhibits the translation repressors, eukaryotic translation Initiation Factor 4E (eIF4E)-Binding Proteins (4E-BPs), via phosphorylation, which causes their release from eIF4E to promote mRNA translation (Hay and Sonenberg, 2004). mTORC1 promotes mitochondrial biogenesis via inhibition of 4E-BPs, by preferentially stimulating the translation of mitochondria-related mRNAs (Gandin et al., 2016; Morita et al., 2013). We investigated the mechanisms at the intersection of 4E-BP-dependent translational regulation and metabolism in microglial response to soluble Aβ.
METHOD: We carried out immunoblot analysis to investigate the phosphorylation status of 4E-BP1, the isoform most abundant in microglia, following exposure to Ab. We manipulated the mTOR pathway by knocking out the downstream effectors, 4E-BPs, to alleviate translation suppression in microglia in vitro and in vivo. We crossed the microglia-specific 4E-BPs knockout mouse with a RiboTag mouse to pull-down ribosome-bound mRNAs, providing a genome-wide pool of actively translating mRNAs in the absence or presence of 4E-BPs. Finally, we examined the relationship between 4E-BP1 levels and neuroinflammation markers in cerebrospinal fluid (CSF) of AD patients.
RESULT: We showed that 4E-BP1 is inhibited acutely upon exposure to soluble Ab, which is dependent on Spleen Tyrosine Kinase (SYK) activation upstream of mTORC1, but is reduced upon chronic exposure. Furthermore, 4E-BP1 expression is induced during prolonged exposure to Ab. The deletion of 4E-BPs in microglia in vitro leads to an increase in mitochondrial mass and reliance on oxidative phosphorylation while decreasing expression of pro-inflammatory mediators and cell death upon exposure to Ab. We observed that increased levels of 4E-BP1 in the CSF of patients with Aβ pathology are associated with higher neurodegeneration (Nfl) in the presence of microglial activation.
CONCLUSION: We demonstrate that mTORC1 signaling critically impacts microglia physiology and promotes neuroprotective functions via 4E-BP1 inhibition. 4E-BP1 activity in microglia engenders a dysfunctional or detrimental state that may lead to increased neurodegeneration. Therefore, 4E-BP1 is an attractive target for microglia modulation in AD.

DOI: https://doi.org/10.1002/alz.087688
Biochem Biophys Res Commun. 2024 Dec 18. pii: S0006-291X(24)01750-9. [Epub ahead of print]745 151214

Mitochondrial transplantation reconstructs the oxidative microenvironment within fibroblasts to reverse photoaging.

Zihan Lu, Wenhui Zhang, Simo Wu, Kai Qi, Simin Zhu, Xiao Zhang, Yicheng Chen, Xi Chen, Yunpeng Li, Fuwei Liu, Liang Kong.

  Fibroblast-mediated oxidative stress is a pivotal factor in the pathogenesis of skin photoaging, predominantly induced by UVA radiation. Diverging from traditional strategies that concentrate on the reduction of reactive oxygen species (ROS), the present study implements mitochondrial transplantation as an innovative therapeutic approach. The objective of this study is to reestablish the oxidative microenvironment and to effectively rejuvenate cellular functionality through the direct introduction of healthy and vibrant mitochondria. In vitro assays have illustrated that the seamless incorporation of exogenous mitochondria into fibroblasts ameliorates UVA radiation perturbations in membrane potential and oxidative stress, while simultaneously reestablishing the oxidative microenvironment. These interventions exert salutary influences on cellular proliferation and migratory capabilities. Subsequent in vivo analyses reveal a mitigation in dermal collagen depletion, alongside an enhancement in collagen fiber density and tissue architecture post-mitochondrial transplantation, thus ameliorating the manifestations of skin photoaging. Collectively, the study underscores the potential of mitochondrial transplantation as a promising therapeutic intervention for the reversal of skin photoaging by modulating the oxidative microenvironment within fibroblasts.

Keywords:  Fibroblasts; Mitochondrial transplantation; Oxidative stress; Photoaging; Ultraviolet a (UVA)

DOI:  https://doi.org/10.1016/j.bbrc.2024.151214
Am J Physiol Cell Physiol. 2024 Dec 31.

CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.

Guiyin Zhu, Haiyang Yu, Xiaoming Li, Wenjing Ye, Xi Chen, Wen Gu.

  CD147 has the potential to serve as a specific target with therapeutic characteristics in several respiratory diseases. Studies have demonstrated that CD147 regulates levels of oxidative phosphorylation (OXPHOS) through the process of mitochondrial translocations. However, there is still limited insight in the distinct mechanism of CD147 in asthmatic macrophages. Here, we found that CD147 expression levels increased significantly both in vivo and in vitro. CD147 undergoes mitochondrial translocation in M2 macrophages. Reducing the expression of CD147 resulted in a decline in M2 polarization levels within macrophages, as well as a decrease in the levels of mitochondrial respiratory chain complex I, II, and IV proteins. This effect may be attained by interacting with ANT1, subsequently impacting the levels of mitophagy. We also discovered that CD147 knockdown significantly reduced airway remodeling and inflammation in addition to lowering the polarization level of M2 in the lung tissues of chronic asthmatic model mice. The findings represent the first evidence of the distinct function of CD147 in the process of airway remodeling in asthma.

Keywords:  CD147; M2 polarization; airway remodeling; macrophages; mitochondrial translocation

DOI:  https://doi.org/10.1152/ajpcell.00735.2024