bims-mitmed 2024-02-04 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–02–04
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.
The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.
A Drosophila model of mitochondrial disease phenotypic heterogeneity.
Advancing the neuroimaging diagnosis and understanding of mitochondrial disorders.
Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.
Stress response silencing by an E3 ligase mutated in neurodegeneration.
OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.
Mitochondrial protein synthesis quality control.
Rescue of mitochondrial import failure by intercellular organellar transfer.
The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.
A RalA between high-fat diet and mitochondrial shape.
Mitochondrial involvement in sarcopenia.
Optineurin provides a mitophagy contact site for TBK1 activation.
Optic Neuropathy Associated with POLG Mutations: A Case Series and Literature Review.
Embryo development is impaired by sperm mitochondrial-derived ROS.
Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.
Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
PPAR-gamma influences developmental competence and trophectoderm lineage specification in bovine embryos.
Why human brain cells grow so slowly.
Human stem-cell-derived embryo models: When bioethical normativity meets biological ontology.
A time window for rescuing dying retinal ganglion cells.
Mitochondrial Morphology and Function Abnormality in Ovarian Granulosa Cells of Patients with Diminished Ovarian Reserve.
Interdisciplinary fetal-neonatal neurology training applies neural exposome perspectives to neurology principles and practice.
Bioprinting functional neural networks.
Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1.

Nat Commun. 2024 Jan 27. 15(1): 830

Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging.

Juan Ignacio Jiménez-Loygorri, Beatriz Villarejo-Zori, Álvaro Viedma-Poyatos, Juan Zapata-Muñoz, Rocío Benítez-Fernández, María Dolores Frutos-Lisón, Francisco A Tomás-Barberán, Juan Carlos Espín, Estela Area-Gómez, Aurora Gomez-Duran, Patricia Boya.

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.

DOI: https://doi.org/10.1038/s41467-024-45044-1
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 26. pii: S0925-4439(24)00018-8. [Epub ahead of print]1870(3): 167033

The striking differences in the bioenergetics of brain and liver mitochondria are enhanced in mitochondrial disease.

Valeria Balmaceda, Timea Komlódi, Marten Szibor, Erich Gnaiger, Anthony L Moore, Erika Fernandez-Vizarra, Carlo Viscomi.

  Mitochondrial disorders are hallmarked by the dysfunction of oxidative phosphorylation (OXPHOS) yet are highly heterogeneous at the clinical and genetic levels. Striking tissue-specific pathological manifestations are a poorly understood feature of these conditions, even if the disease-causing genes are ubiquitously expressed. To investigate the functional basis of this phenomenon, we analyzed several OXPHOS-related bioenergetic parameters, including oxygen consumption rates, electron transfer system (ETS)-related coenzyme Q (mtCoQ) redox state and production of reactive oxygen species (ROS) in mouse brain and liver mitochondria fueled by different substrates. In addition, we determined how these functional parameters are affected by ETS impairment in a tissue-specific manner using pathologically relevant mouse models lacking either Ndufs4 or Ttc19, leading to Complex I (CI) or Complex III (CIII) deficiency, respectively. Detailed OXPHOS analysis revealed striking differences between brain and liver mitochondria in the capacity of the different metabolic substrates to fuel the ETS, reduce the ETS-related mtCoQ, and to induce ROS production. In addition, ETS deficiency due to either CI or CIII dysfunction had a much greater impact on the intrinsic bioenergetic parameters of brain compared with liver mitochondria. These findings are discussed in terms of the still rather mysterious tissue-specific manifestations of mitochondrial disease.

Keywords:  Coenzyme Q redox state; Complex I deficiency; Complex III deficiency; Isolated mitochondria; Oxygen consumption; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbadis.2024.167033
Biol Open. 2024 Feb 02. pii: bio.060278. [Epub ahead of print]

A Drosophila model of mitochondrial disease phenotypic heterogeneity.

Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Ram Prosad Chakrabarty, Navdeep S Chandel, Joseph M Bateman.

  Mutations in genes that affect mitochondrial function cause primary mitochondrial diseases. Mitochondrial diseases are highly heterogeneous and even patients with the same mitochondrial disease can exhibit broad phenotypic heterogeneity, which is poorly understood. Mutations in subunits of mitochondrial respiratory complex I cause complex I deficiency, which can result in severe neurological symptoms and death in infancy. However, some complex I deficiency patients present with much milder symptoms. The most common nuclear gene mutated in complex I deficiency is the highly conserved core subunit NDUFS1. To model the phenotypic heterogeneity in complex I deficiency we used RNAi lines targeting the Drosophila NDUFS1 homolog ND-75 with different efficiencies. Strong knockdown of ND-75 in Drosophila neurons resulted in severe behavioural phenotypes, reduced lifespan, altered mitochondrial morphology, reduced endoplasmic reticulum (ER)-mitochondria contacts and activation of the unfolded protein response (UPR). By contrast, weak ND-75 knockdown caused much milder behavioural phenotypes and changes in mitochondrial morphology. Moreover, weak ND-75 did not alter ER-mitochondria contacts or activate the UPR. Weak and strong ND-75 knockdown resulted in overlapping but distinct transcriptional responses in the brain, with weak knockdown specifically affecting proteosome activity and immune response genes. Metabolism was also differentially affected by weak and strong ND-75 knockdown including gamma-aminobutyric acid (GABA) levels, which may contribute to neuronal dysfunction in ND-75 knockdown flies. Several metabolic processes were only affected by strong ND-75 knockdown including the pentose phosphate pathway and the metabolite 2-hydroxyglutarate (2-HG), suggesting 2-HG as a candidate biomarker of severe neurological mitochondrial disease. Thus, our Drosophila model provides the means to dissect the mechanisms underlying phenotypic heterogeneity in mitochondrial disease.

Keywords:  Complex I deficiency; Metabolism; Mitochondria; Phenotypic heterogeneity; Signalling

DOI:  https://doi.org/10.1242/bio.060278
Neurotherapeutics. 2024 Feb 01. pii: S1878-7479(24)00010-2. [Epub ahead of print]21(1): e00324

Advancing the neuroimaging diagnosis and understanding of mitochondrial disorders.

César Augusto P F Alves, Matthew T Whitehead.

  Mitochondrial diseases, a diverse and intricate group of disorders, result from both nuclear DNA and mitochondrial DNA malfunctions, leading to a decrease in cellular energy (ATP) production. The increasing understanding of molecular, biochemical, and genetic irregularities associated with mitochondrial dysfunction has led to a wider recognition of varying mitochondrial disease phenotypes. This broadening landscape has led to a diverse array of neuroimaging findings, posing a challenge to radiologists in identifying the extensive range of possible patterns. This review meticulously describes the central imaging features of mitochondrial diseases in children, as revealed by neuroimaging. It spans from traditional imaging findings to more recent and intricate diagnoses, offering insights and highlighting advancements in neuroimaging technology that can potentially guide a more efficient and accurate diagnostic approach.

Keywords:  Mitochondrial dysfunction; Mitochondrial neuroimaging; Mitochondrial syndromes

DOI:  https://doi.org/10.1016/j.neurot.2024.e00324
Acta Neuropathol. 2024 Jan 29. 147(1): 26

Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6.

Tsz Chui Sophia Leung, Eviatar Fields, Namrata Rana, Ru Yi Louisa Shen, Alexandra E Bernstein, Anna A Cook, Daniel E Phillips, Alanna J Watt.

  Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset.

Keywords:  Ataxia; Disease progression; Metabolomics; Mitochondria; Purkinje cell; Transcriptome

DOI:  https://doi.org/10.1007/s00401-023-02680-z
Nature. 2024 Jan 31.

Stress response silencing by an E3 ligase mutated in neurodegeneration.

Diane L Haakonsen, Michael Heider, Andrew J Ingersoll, Kayla Vodehnal, Samuel R Witus, Takeshi Uenaka, Marius Wernig, Michael Rapé.

Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.

DOI: https://doi.org/10.1038/s41586-023-06985-7
Hum Mol Genet. 2024 Jan 27. pii: ddae008. [Epub ahead of print]

OPA1 mutation affects autophagy and triggers senescence in autosomal dominant optic atrophy plus fibroblasts.

Paola Zanfardino, Alessandro Amati, Stefano Doccini, Sharon N Cox, Apollonia Tullo, Giovanna Longo, Annamaria D'Erchia, Ernesto Picardi, Claudia Nesti, Filippo M Santorelli, Vittoria Petruzzella.

  In several cases of mitochondrial diseases, the underlying genetic and bioenergetic causes of reduced oxidative phosphorylation (OxPhos) in mitochondrial dysfunction are well understood. However, there is still limited knowledge about the specific cellular outcomes and factors involved for each gene and mutation, which contributes to the lack of effective treatments for these disorders. This study focused on fibroblasts from a patient with Autosomal Dominant Optic Atrophy (ADOA) plus syndrome harboring a mutation in the Optic Atrophy 1 (OPA1) gene. By combining functional and transcriptomic approaches, we investigated the mitochondrial function and identified cellular phenotypes associated with the disease. Our findings revealed that fibroblasts with the OPA1 mutation exhibited a disrupted mitochondrial network and function, leading to altered mitochondrial dynamics and reduced autophagic response. Additionally, we observed a premature senescence phenotype in these cells, suggesting a previously unexplored role of the OPA1 gene in inducing senescence in ADOA plus patients. This study provides novel insights into the mechanisms underlying mitochondrial dysfunction in ADOA plus and highlights the potential importance of senescence in disease progression.

Keywords:  ADOA plus; Autophagy; OPA1; mitochondria; mitophagy; senescence

DOI:  https://doi.org/10.1093/hmg/ddae008
Hum Mol Genet. 2024 Jan 27. pii: ddae012. [Epub ahead of print]

Mitochondrial protein synthesis quality control.

Lidiia Koludarova, Brendan J Battersby.

  Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.

Keywords:  AFG3L2; MTRFR; OMA1; OPA1; OXA1L; RNA processing; cell stress; co-translational quality control; fusion open reading frames; membrane morphology; mitochondria; non-stop mRNA; post-transcriptional; protein synthesis; proteostasis; ribosome quality control; ribosomes

DOI:  https://doi.org/10.1093/hmg/ddae012
Nat Commun. 2024 Feb 02. 15(1): 988

Rescue of mitochondrial import failure by intercellular organellar transfer.

Hope I Needs, Emily Glover, Gonçalo C Pereira, Alina Witt, Wolfgang Hübner, Mark P Dodding, Jeremy M Henley, Ian Collinson.

Mitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell's energy supplies - particularly troublesome for energy-demanding cells of nervous tissue and muscle. Unsurprisingly then, import breakdown is implicated in disease. Here, we explore the consequences of import failure in mammalian cells; wherein, blocking the import machinery impacts mitochondrial ultra-structure and dynamics, but, surprisingly, does not affect import. Our data are consistent with a response involving intercellular mitochondrial transport via tunnelling nanotubes to import healthy mitochondria and jettison those with blocked import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-024-45283-2
J Biol Chem. 2024 Jan 25. pii: S0021-9258(24)00066-8. [Epub ahead of print] 105690

The inhibitor protein IF1 from mammalian mitochondria inhibits ATP hydrolysis but not ATP synthesis by the ATP synthase complex.

Joe Carroll, Ian N Watt, Charlotte J Wright, Shujing Ding, Ian M Fearnley, John E Walker.

  The hydrolytic activity of the ATP synthase in bovine mitochondria is inhibited by a protein called IF1, but bovine IF1 has no effect on the synthetic activity of the bovine enzyme in mitochondrial vesicles in the presence of a proton motive force. In contrast, it has been suggested based on indirect observations that human IFI inhibits both the hydrolytic and synthetic activities of the human ATP synthase, and that the activity of human IF1 is regulated by the phosphorylation of serine-14 of mature IF1. Here, we have made both human and bovine IF1 which are 81 and 84 amino acids long, respectively, and identical in 71.4% of their amino acids, and have investigated their inhibitory effects on the hydrolytic and synthetic activities of ATP synthase in bovine sub-mitochondrial particles. Over a wide range of conditions, including physiological conditions, both human and bovine IF1 are potent inhibitors of ATP hydrolysis, with no effect on ATP synthesis. Also, substitution of serine-14 with phosphomimetic aspartic and glutamic acids had no effect on inhibitory properties, and serine-14 is not conserved throughout mammals. Therefore, it is unlikely that the inhibitory activity of mammalian IF1 is regulated by phosphorylation of this residue.

Keywords:  ATP synthase; inhibitor protein IF(1); mitochondria; regulation; unidirectional inhibition

DOI:  https://doi.org/10.1016/j.jbc.2024.105690
Nat Metab. 2024 Jan 29.

A RalA between high-fat diet and mitochondrial shape.

Ludovica Zambello, Luca Scorrano.

DOI: https://doi.org/10.1038/s42255-023-00969-7
Acta Physiol (Oxf). 2024 Feb 02. e14107

Mitochondrial involvement in sarcopenia.

Charles Affourtit, Jane E Carré.

  Sarcopenia lowers the quality-of-life for millions of people across the world, as accelerated loss of skeletal muscle mass and function contributes to both age- and disease-related frailty. Physical activity remains the only proven therapy for sarcopenia to date, but alternatives are much sought after to manage this progressive muscle disorder in individuals who are unable to exercise. Mitochondria have been widely implicated in the etiology of sarcopenia and are increasingly suggested as attractive therapeutic targets to help restore the perturbed balance between protein synthesis and breakdown that underpins skeletal muscle atrophy. Reviewing current literature, we note that mitochondrial bioenergetic changes in sarcopenia are generally interpreted as intrinsic dysfunction that renders muscle cells incapable of making sufficient ATP to fuel protein synthesis. Based on the reported mitochondrial effects of therapeutic interventions, however, we argue that the observed bioenergetic changes may instead reflect an adaptation to pathologically decreased energy expenditure in sarcopenic muscle. Discrimination between these mechanistic possibilities will be crucial for improving the management of sarcopenia.

Keywords:  cellular bioenergetics; sarcopenia; skeletal muscle mitochondria

DOI:  https://doi.org/10.1111/apha.14107
EMBO J. 2024 Jan 29.

Optineurin provides a mitophagy contact site for TBK1 activation.

Koji Yamano, Momoha Sawada, Reika Kikuchi, Kafu Nagataki, Waka Kojima, Ryu Endo, Hiroki Kinefuchi, Atsushi Sugihara, Tomoshige Fujino, Aiko Watanabe, Keiji Tanaka, Gosuke Hayashi, Hiroshi Murakami, Noriyuki Matsuda.

  Tank-binding kinase 1 (TBK1) is a Ser/Thr kinase that is involved in many intracellular processes, such as innate immunity, cell cycle, and apoptosis. TBK1 is also important for phosphorylating the autophagy adaptors that mediate the selective autophagic removal of damaged mitochondria. However, the mechanism by which PINK1-Parkin-mediated mitophagy activates TBK1 remains largely unknown. Here, we show that the autophagy adaptor optineurin (OPTN) provides a unique platform for TBK1 activation. Both the OPTN-ubiquitin and the OPTN-pre-autophagosomal structure (PAS) interaction axes facilitate assembly of the OPTN-TBK1 complex at a contact sites between damaged mitochondria and the autophagosome formation sites. At this assembly point, a positive feedback loop for TBK1 activation is initiated that accelerates hetero-autophosphorylation of the protein. Expression of monobodies engineered here to bind OPTN impaired OPTN accumulation at contact sites, as well as the subsequent activation of TBK1, thereby inhibiting mitochondrial degradation. Taken together, these data show that a positive and reciprocal relationship between OPTN and TBK1 initiates autophagosome biogenesis on damaged mitochondria.

Keywords:  Autophagy; Mitochondria; PINK1; Parkin; Ubiquitin

DOI:  https://doi.org/10.1038/s44318-024-00036-1
J Neuroophthalmol. 2024 Jan 31.

Optic Neuropathy Associated with POLG Mutations: A Case Series and Literature Review.

Jeremy C Reitinger, Devin D Mackay.

BACKGROUND: The clinical characteristics of patients with polymerase gamma (POLG) mutation-associated optic neuropathy remain incompletely characterized.
METHODS: We describe the clinical characteristics of 3 patients with POLG-associated optic neuropathy. We performed a literature review of optic neuropathy cases associated with POLG mutations and compared them with our cohort.
RESULTS: Many published cases of POLG-associated optic neuropathy in our literature review lacked details regarding severity of vision loss, visual field defects, and optical coherence tomography analysis. The clinical presentation of POLG mutations remains widely variable in age (from pediatric cases to adults) and associated systemic findings. All patients in our literature review presented with systemic symptoms, most commonly muscle weakness, ptosis, and ophthalmoplegia, whereas many young patients had severe systemic symptoms. In our case series, all 3 cases had isolated optic neuropathy affecting the papillomacular bundle, with signs such as reduced visual acuity and color vision, central visual field defects, temporal retinal nerve fiber layer loss with temporal optic disc pallor, and retinal ganglion cell complex loss. In addition, 2 of the 3 cases had added mitochondrial stressors in addition to the POLG mutation.
CONCLUSIONS: Clinicians should be aware that POLG mutations can present as isolated optic neuropathy primarily affecting the papillomacular bundle. With mitochondrial failure being the likely underlying pathogenic mechanism in POLG-associated optic neuropathy, helping affected patients eliminate mitochondrial stressors may be important in reducing the risk for progressive vision loss in this otherwise currently untreatable disorder.

DOI: https://doi.org/10.1097/WNO.0000000000002089
Biol Res. 2024 Jan 30. 57(1): 5

Embryo development is impaired by sperm mitochondrial-derived ROS.

Yentel Mateo-Otero, Marc Llavanera, Marc Torres-Garrido, Marc Yeste.

   BACKGROUND: Basal energetic metabolism in sperm, particularly oxidative phosphorylation, is known to condition not only their oocyte fertilising ability, but also the subsequent embryo development. While the molecular pathways underlying these events still need to be elucidated, reactive oxygen species (ROS) could have a relevant role. We, therefore, aimed to describe the mechanisms through which mitochondrial activity can influence the first stages of embryo development.
RESULTS: We first show that embryo development is tightly influenced by both intracellular ROS and mitochondrial activity. In addition, we depict that the inhibition of mitochondrial activity dramatically decreases intracellular ROS levels. Finally, we also demonstrate that the inhibition of mitochondrial respiration positively influences sperm DNA integrity, most likely because of the depletion of intracellular ROS formation.
CONCLUSION: Collectively, the data presented in this work reveals that impairment of early embryo development may result from the accumulation of sperm DNA damage caused by mitochondrial-derived ROS.

Keywords:  Cyanide; Embryo development; Mitochondrial respiration; Oocyte fertilisation; Oxidative phosphorylation; Sperm metabolism; electron transport chain

DOI:  https://doi.org/10.1186/s40659-024-00483-4
Front Immunol. 2023 ;14 1270268

Mitochondrial dynamics and metabolic regulation control T cell fate in the thymus.

Rima Elhage, Mairead Kelly, Nicolas Goudin, Jérôme Megret, Agnès Legrand, Ivan Nemazanyy, Cécilia Patitucci, Véronique Quellec, Timothy Wai, Ahmed Hamaï, Sophie Ezine.

  Several studies demonstrated that mitochondrial dynamics and metabolic pathways control T cell fate in the periphery. However, little is known about their implication in thymocyte development. Our results showed that thymic progenitors (CD3-CD4-CD8- triple negative, TN), in active division, have essentially a fused mitochondrial morphology and rely on high glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). As TN cells differentiate to double positive (DP, CD4+CD8+) and single positive (SP, CD4+ and CD8+) stages, they became more quiescent, their mitochondria fragment and they downregulate glycolysis and OXPHOS. Accordingly, in vitro inhibition of the mitochondrial fission during progenitor differentiation on OP9-DL4 stroma, affected the TN to DP thymocyte transition by enhancing the percentage of TN and reducing that of DP, leading to a decrease in the total number of thymic cells including SP T cells. We demonstrated that the stage 3 triple negative pre-T (TN3) and the stage 4 triple negative pre-T (TN4) have different metabolic and functional behaviors. While their mitochondrial morphologies are both essentially fused, the LC-MS based analysis of their metabolome showed that they are distinct: TN3 rely more on OXPHOS whereas TN4 are more glycolytic. In line with this, TN4 display an increased Hexokinase II expression in comparison to TN3, associated with high proliferation and glycolysis. The in vivo inhibition of glycolysis using 2-deoxyglucose (2-DG) and the absence of IL-7 signaling, led to a decline in glucose metabolism and mitochondrial membrane potential. In addition, the glucose/IL-7R connection affects the TN3 to TN4 transition (also called β-selection transition), by enhancing the percentage of TN3, leading to a decrease in the total number of thymocytes. Thus, we identified additional components, essential during β-selection transition and playing a major role in thymic development.

Keywords:  OxPhos; T cell progenitors; glycolysis; metabolome; mitochondrial dynamics; thymus; β-selection checkpoint

DOI:  https://doi.org/10.3389/fimmu.2023.1270268
Nat Commun. 2024 Feb 01. 15(1): 953

Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.

Yuki Takakura, Moeka Machida, Natsumi Terada, Yuka Katsumi, Seika Kawamura, Kenta Horie, Maki Miyauchi, Tatsuya Ishikawa, Nobuko Akiyama, Takao Seki, Takahisa Miyao, Mio Hayama, Rin Endo, Hiroto Ishii, Yuya Maruyama, Naho Hagiwara, Tetsuya J Kobayashi, Naoto Yamaguchi, Hiroyuki Takano, Taishin Akiyama, Noritaka Yamaguchi.

Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.

DOI: https://doi.org/10.1038/s41467-024-45206-1
Reproduction. 2024 Feb 01. pii: e230334. [Epub ahead of print]167(2):

PPAR-gamma influences developmental competence and trophectoderm lineage specification in bovine embryos.

Maura S McGraw, Sandeep K Rajput, Bradford W Daigneault.

In brief: Peroxisome proliferator-activated receptor gamma (PPARG) is a critical regulator of placental function, but earlier roles in preimplantation embryo development and embryonic origins of placental formation have not been established. Results herein demonstrate that PPARG responds to pharmacologic stimulation in the bovine preimplantation embryo and influences blastocyst development, cell lineage specification, and transcripts important for placental function.
Abstract: Peroxisome proliferator-activated receptor gamma (PPARG) is a key regulator of metabolism with conserved roles that are indispensable for placental function, suggesting previously unidentified and important roles in preimplantation embryo development. Herein, we report the functional characterization of bovine PPARG to reveal expression beginning on D6 of development with nuclear and ubiquitous patterns. Day 6 PPARG+ embryos have fewer total cells and a lower proportion of trophectoderm cells compared to PPARG- embryos (P < 0.05). Coculture with a PPARG agonist, rosiglitazone (Ros), or antagonist GW9662 (GW), decreases blastocyst development (P < 0.01). Day 7.5 (D7.5) developmentally delayed embryos exposed to Ros express lower transcript abundance of key genes important for placental development and cell lineage formation (CDX2, RXRB, SP1, TFAP2C, SIRT1, and PTEN). In contrast, Ros does not alter transcript abundance in D7.5 blastocysts, but GW treatment lowers RXRA, RXRB, SP1, and NFKB1 expression. Knockout of embryonic PPARG does not alter blastocyst formation and hatching ability but decreases total cell number in D7.5 blastocysts. The decreased embryo development response and affected pathways following targeted pharmacological perturbation vs embryonic knockout of PPARG suggest roles of both maternal and embryonic origins. These data reveal regulatory contributions of PPARG in preimplantation embryo development, cell lineage formation, and regulation of transcripts associated with placental function.

DOI: https://doi.org/10.1530/REP-23-0334
Nature. 2024 Jan 31.

Why human brain cells grow so slowly.

Shamini Bundell.



Keywords:  Ageing; Cell biology; Epigenetics; Neuroscience

DOI:  https://doi.org/10.1038/d41586-024-00280-9
Dev Biol. 2024 Jan 28. pii: S0012-1606(24)00015-0. [Epub ahead of print]508 88-92

Human stem-cell-derived embryo models: When bioethical normativity meets biological ontology.

Adrian Villalba, Jon Rueda, Íñigo de Miguel Beriain.

The use of human stem-cell-derived embryo models in biomedical research has recently sparked intense bioethical debates. In this article, we delve into the ethical complexities surrounding these models and advocate for a deeper exploration of their biological ontology to discuss their bioethical normativity. We examine the ethical considerations arising from the implementation of these models, emphasizing varying viewpoints on their ethical standing and the ethical obligations associated with their development and utilization. We contend that a nuanced comprehension of their biological ontology is crucial for navigating these ethical quandaries. Furthermore, we underscore the indispensability of interdisciplinary cooperation among bioethicists, biologists, and philosophers to unravel the complex interplay between biological ontology and the normative framework of bioethics. Moreover, this article introduces a novel combinatorial approach to resolve the ethical dilemma surrounding these models. We propose a distinction between models that closely emulate natural embryos, based on the status of synthetic embryos, and those capable of reproducing specific dimensions of embryonic development. Such differentiation allows for nuanced ethical considerations while harnessing the value of these models in scientific research, paving the way for a more comprehensive ethical framework in the context of evolving biotechnologies.

DOI: https://doi.org/10.1016/j.ydbio.2024.01.009
Cell Commun Signal. 2024 Jan 31. 22(1): 88

A time window for rescuing dying retinal ganglion cells.

Wenting You, Kèvin Knoops, Iris Boesten, Tos T J M Berendschot, Marc A M J van Zandvoort, Birke J Benedikter, Carroll A B Webers, Chris P M Reutelingsperger, Theo G M F Gorgels.

   BACKGROUND: Retinal ganglion cell (RGC) degeneration and death cause vision loss in patients with glaucoma. Regulated cell death, once initiated, is generally considered to be an irreversible process. Recently, we showed that, by timely removing the cell death stimulus, stressed neuronal PC12 cells can recover from phosphatidylserine (PS) exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation, mitochondrial membrane potential loss, and retraction of neurites, all hallmarks of an activated cell death program. Whether the cell death process can be reversed in neurons of the central nervous system, like RGCs, is still unknown. Here, we studied reversibility of the activated cell death program in primary rat RGCs (prRGCs).
METHODS: prRGCs were exposed to ethanol (5%, vol/vol) to induce cell death. At different stages of the cell death process, ethanol was removed by washing and injured prRGCs were further cultured in fresh medium to see whether they recovered. The dynamics of single cells were monitored by high-resolution live-cell spinning disk microscopy. PS exposure, mitochondrial structure, membrane potential, and intracellular Ca2+ were revealed by annexin A5-FITC, Mito-tracker, TMRM, and Fluo 8-AM staining, respectively. The distribution of cytochrome c was investigated by immunofluorescence. The ultrastructure of mitochondria was studied by electron microscopy.
RESULTS: Analysis of temporal relationships between mitochondrial changes and PS exposure showed that fragmentation of the mitochondrial network and loss of mitochondrial membrane potential occurred before PS exposure. Mitochondrial changes proceeded caspase-independently, while PS exposure was caspase dependent. Interestingly, prRGCs recovered quickly from these mitochondrial changes but not from PS exposure at the plasma membrane. Correlative light and electron microscopy showed that stress-induced decrease in mitochondrial area, length and cristae number was reversible. Intracellular Ca2+ was elevated during this stage of reversible mitochondrial injury, but there was no sign of mitochondrial cytochrome c release.
CONCLUSIONS: Our study demonstrates that RGCs with impaired mitochondrial structure and function can fully recover if there is no mitochondrial cytochrome c release yet, and no PS is exposed at the plasma membrane. This finding indicates that there is a time window for rescuing dying or injured RGCs, by simply removing the cell death stimulus. Video Abstract.

Keywords:  Cytochrome c release; Mitochondrial fragmentation; PS exposure; Primary RGCs; Reversible cell death program

DOI:  https://doi.org/10.1186/s12964-023-01427-3
Reprod Sci. 2024 Jan 31.

Mitochondrial Morphology and Function Abnormality in Ovarian Granulosa Cells of Patients with Diminished Ovarian Reserve.

Zhuo An, Congcong Xie, Hui Lu, Shusong Wang, Xiujia Zhang, Wenbo Yu, Xiaoli Guo, Zehao Liu, Dandan Shang, Xueying Wang.

  In this study, we examined the changes in the mitochondrial structure and function in cumulus granulosa cells of patients with diminished ovarian reserve (DOR) to explore the causes and mechanisms of decreased mitochondrial quality. The mitochondrial ultrastructure was observed by transmission electron microscope, and the function was determined by detecting the ATP content, reactive oxygen species (ROS) levels, the number of mitochondria, and the mitochondrial membrane potential. The expression of ATP synthases in relation to mitochondrial function was analyzed. Additionally, protein immunoblotting was used to compare the expression levels of mitochondrial kinetic protein, the related channel protein in the two groups. Patients with DOR had abnormal granulosa cell morphology, increased mitochondrial abnormalities, decreased mitochondrial function, and disturbed mitochondrial dynamics. Additionally, the silent information regulator 1 (SIRT1)/phospho-AMP-activated protein kinase (P-AMPK)-peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) pathway expression was decreased, which was speculated to be associated with the decreased mitochondrial mass in the DOR group. The mitochondrial mass was decreased in granulosa cells of patients in the DOR group. The mitochondrial dysfunction observed in granulosa cells of patients in the DOR group may be associated with dysregulation of the SIRT1/P-AMPK-PGC-1α-mitochondrial transcription factor A (TFAM) pathway.

Keywords:  Cumulus granulosa cells; Diminished ovarian reserve; Mitochondria; PGC-1α; SIRT1

DOI:  https://doi.org/10.1007/s43032-024-01459-1
Front Neurol. 2023 ;14 1321674

Interdisciplinary fetal-neonatal neurology training applies neural exposome perspectives to neurology principles and practice.

Mark S Scher.

  An interdisciplinary fetal-neonatal neurology (FNN) program over the first 1,000 days teaches perspectives of the neural exposome that are applicable across the life span. This curriculum strengthens neonatal neurocritical care, pediatric, and adult neurology training objectives. Teaching at maternal-pediatric hospital centers optimally merges reproductive, pregnancy, and pediatric approaches to healthcare. Phenotype-genotype expressions of health or disease pathways represent a dynamic neural exposome over developmental time. The science of uncertainty applied to FNN training re-enforces the importance of shared clinical decisions that minimize bias and reduce cognitive errors. Trainees select mentoring committee participants that will maximize their learning experiences. Standardized questions and oral presentations monitor educational progress. Master or doctoral defense preparation and competitive research funding can be goals for specific individuals. FNN principles applied to practice offer an understanding of gene-environment interactions that recognizes the effects of reproductive health on the maternal-placental-fetal triad, neonate, child, and adult. Pre-conception and prenatal adversities potentially diminish life-course brain health. Endogenous and exogenous toxic stressor interplay (TSI) alters the neural exposome through maladaptive developmental neuroplasticity. Developmental disorders and epilepsy are primarily expressed during the first 1,000 days. Communicable and noncommunicable illnesses continue to interact with the neural exposome to express diverse neurologic disorders across the lifespan, particularly during the critical/sensitive time periods of adolescence and reproductive senescence. Anomalous or destructive fetal neuropathologic lesions change clinical expressions across this developmental-aging continuum. An integrated understanding of reproductive, pregnancy, placental, neonatal, childhood, and adult exposome effects offers a life-course perspective of the neural exposome. Exosome research promises improved disease monitoring and drug delivery starting during pregnancy. Developmental origins of health and disease principles applied to FNN practice anticipate neurologic diagnoses with interventions that can benefit successive generations. Addressing health care disparities in the Global South and high-income country medical deserts require constructive dialogue among stakeholders to achieve medical equity. Population health policies require a brain capital strategy that reduces the global burden of neurologic diseases by applying FNN principles and practice. This integrative neurologic care approach will prolong survival with an improved quality of life for persons across the lifespan confronted with neurological disorders.

Keywords:  developmental origins; exosomes; fetal-neonatal neurology; neural exposome; pregnancy; reproductive health; social determinants of health; toxic stressors

DOI:  https://doi.org/10.3389/fneur.2023.1321674
Cell Stem Cell. 2024 Feb 01. pii: S1934-5909(23)00444-7. [Epub ahead of print]31(2): 151-152

Bioprinting functional neural networks.

Stephanie M Willerth.

3D printing human tissue models derived from stem cells provides an increasingly popular tissue engineering strategy for probing biological questions. Here Yan et al.1 demonstrate how this technology can be used to model mature human neural tissues with functional neural networks in healthy and disease states.

DOI: https://doi.org/10.1016/j.stem.2023.12.014
FEBS Lett. 2024 Feb 01.

Mitochondrial dysfunction in NPC1-deficiency is not rescued by drugs targeting the glucosylceramidase GBA2 and the cholesterol-binding proteins TSPO and StARD1.

Simon Wheeler, Meenakshi Bhardwaj, Victor Kenyon, Maria J Ferraz, Johannes M F G Aerts, Dan J Sillence.

  Niemann-Pick type C disease (NPCD) is a rare neurodegenerative disorder most commonly caused by mutations in the lysosomal protein Niemann-Pick C1 (NPC1), which is implicated in cholesterol export. Mitochondrial insufficiency forms a significant feature of the pathology of this disease, yet studies attempting to address this are rare. The working hypothesis is that mitochondria become overloaded with cholesterol which renders them dysfunctional. We examined two potential protein targets-translocator protein (TSPO) and steroidogenic acute regulatory protein D1 (StARD1)-which are implicated in cholesterol transport to mitochondria, in addition to glucocerbrosidase 2 (GBA2), the target of miglustat, which is currently the only approved treatment for NPCD. However, inhibiting these proteins did not correct the mitochondrial defect in NPC1-deficient cells.

Keywords:  GBA2; NPC1; Niemann-Pick C; StARD1; TSPO; mitochondria

DOI:  https://doi.org/10.1002/1873-3468.14802