bims-mitmed 2023-09-24 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–09–24
thirty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of the phenotype.
Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.
Molecular basis for maternal inheritance of human mitochondrial DNA.
MYC-an emerging player in mitochondrial diseases.
Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.
Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.
Mitochondrial protein and organelle quality control-Lessons from budding yeast.
Development of a novel in vitro model to study the modulatory role of the respiratory complex I in macrophage effector functions.
Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches.
Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
Cardiolipin deficiency leads to the destabilization of mitochondrial magnesium channel MRS2 in Barth syndrome.
Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells.
Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
Mitochondrial disease in New Zealand: a nationwide prevalence study.
Yeast mitochondria can process de novo designed β-barrel proteins.
Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice.
Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application.
Metabolic control of antitumor immunity.
TORC1 mediated regulation of mitochondrial integrity and calcium ion homeostasis by Wat1/mLst8 in S. pombe.
The Constraints of Allotopic Expression.
Generation of embryo-like structures from mouse embryonic stem cells treated with a chemical inhibitor of SUMOylation and cultured in microdroplets.
The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.
Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism.
The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease.
Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder.
Higher incidence of embryonic defects in mouse offspring conceived with assisted reproduction from fathers with sperm Epimutations.
Maternal and paternal obesity differentially reprogram the ovarian mitochondrial biogenesis of F1 female rats.
Expressions of mitochondria-related genes in pregnant women with subclinical hypothyroidism, and expressions of miRNAs in maternal and cord blood.
Platelet mitochondria, a potent immune mediator in neurological diseases.

Ultrasound Obstet Gynecol. 2023 Sep 18.

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of the phenotype.

D Brabbing-Goldstein, D Kozlova, L Bazak, L Basel-Salmon, Y Gilboa, I Marciano-Levi, J Zahra, B Kanengisser-Pines, A Botvinik, A Kurolap, R Birnbaum, Y Yaron.

   OBJECTIVES: Mitochondrial complex I deficiency, nuclear type 16 is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) [OMIM 618238]. This entity belongs to a genetically and clinically heterogenic group of complex I deficiency which accounts for up to 30% of childhood mitochondrial disorders presenting as Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, and other early-onset neurodegenerative disorders. We present very early, unique, and severe prenatal manifestation of this disorder, previously considered to manifest post-natally.
METHODS: We describe five fetuses from three non-related families sharing common sonographic abnormalities including brain cysts, callosal malformations, hydrops fetalis, and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from one family were also available for pathology examination, including electronic microscopy.
RESULTS: Chromosomal microarray revealed no chromosomal abnormalities. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygotes or homozygotes for likely pathogenic variants in NDUFAF5. No other causative variants were detected. NDUFAF5 variants association with fetal malformations was further confirmed by segregation studies. Histologic evaluation of fetal tissues and electronic microscopy of muscle, liver, proximal tubules of kidney and heart, demonstrated changes resembling those described in postmortem autopsies of patients with mitochondrial depletion disorders as well as previously undescribed findings.
CONCLUSIONS: Mitochondrial complex I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development presenting with severe congenital malformations. Complex I mitochondrial disorders should be considered in the differential diagnosis of callosal malformations and brain cysts, especially when associated with extra central nervous system (CNS) abnormalities such as fetal growth restriction or nonimmune hydrops fetalis. This article is protected by copyright. All rights reserved.

Keywords:  Brain cysts; Corpus Callosum; Hydrops Fetalis, FGR, Exome sequencing, complex I deficiency; NDUFAF5

DOI:  https://doi.org/10.1002/uog.27482
Nat Commun. 2023 09 18. 14(1): 5781

Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.

Ting Huang, Ruyi Lin, Yuanqin Su, Hao Sun, Xixi Zheng, Jinsong Zhang, Xiaoyan Lu, Baiqin Zhao, Xinchi Jiang, Lingling Huang, Ni Li, Jing Shi, Xiaohui Fan, Donghang Xu, Tianyuan Zhang, Jianqing Gao.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.

DOI: https://doi.org/10.1038/s41467-023-41529-7
Nat Genet. 2023 Sep 18.

Molecular basis for maternal inheritance of human mitochondrial DNA.

William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.

DOI: https://doi.org/10.1038/s41588-023-01505-9
Front Cell Dev Biol. 2023 ;11 1257651

MYC-an emerging player in mitochondrial diseases.

Janne Purhonen, Juha Klefström, Jukka Kallijärvi.

  The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.

Keywords:  Warburg effect; cellular senescence; electron transport chain; mitochondrial integrated stress response; oxidative phosphorylation; respiratory complex III

DOI:  https://doi.org/10.3389/fcell.2023.1257651
J Med Genet. 2023 Sep 21. pii: jmg-2023-109340. [Epub ahead of print]

Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.

Claudio Fiorini, Andrea Degiorgi, Maria Lucia Cascavilla, Concetta Valentina Tropeano, Chiara La Morgia, Marco Battista, Danara Ormanbekova, Flavia Palombo, Michele Carbonelli, Francesco Bandello, Valerio Carelli, Alessandra Maresca, Piero Barboni, Enrico Baruffini, Leonardo Caporali.

   BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30, NDUFS2 and MCAT. MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities.
METHODS: We studied through whole exome sequencing two sisters affected by sudden and painless visual loss at young age, with partial recovery and persistent central scotoma. We modelled the candidate variant in yeast and studied mitochondrial dysfunction in yeast and fibroblasts. We tested protein lipoylation and cell response to oxidative stress in yeast.
RESULTS: Both sisters carried a homozygous pathogenic variant in MECR (p.Arg258Trp). In yeast, the MECR-R258W mutant showed an impaired oxidative growth, 30% reduction in oxygen consumption rate and 80% decrease in protein levels, pointing to structure destabilisation. Fibroblasts confirmed the reduced amount of MECR protein, but failed to reproduce the OXPHOS defect. Respiratory complexes assembly was normal. Finally, the yeast mutant lacked lipoylation of key metabolic enzymes and was more sensitive to H2O2 treatment. Lipoic Acid supplementation partially rescued the growth defect.
CONCLUSION: We report the first family with homozygous MECR variant causing an LHON-like optic neuropathy, which pairs the recent MCAT findings, reinforcing the impairment of mtFAS as novel pathogenic mechanism in LHON.

Keywords:  Genetics, Medical; Neuromuscular Diseases; Ophthalmology

DOI:  https://doi.org/10.1136/jmg-2023-109340
J Biomed Sci. 2023 Sep 22. 30(1): 82

Induced pluripotent stem cells: ex vivo models for human diseases due to mitochondrial DNA mutations.

Chao Chen, Min-Xin Guan.

  Mitochondria are essential organelles for cellular metabolism and physiology in eukaryotic cells. Human mitochondria have their own genome (mtDNA), which is maternally inherited with 37 genes, encoding 13 polypeptides for oxidative phosphorylation, and 22 tRNAs and 2 rRNAs for translation. mtDNA mutations are associated with a wide spectrum of degenerative and neuromuscular diseases. However, the pathophysiology of mitochondrial diseases, especially for threshold effect and tissue specificity, is not well understood and there is no effective treatment for these disorders. Especially, the lack of appropriate cell and animal disease models has been significant obstacles for deep elucidating the pathophysiology of maternally transmitted diseases and developing the effective therapy approach. The use of human induced pluripotent stem cells (iPSCs) derived from patients to obtain terminally differentiated specific lineages such as inner ear hair cells is a revolutionary approach to deeply understand pathogenic mechanisms and develop the therapeutic interventions of mitochondrial disorders. Here, we review the recent advances in patients-derived iPSCs as ex vivo models for mitochondrial diseases. Those patients-derived iPSCs have been differentiated into specific targeting cells such as retinal ganglion cells and eventually organoid for the disease modeling. These disease models have advanced our understanding of the pathophysiology of maternally inherited diseases and stepped toward therapeutic interventions for these diseases.

Keywords:  Maternally inherited diseases; Mitochondria; iPSCs; mtDNA mutations

DOI:  https://doi.org/10.1186/s12929-023-00967-7
IUBMB Life. 2023 Sep 20.

Mitochondrial protein and organelle quality control-Lessons from budding yeast.

Emily Jie-Ning Yang, Pin-Chao Liao, Liza Pon.

  Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.

Keywords:  ageing; mitochondria; mitochondrial reactive oxygen species; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1002/iub.2783
PLoS One. 2023 ;18(9): e0291442

Development of a novel in vitro model to study the modulatory role of the respiratory complex I in macrophage effector functions.

Pablo Serrano-Lorenzo, Dino Gobelli, Rocío Garrido-Moraga, María J Esteban-Amo, José R López-López, Antonio Orduña, Miguel A de la Fuente, Miguel A Martín, María Simarro.

Increasing evidence demonstrate that the electron transfer chain plays a critical role in controlling the effector functions of macrophages. In this work, we have generated a Ndufs4-/- murine macrophage cell lines. The Ndufs4 gene, which encodes a supernumerary subunit of complex I, is a mutational hotspot in Leigh syndrome patients. Ndufs4-/- macrophages showed decreased complex I activity, altered complex I assembly, and lower levels of maximal respiration and ATP production. These mitochondrial respiration alterations were associated with a shift towards a pro-inflammatory cytokine profile after lipopolysaccharide challenge and improved ability to phagocytose Gram-negative bacteria.

DOI: https://doi.org/10.1371/journal.pone.0291442
Free Radic Biol Med. 2023 Sep 20. pii: S0891-5849(23)00643-3. [Epub ahead of print]

Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches.

Cristina Mas-Bargues.

  Aging is a complex biological process characterized by a progressive decline in cellular and tissue function, ultimately leading to organismal aging. Stem cells, with their regenerative potential, play a crucial role in maintaining tissue homeostasis and repair throughout an organism's lifespan. Mitochondria, the powerhouses of the cell, have emerged as key players in the aging process, impacting stem cell function and contributing to age-related tissue dysfunction. Here are discuss the mechanisms through which mitochondria influence stem cell fate decisions, including energy production, metabolic regulation, ROS signalling, and epigenetic modifications. Therefore, this review highlights the role of mitochondria in driving stem cell senescence and the subsequent impact on tissue function, leading to overall organismal aging and age-related diseases. Finally, we explore potential anti-aging therapies targeting mitochondrial health and discuss their implications for promoting healthy aging. This comprehensive review sheds light on the critical interplay between mitochondrial function, stem cell senescence, and organismal aging, offering insights into potential strategies for attenuating age-related decline and promoting healthy longevity.

Keywords:  Aging; Anti-aging therapies; Mitochondria; Senescence; Stem cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.019
iScience. 2023 Oct 20. 26(10): 107780

Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.

Margaret E Maes, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E Pohl, Sandra Siegert.

  Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.

Keywords:  Biological sciences; Natural sciences; Neuroscience; Physiology; Sensory neuroscience; Systems neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.107780
Hum Mol Genet. 2023 Sep 18. pii: ddad153. [Epub ahead of print]

Cardiolipin deficiency leads to the destabilization of mitochondrial magnesium channel MRS2 in Barth syndrome.

Alaumy Joshi, Vishal M Gohil.

  Barth syndrome (BTHS) is a debilitating X-linked cardio-skeletal myopathy caused by loss-of-function mutations in TAFAZZIN, a cardiolipin (CL)-remodeling enzyme required for the maintenance of normal levels of CL species in mitochondrial membranes. At present, how perturbations in CL abundance and composition lead to many debilitating clinical presentations in BTHS patients have not been fully elucidated. Inspired by our recent findings that CL is essential for optimal mitochondrial calcium uptake, we measured the levels of other biologically important metal ions in BTHS mitochondria and found that in addition to calcium, magnesium levels are significantly reduced. Consistent with this observation, we report a decreased abundance of the mitochondrial magnesium influx channel MRS2 in multiple models of BTHS including yeast, murine myoblast, and BTHS patient cells and cardiac tissue. Mechanistically, we attribute reduced steady-state levels of MRS2 to its increased turnover in CL-deficient BTHS models. By expressing Mrs2 in well-characterized yeast mutants of the phospholipid biosynthetic pathways, we demonstrate a specific requirement of CL for Mrs2 abundance and assembly. Finally, we provide in vitro evidence for the direct binding of CL with human MRS2. Together, our study has identified a critical requirement of CL for MRS2 stability and suggests perturbation of mitochondrial magnesium homeostasis as a novel contributing factor to BTHS pathology.

Keywords:  Barth syndrome; MRS2; cardiolipin; magnesium; mitochondria

DOI:  https://doi.org/10.1093/hmg/ddad153
PLoS Biol. 2023 Sep 18. 21(9): e3002310

Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.

Xenia Chelius, Veronika Bartosch, Nathalie Rausch, Magdalena Haubner, Jana Schramm, Ralf J Braun, Till Klecker, Benedikt Westermann.

Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.

DOI: https://doi.org/10.1371/journal.pbio.3002310
Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2304884120

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.

Jack T Fuller, Steven Barnes, Lorenzo A Sadun, Pujan Ajmera, Anastassia N Alexandrova, Alfredo A Sadun.

  How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

Keywords:  Coenzyme Q10; blinding genetic disease; mitochondria; molecular dynamics simulation; quantum electron tunneling

DOI:  https://doi.org/10.1073/pnas.2304884120
EMBO J. 2023 Sep 22. e113448

BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells.

Rui Liao, Yi Wu, Le Qin, Zhiwu Jiang, Shixue Gou, Linfu Zhou, Qilan Hong, Yao Li, Jingxuan Shi, Yao Yao, Liangxue Lai, Yangqiu Li, Pentao Liu, Jean Paul Thiery, Dajiang Qin, Thomas Graf, Xingguo Liu, Peng Li.

  The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T-cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)-cell fate in T cells. In addition, T cells upregulate the NK cell-associated receptors and transcription factors, lyse NK-cell targets, and are reprogrammed into NK-like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B. ITNKs increase OPA1 expression and exhibit characteristically elongated mitochondria with augmented oxidative phosphorylation (OXPHOS) activity. OPA1-mediated elevated OXPHOS enhances cellular acetyl-CoA levels, thereby promoting the reprogramming efficiency and antitumor effects of ITNKs via regulating H3K27 acetylation at specific targets. In conclusion, our findings demonstrate that the NuRD complex and BCL11B cooperatively maintain T-cell fate directly by repressing NK cell-associated transcription and indirectly through a metabolic-epigenetic axis, providing strategies to improve the reprogramming efficiency and antitumor effects of ITNKs.

Keywords:  CHD4; MBD2; MTA2; OPA1; T-cell fate

DOI:  https://doi.org/10.15252/embj.2023113448
Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00280-5. [Epub ahead of print]

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Kiran Kurmi, Dan Liang, Robert van de Ven, Peter Georgiev, Brandon Mark Gassaway, SeongJun Han, Giulia Notarangelo, Isaac S Harris, Cong-Hui Yao, Joon Seok Park, Song-Hua Hu, Jingyu Peng, Jefte M Drijvers, Sarah Boswell, Artem Sokolov, Stephanie K Dougan, Peter K Sorger, Steven P Gygi, Arlene H Sharpe, Marcia C Haigis.

  Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

Keywords:  CD4(+) T cells; T cell differentiation; high-throughput metabolic screen; mitochondrial biogenesis; pyruvate oxidation; pyrvinium pamoate

DOI:  https://doi.org/10.1016/j.chembiol.2023.08.008
Intern Med J. 2023 Sep 21.

Mitochondrial disease in New Zealand: a nationwide prevalence study.

Sarah Missen, Callum Wilson, Howard Potter, Andrea L Vincent, Rinki Murphy, Richard Roxburgh, Miriam Rodrigues, Gemma Poke, Stephen P Robertson, David R Thorburn, Emma Glamuzina.

   BACKGROUND: The complexities of mitochondrial disease make epidemiological studies challenging, yet this information is important in understanding the healthcare burden and addressing service and educational needs. Existing studies are limited to quaternary centres or focus on a single genotype or phenotype and estimate disease prevalence at 12.5 per 100 000. New Zealand's (NZ) size and partially integrated national healthcare system make it amenable to a nationwide prevalence study.
AIM: To estimate the prevalence of molecularly confirmed and suspected mitochondrial disease on 31 December 2015 in NZ.
METHODS: Cases were identified from subspecialists and laboratory databases and through interrogation of the Ministry of Health National Minimum Dataset with a focus on presentations between 2000 and 2015. Patient records were reviewed, and those with a diagnosis of 'mitochondrial disease' who were alive and residing in NZ on the prevalence date were included. These were divided into molecularly confirmed and clinically suspected cases. Official NZ estimated resident population data were used to calculate prevalence.
RESULTS: Seven hundred twenty-three unique national health index numbers were identified. Five hundred five were excluded. The minimum combined prevalence for mitochondrial disease was 4.7 per 100 000 (95% confidence interval (CI): 4.1-5.4). The minimum prevalence for molecularly confirmed and suspected disease was 2.9 (95% CI 2.4-3.4) and 1.8 (95% CI 1.4-2.2) cases per 100 000 respectively.
CONCLUSIONS: Within the limitations of this study, comparison to similar prevalence studies performed by specialist referral centres suggests mitochondrial disease is underdiagnosed in NZ. This highlights a need for improved education and referral pathways for mitochondrial disease in NZ.

Keywords:  New Zealand/epidemiology*; mitochondrial diseases/diagnosis*; mitochondrial diseases/epidemiology*; mutation/genetics*; prevalence

DOI:  https://doi.org/10.1111/imj.16211
FEBS J. 2023 Sep 18.

Yeast mitochondria can process de novo designed β-barrel proteins.

Anasuya Moitra, Vitasta Tiku, Doron Rapaport.

  Mitochondrial outer membrane β-barrel proteins are encoded in the nucleus, translated in the cytosol, and then targeted to and imported into the respective organelles. Detailed studies have uncovered the mechanisms involved in the import of these proteins and identified the targeting signals and the cytosolic factors that govern their proper biogenesis. Recently, de novo designed eight stranded β-barrel proteins (Tmb2.3 and Tmb2.17) were shown to fold and assemble into lipid membranes. To better understand the general aspects of the biogenesis of β-barrel proteins, we investigated the fate of these artificial proteins upon their expression in yeast cells. We demonstrate that although these proteins are de novo designed and are not related to bona fide mitochondrial β-barrel proteins, they were targeted to mitochondria and integrated into the organelle outer membrane. We further studied whether this integration requires components of the yeast mitochondrial import machinery like Tom20, Tom70, Tob55/Sam50, and Mas37/Sam37. Whereas it seems that none of the import receptors was required for the biogenesis of the artificial β-barrel proteins, we observed a strong dependency on the TOB/SAM complex. Collectively, our findings demonstrate that the mitochondrial outer membrane is the preferential location in yeast cells for any membrane embedded β-barrel protein.

Keywords:  TOB/SAM complex; de novo designed proteins; mitochondria; outer membrane; β-barrel proteins

DOI:  https://doi.org/10.1111/febs.16950
Sci Adv. 2023 Sep 22. 9(38): eadh8228

Temporal landscape of mitochondrial proteostasis governed by the UPRmt.

Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.

Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.

DOI: https://doi.org/10.1126/sciadv.adh8228
Mol Neurobiol. 2023 Sep 19.

Urolithin A Prevents Sleep-deprivation-induced Neuroinflammation and Mitochondrial Dysfunction in Young and Aged Mice.

Afzal Misrani, Sidra Tabassum, Zai-Yong Zhang, Shao-Hua Tan, Cheng Long.

  Sleep deprivation (SD) has reached epidemic proportions worldwide and negatively affects people of all ages. Cognitive impairment induced by SD involves neuroinflammation and mitochondrial dysfunction, but the underlying mechanisms are largely unknown. Urolithin A (UA) is a natural compound that can reduce neuroinflammation and improve mitochondrial health, but its therapeutic effects in a SD model have not yet been studied. Young (3-months old) and aged (12-months old) mice were sleep deprived for 24 h, and UA (2.5 mg/kg or 10 mg/kg) was injected intraperitoneally for 7 consecutive days before the SD period. Immunofluorescent staining, western blotting, and RT-PCR were employed to evaluate levels of proteins involved in neuroinflammation and mitochondrial function. Transmission electron microscope and Golgi-Cox staining were used to evaluate mitochondrial and neuronal morphology, respectively. Finally, contextual fear conditioning and the Morris water maze test were conducted to assess hippocampal learning and memory. In the hippocampus of young (3 months-old) and aged (12 months-old) mice subjected to 24 h SD, pretreatment with UA prevented the activation of microglia and astrocytes, NF-κB-NLRP3 signaling and IL-1β, IL6, TNF-α cytokine production, thus ameliorating neuroinflammation. Furthermore, UA also attenuated SD-induced mitochondrial dysfunction, normalized autophagy and mitophagy and protected hippocampal neuronal morphology. Finally, UA prevented SD-induced hippocampal memory impairment. Cumulatively, the results show that UA imparts cognitive protection by reducing neuroinflammation and enhancing mitochondrial function in SD mice. This suggests that UA shows promise as a therapeutic for the treatment of SD-induced neurological disorders.

Keywords:  Hippocampus; Memory impairment; Mitochondrial dysfunction; Neuroinflammation; Sleep deprivation; Urolithin A

DOI:  https://doi.org/10.1007/s12035-023-03651-x
Transl Neurodegener. 2023 Sep 20. 12(1): 45

Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application.

Saumya Maheshwari, Gabriela Vilema-Enríquez, Richard Wade-Martins.

  Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.

Keywords:  Disease modelling; Disease pathogenesis; Drug development; Friedreich ataxia; Induced pluripotent stem cells

DOI:  https://doi.org/10.1186/s40035-023-00376-8
Science. 2023 Sep 22. 381(6664): 1287-1288

Metabolic control of antitumor immunity.

Andromachi Pouikli, Christian Frezza.

Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.

DOI: https://doi.org/10.1126/science.adk1785
Int J Biol Macromol. 2023 Sep 17. pii: S0141-8130(23)03804-7. [Epub ahead of print]253(Pt 3): 126907

TORC1 mediated regulation of mitochondrial integrity and calcium ion homeostasis by Wat1/mLst8 in S. pombe.

Simmi Anjum, Swati Srivastava, Lalita Panigrahi, Uzair Ahmad Ansari, Arun Kumar Trivedi, Shakil Ahmed.

  The mTOR complexes play a fundamental role in mitochondrial biogenesis and cellular homeostasis. Wat1, an ortholog of mammalian Lst8 is an important component of TOR complex and is essential for the regulation of downstream signaling. Earlier we reported the role of Wat1 in oxidative stress response. Here, we have shown that the abrogation of wat1 causes respiratory defects and mitochondrial depolarization that leads to a decrease in ATP production. The confocal and electron microscopy in wat1Δ cells revealed the fragmented mitochondrial morphology implying its role in mitochondrial fission. Furthermore, we also showed its role in autophagy and the maintenance of calcium ion homeostasis. Additionally, tor2-287 mutant cells also exhibit defects in mitochondrial integrity indicating the TORC1-dependent involvement of Wat1 in the maintenance of mitochondrial homeostasis. The interaction studies of Wat1 and Tor2 with Por1 and Mmm1 proteins revealed a plausible cross-talk between mitochondria and endoplasmic reticulum through the Mitochondria-associated membranes (MAM) and endoplasmic reticulum-mitochondria encounter structure (ERMES) complex, involving TORC1. Taken together, this study demonstrates the involvement of Wat1/mLst8 in harmonizing various mitochondrial functions, redox status, and Ca2+ homeostasis.

Keywords:  Calcium homeostasis; Mitochondrial integrity; S. pombe; TOR complex; Wat1

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.126907
Mitochondrion. 2023 Sep 20. pii: S1567-7249(23)00083-1. [Epub ahead of print]

The Constraints of Allotopic Expression.

Felipe Nieto-Panqueva, Diana Rubalcava-Gracia, Patrice P Hamel, Diego González-Halphen.

  Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression ━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━ three additional constraints should be considered: i) the average apparent free energy of membrane insertion (μΔGapp) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔGapp) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔGapp maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms.

Keywords:  TIM23; allotopic expression; apparent free energy of membrane insertion; membrane embedded proteins; mitochondrial complexes; oxidative phosphorylation; protein import; transmembrane stretches

DOI:  https://doi.org/10.1016/j.mito.2023.09.004
STAR Protoc. 2023 Sep 17. pii: S2666-1667(23)00540-3. [Epub ahead of print]4(4): 102573

Generation of embryo-like structures from mouse embryonic stem cells treated with a chemical inhibitor of SUMOylation and cultured in microdroplets.

Tatiana Traboulsi, Sébastien Sart, Charles N Baroud, Anne Dejean, Jack-Christophe Cossec.

  The field of stem cell-based embryo-like models is rapidly evolving, providing in vitro models of in utero stages of mammalian development. Here, we detail steps to first establish adherent spheroids composed of three cell types from mouse embryonic stem cells solely treated with a chemical inhibitor of SUMOylation. We then describe procedures for generating highly reproducible gastruloids from these dissociated spheroid cells, as well as embryo-like structures comprising anterior neural and trunk somite-like regions using an optimized microfluidics platform. For complete details on the use and execution of this protocol, please refer to Cossec et al. (2023).1.

Keywords:  Cell Biology; Developmental Biology; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2023.102573
BMC Genomics. 2023 Sep 22. 24(1): 561

The mitoepigenome responds to stress, suggesting novel mito-nuclear interactions in vertebrates.

John Lees, Fábio Pèrtille, Pia Løtvedt, Per Jensen, Carlos Guerrero Bosagna.

  The mitochondria are central in the cellular response to changing environmental conditions resulting from disease states, environmental exposures or normal physiological processes. Although the influences of environmental stressors upon the nuclear epigenome are well characterized, the existence and role of the mitochondrial epigenome remains contentious. Here, by quantifying the mitochondrial epigenomic response of pineal gland cells to circadian stress, we confirm the presence of extensive cytosine methylation within the mitochondrial genome. Furthermore, we identify distinct epigenetically plastic regions (mtDMRs) which vary in cytosinic methylation, primarily in a non CpG context, in response to stress and in a sex-specific manner. Motifs enriched in mtDMRs contain recognition sites for nuclear-derived DNA-binding factors (ATF4, HNF4A) important in the cellular metabolic stress response, which we found to be conserved across diverse vertebrate taxa. Together, these findings suggest a new layer of mito-nuclear interaction in which the nuclear metabolic stress response could alter mitochondrial transcriptional dynamics through the binding of nuclear-derived transcription factors in a methylation-dependent context.

Keywords:  DNA-binding; Epigenome; Methylation; Mitochondrial genome; Pineal gland

DOI:  https://doi.org/10.1186/s12864-023-09668-9
iScience. 2023 Oct 20. 26(10): 107790

Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism.

Xiaolei Sun, Hang Chen, Rifeng Gao, Ya Huang, Yanan Qu, Heng Yang, Xiang Wei, Shiyu Hu, Jian Zhang, Peng Wang, Yunzeng Zou, Kai Hu, Junbo Ge, Aijun Sun.

  Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.

Keywords:  Biochemistry; Cell biology; Cellular physiology; Metabolomics; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2023.107790
J Gerontol A Biol Sci Med Sci. 2023 Sep 21. pii: glad226. [Epub ahead of print]

The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease.

Santosh K Prajapati, Ria Shah, Nicholas Alford, Sidharth P Mishra, Shalini Jain, Barbara Hansen, Paul Sanburg, Anthony J A Molina, Hariom Yadav.

  Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder that affects a large proportion of the elderly population. It currently lacks effective treatments, placing a heavy burden on patients, families, healthcare systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier (BBB) permeability and neuroinflammation by impacting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and BBB barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.

Keywords:  Aging; Alzheimer’s Disease; Brain; Cognition; Gut; Metabolites; Microbiome; Mitochondria

DOI:  https://doi.org/10.1093/gerona/glad226
Mol Psychiatry. 2023 Sep 15.

Mitochondrial health index correlates with plasma circulating cell-free mitochondrial DNA in bipolar disorder.

Rafaela C Cordeiro, Camila N C Lima, Gabriel R Fries, Giovana Zunta-Soares, Jair C Soares, João Quevedo, Giselli Scaini.

Although mitochondrial dysfunction is known to play an essential role in the pathophysiology of bipolar disorder (BD), there is a glaring gap in our understanding of how mitochondrial dysfunction can modulate clinical phenotypes. An emerging paradigm suggests mitochondria play an important non-energetic role in adaptation to stress, impacting cellular resilience and acting as a source of systemic allostatic load. Known as mitochondrial allostatic load, this (phenomenon) occurs when mitochondria are unable to recalibrate and maintain cell homeostasis. This study aimed to evaluate the composite mitochondrial health index (MHI) in BD subjects and non-psychiatry controls. We will also explore whether lower MIH will be related to higher cell-free mtDNA (ccf-mtDNA) levels and poor clinical outcomes. In this study, 14 BD-I patients and 16 age- and sex-matched non-psychiatry controls were enrolled. Peripheral blood mononuclear cells (PBMCs) were used to measure the enzymatic activities of citrate synthase and complexes I, II, and IV and mtDNA copy number. Ccf-mtDNA was evaluated by qPCR in plasma. Mitochondrial quality control (MQC) proteins were evaluated by western blotting. After adjusting for confounding variables, such as age, sex, body mass index (BMI), and smoking status, patients with BD presented lower MHI compared to non-psychiatry controls, as well as higher ccf-mtDNA levels that negatively correlated with MHI. Because the MQC network is essential to maintain mitochondrial health, MHI and ccf-mtDNA were also examined in relation to several MQC-related proteins, such as Fis-1, Opa-1, and LC3. Our results showed that MHI correlated negatively with Fis-1 and positively with Opa-1 and LC3. Accordingly, ccf-mtDNA had a positive correlation with Fis-1 and a negative correlation with Opa-1 and LC3. Furthermore, we found a noteworthy inverse correlation between illness severity and MHI, with lower MHI and higher ccf-mtDNA levels in subjects with a longer illness duration, worse functional status, and higher depressive symptoms. Our findings indicate that mitochondrial allostatic load contributes to BD, suggesting mitochondria represent a potential biological intersection point that could contribute to impaired cellular resilience and increased vulnerability to stress and mood episodes. Ultimately, by linking mitochondrial dysfunction to disease progression and poor outcomes, we might be able to build a predictive marker that explains how mitochondrial function and its regulation contribute to BD development and that may eventually serve as a treatment guide for both old and new therapeutic targets.

DOI: https://doi.org/10.1038/s41380-023-02249-y
Hum Mol Genet. 2023 Sep 22. pii: ddad160. [Epub ahead of print]

Higher incidence of embryonic defects in mouse offspring conceived with assisted reproduction from fathers with sperm Epimutations.

Gurbet Karahan, Josée Martel, Sophia Rahimi, Mena Farag, Fernando Matias, Amanda J MacFarlane, Donovan Chan, Jacquetta Trasler.

  Assisted reproductive technologies (ART) account for 1-6% of births in developed countries. While most children conceived are healthy, increases in birth and genomic imprinting defects have been reported; such abnormal outcomes have been attributed to underlying parental infertility and/or the ART used. Here, we assessed whether paternal genetic and lifestyle factors that are associated with male infertility and affect the sperm epigenome, can influence ART outcomes. We examined how paternal factors, haploinsufficiency for Dnmt3L, an important co-factor for DNA methylation reactions, and/or diet-induced obesity, in combination with ART (superovulation, in vitro fertilization, embryo culture and embryo transfer), could adversely influence embryo development and DNA methylation patterning in mice. While male mice fed high-fat diets (HFD) gained weight and showed perturbed metabolic health, their sperm DNA methylation was minimally affected by the diet. In contrast, Dnmt3L haploinsufficiency induced a marked loss of DNA methylation in sperm; notably, regions affected were associated with neurodevelopmental pathways and enriched in young retrotransposons, sequences that can have functional consequences in the next generation. Following ART, placental imprinted gene methylation and growth parameters were impacted by one or both paternal factors. For embryos conceived by natural conception, abnormality rates were similar for WT and Dnmt3L+/- fathers. In contrast, paternal Dnmt3L+/- genotype, as compared to WT fathers, resulted in a 3-fold increase in the incidence of morphological abnormalities in embryos generated by ART. Together, the results indicate that embryonic morphological and epigenetic defects associated with ART may be exacerbated in offspring conceived by fathers with sperm epimutations.

Keywords:  DNA methylation; Dnmt3L-haploinsufficiency; assisted reproduction; male infertility; sperm epimutations

DOI:  https://doi.org/10.1093/hmg/ddad160
Sci Rep. 2023 Sep 19. 13(1): 15480

Maternal and paternal obesity differentially reprogram the ovarian mitochondrial biogenesis of F1 female rats.

Amina G Ramadan, Wafaa M Abdel-Rehim, Rasha A El-Tahan, Samar S Elblehi, Maher A Kamel, Sara A Shaker.

Obesity has harmful consequences on reproductive outcomes and the rapid increase in obesity is assumed to be influenced by epigenetics and trans-generation effects. Our study aimed to explore the effect of maternal and/or paternal obesity on the ovarian tissues of the first-generation female offspring in rats. The study was conducted on 40 adult Wistar albino rats (20 males and 20 females). Obesity was induced by feeding them an obesogenic diet for 3 months. The pregnancy was induced in the females by mating with males in four combinations: healthy mother with healthy father (control parents, CP), healthy mother with obese fathers (OF), obese mothers with healthy father (OM), and obese mother with obese father (obese parents, OP). After delivery, the female offspring at two months were sacrificed, and the blood and ovarian tissues were collected to assess the studied parameters. Our result showed differential impacts of maternal and paternal obesity on the ovarian health of the female offspring. The female offspring of obese OM or OP showed early signs of obesity. These metabolic abnormalities were associated with signs of ovarian lesions, impaired folliculogenesis, and decreased oocyte quality and also showed significant alterations in mitochondrial biogenesis, redox status, inflammation, and microRNAs expression (miR-149 and miR-494). In conclusion, altered ovarian expression of microRNAs and associated impaired mitochondrial biogenesis pathways may be the root causes for the observed intergeneration transmission of the obesogenic phenotype.

DOI: https://doi.org/10.1038/s41598-023-42468-5
Thyroid Res. 2023 Sep 18. 16(1): 38

Expressions of mitochondria-related genes in pregnant women with subclinical hypothyroidism, and expressions of miRNAs in maternal and cord blood.

Julie Kristine Guldberg Stryhn, Jacob Larsen, Palle Lyngsie Pedersen, Peter Haulund Gæde.

   BACKGROUND: Subclinical hypothyroidism in pregnancy and definition by upper thyrotropin (TSH) cutoff are controversial. As mitochondria are influenced by thyroid hormones, the purpose in this study was to measure expression of mitochondria-related genes in euthyroid and subclinical hypothyroid pregnant women to obtain more knowledge of potential metabolic consequences of maternal subclinical hypothyroidism. In addition, we wished to test if applied TSH-cutoff significantly changed our results of expressed gene-levels. Moreover, we aimed to identify potential microRNA-biomarkers for subclinical hypothyroidism - markers that could be traced to offspring as well.
METHODS: From a cohort of at-term pregnant women undergoing planned cesarean section, 77 women had expression levels of the mitochondria-related genes Peroxisome Proliferator-activated Receptor-γ coactivator-1β (PGC-1β), mitochondrial Transcription Factor A (TFAM), Superoxide Dismutase 2 (SOD2) and Nuclear Respiratory Factor 2 (NRF-2) determined by qPCR from blood sampled in prior to delivery. Two TSH-cutoff levels defining subclinical hypothyroidism (> 3.0 and > 3.7 mIU/L) were applied for the procession of results, generating two data analyses of the same cohort. In 22 pairwise maternal-cord samples (subclinical hypothyroid/euthyroid-rate 0.5, TSH-cutoff > 3.0 mIU/L), microRNA-expressions (miRNA) were analyzed.
RESULTS: All gene expressions were lower in the subclinical hypothyroid group regardless of applied TSH-cutoff, but insignificant except for PGC-1β at TSH cutoff > 3.0 mIU/L. Two miRNAs (hsa-let-7d-3p and hsa-miR-345-5p) were upregulated in blood from women and offspring (cord blood) with subclinical hypothyroidism.
CONCLUSIONS: A trend towards decreased mitochondrial gene expressions in subclinical hypothyroidism were demonstrated. The miRNAs hsa-let-7d-3p and hsa-miR-345-5p might be potential markers of maternal subclinical hypothyroidism. However, larger studies are needed to verify the findings.

Keywords:  Biomarker; Blood; Genes; MicroRNAs; Mitochondrial; Pregnancy; Subclinical hypothyroidism; Thyroid reference range; Thyrotropin; Umbilical cord

DOI:  https://doi.org/10.1186/s13044-023-00180-6
Front Physiol. 2023 ;14 1210509

Platelet mitochondria, a potent immune mediator in neurological diseases.

Yan Ma, Qian Jiang, Bingxin Yang, Xiaoyu Hu, Gang Shen, Wei Shen, Jing Xu.

  Dysfunction of the immune response is regarded as a prominent feature of neurological diseases, including neurodegenerative diseases, malignant tumors, acute neurotraumatic insult, and cerebral ischemic/hemorrhagic diseases. Platelets play a fundamental role in normal hemostasis and thrombosis. Beyond those normal functions, platelets are hyperactivated and contribute crucially to inflammation and immune responses in the central nervous system (CNS). Mitochondria are pivotal organelles in platelets and are responsible for generating most of the ATP that is used for platelet activation and aggregation (clumping). Notably, platelet mitochondria show marked morphological and functional alterations under heightened inflammatory/oxidative stimulation. Mitochondrial dysfunction not only leads to platelet damage and apoptosis but also further aggravates immune responses. Improving mitochondrial function is hopefully an effective strategy for treating neurological diseases. In this review, the authors discuss the immunomodulatory roles of platelet-derived mitochondria (PLT-mitos) in neurological diseases and summarize the neuroprotective effects of platelet mitochondria transplantation.

Keywords:  central nervous system; mitochondria; neuroinflammation; platelet; transplantation

DOI:  https://doi.org/10.3389/fphys.2023.1210509