bims-mitmed 2024-07-14 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒07‒14
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.
Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.
Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.
PINK1 regulated mitophagy is evident in skeletal muscles.
PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.
Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.
Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.
Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.
The caspase-activated DNase promotes cellular senescence.
Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.
Lipid Droplet-Mitochondria Contacts in Health and Disease.
GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.
A roadmap for ribosome assembly in human mitochondria.
Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment.
Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.
Leber's hereditary optic neuropathy: Update on current diagnosis and treatment.
Extracellular Microvesicles vs. Mitochondria: Competing for the Top Spot in Cardiovascular Regenerative Medicine.
Mitochondrial targeted antioxidants as potential therapy for huntington's disease.
A single-cell atlas of chromatin accessibility in mouse organogenesis.
Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.
Mitochondrial Quality Control in Ovarian Function: From Mechanisms to Therapeutic Strategies.
Interorganelle phospholipid communication, a house not so divided.
Discovery and characterization of a new class of NAD+-independent SIRT1 activators.
Recovery from cold-induced mitochondrial fission in endothelial cells requires reconditioning temperatures of ≥ 25◦C.
Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation.
Ubiquitin system mutations in neurological diseases.
Prenatal diagnosis of SLC25A24 Fontaine progeroid syndrome: description of the fetal phenotype, genotype and detection of parental mosaicism.
New variants expand the neurological phenotype of COQ7 deficiency.

Nat Commun. 2024 Jul 08. 15(1): 5715

Egg multivesicular bodies elicit an LC3-associated phagocytosis-like pathway to degrade paternal mitochondria after fertilization.

Sharon Ben-Hur, Shoshana Sernik, Sara Afar, Alina Kolpakova, Yoav Politi, Liron Gal, Anat Florentin, Ofra Golani, Ehud Sivan, Nili Dezorella, David Morgenstern, Shmuel Pietrokovski, Eyal Schejter, Keren Yacobi-Sharon, Eli Arama.

Mitochondria are maternally inherited, but the mechanisms underlying paternal mitochondrial elimination after fertilization are far less clear. Using Drosophila, we show that special egg-derived multivesicular body vesicles promote paternal mitochondrial elimination by activating an LC3-associated phagocytosis-like pathway, a cellular defense pathway commonly employed against invading microbes. Upon fertilization, these egg-derived vesicles form extended vesicular sheaths around the sperm flagellum, promoting degradation of the sperm mitochondrial derivative and plasma membrane. LC3-associated phagocytosis cascade of events, including recruitment of a Rubicon-based class III PI(3)K complex to the flagellum vesicular sheaths, its activation, and consequent recruitment of Atg8/LC3, are all required for paternal mitochondrial elimination. Finally, lysosomes fuse with strings of large vesicles derived from the flagellum vesicular sheaths and contain degrading fragments of the paternal mitochondrial derivative. Given reports showing that in some mammals, the paternal mitochondria are also decorated with Atg8/LC3 and surrounded by multivesicular bodies upon fertilization, our findings suggest that a similar pathway also mediates paternal mitochondrial elimination in other flagellated sperm-producing organisms.

DOI: https://doi.org/10.1038/s41467-024-50041-5
Int J Mol Sci. 2024 Jul 03. pii: 7305. [Epub ahead of print]25(13):

Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways.

Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior, Anna Picca.

  Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.

Keywords:  DAMPs; SASP; cell death; extracellular vesicles; inflammaging; interleukin; mitochondrial quality control; mitochondrial-derived vesicles; mtDNA; pyroptosis

DOI:  https://doi.org/10.3390/ijms25137305
Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00386-1. [Epub ahead of print]

Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.

Daisuke Murata, Shubhrajit Roy, Svetlana Lutsenko, Miho Iijima, Hiromi Sesaki.

  Following the Goldilocks principle, mitochondria size must be "just right." Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering-short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.

Keywords:  division; fusion; mitochondria; stress response; transporter

DOI:  https://doi.org/10.1016/j.devcel.2024.06.008
Autophagy Rep. 2024 Mar 11. 3(1): 2326402

PINK1 regulated mitophagy is evident in skeletal muscles.

Francois Singh, Lea Wilhelm, Alan R Prescott, Kevin Ostacolo, Jin-Feng Zhao, Margret H Ogmundsdottir, Ian G Ganley.

  PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLGD257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLGD257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.

Keywords:  PINK1; POLG; Parkinson’s; mitophagy; muscle; mutator

DOI:  https://doi.org/10.1080/27694127.2024.2326402
EMBO Rep. 2024 Jul 11.

PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4.

Giang Thanh Nguyen-Dien, Brendan Townsend, Prajakta Gosavi Kulkarni, Keri-Lyn Kozul, Soo Siang Ooi, Denaye N Eldershaw, Saroja Weeratunga, Meihan Liu, Mathew Jk Jones, S Sean Millard, Dominic Ch Ng, Michele Pagano, Alexis Bonfim-Melo, Tobias Schneider, David Komander, Michael Lazarou, Brett M Collins, Julia K Pagan.

  Mitophagy must be carefully regulated to ensure that cells maintain appropriate numbers of functional mitochondria. The SCFFBXL4 ubiquitin ligase complex suppresses mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors, and FBXL4 mutations result in mitochondrial disease as a consequence of elevated mitophagy. Here, we reveal that the mitochondrial phosphatase PPTC7 is an essential cofactor for SCFFBXL4-mediated destruction of BNIP3 and NIX, suppressing both steady-state and induced mitophagy. Disruption of the phosphatase activity of PPTC7 does not influence BNIP3 and NIX turnover. Rather, a pool of PPTC7 on the mitochondrial outer membrane acts as an adaptor linking BNIP3 and NIX to FBXL4, facilitating the turnover of these mitophagy receptors. PPTC7 accumulates on the outer mitochondrial membrane in response to mitophagy induction or the absence of FBXL4, suggesting a homoeostatic feedback mechanism that attenuates high levels of mitophagy. We mapped critical residues required for PPTC7-BNIP3/NIX and PPTC7-FBXL4 interactions and their disruption interferes with both BNIP3/NIX degradation and mitophagy suppression. Collectively, these findings delineate a complex regulatory mechanism that restricts BNIP3/NIX-induced mitophagy.

Keywords:  BNIP3; FBXL4; Mitophagy; NIX; PPTC7

DOI:  https://doi.org/10.1038/s44319-024-00181-y
J Neurogenet. 2024 Jul 08. 1-8

Exploring the evidence for mitochondrial dysfunction and genetic abnormalities in the etiopathogenesis of tropical ataxic neuropathy.

Shivani Sharma, Anita Mahadevan, Gayathri Narayanappa, Monojit Debnath, Periyasamy Govindaraj, Sumanth Shivaram, Doniparthi V Seshagiri, Ramesh Siram, Akhilesh Shroti, Parayil S Bindu, Yasha T Chickabasaviah, Arun B Taly, Madhu Nagappa.

  Tropical ataxic neuropathy (TAN) is characterised by ataxic polyneuropathy, degeneration of the posterior columns and pyramidal tracts, optic atrophy, and sensorineural hearing loss. It has been attributed to nutritional/toxic etiologies, but evidence for the same has been equivocal. TAN shares common clinical features with inherited neuropathies and mitochondrial disorders, it may be hypothesised that genetic abnormalities may underlie the pathophysiology of TAN. This study aimed to establish evidence for mitochondrial dysfunction by adopting an integrated biochemical and multipronged genetic analysis. Patients (n = 65) with chronic progressive ataxic neuropathy with involvement of visual and/or auditory pathways underwent deep phenotyping, genetic studies including mitochondrial DNA (mtDNA) deletion analysis, mtDNA and clinical exome sequencing (CES), and respiratory chain complex (RCC) assay. The phenotypic characteristics included dysfunction of visual (n = 14), auditory (n = 12) and visual + auditory pathways (n = 29). Reduced RCC activity was present in 13 patients. Mitochondrial DNA deletions were noted in five patients. Sequencing of mtDNA (n = 45) identified a homoplasmic variant (MT-ND6) and a heteroplasmic variant (MT-COI) in one patient each. CES (n = 45) revealed 55 variants in nuclear genes that are associated with neuropathy (n = 27), deafness (n = 7), ataxia (n = 4), and mitochondrial phenotypes (n = 5) in 36 patients. This study provides preliminary evidence that TAN is associated with a spectrum of genetic abnormalities, including those associated with mitochondrial dysfunction, which is in contradistinction from the prevailing hypothesis that TAN is related to dietary toxins. Analysing the functional relevance of these genetic variants may improve the understanding of the pathogenesis of TAN.

Keywords:  Deafness; mitochondria; optic atrophy; tropical ataxic neuropathy

DOI:  https://doi.org/10.1080/01677063.2024.2373363
Front Cell Neurosci. 2024 ;18 1403734

Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.

Raquel Coronel, Enrique García-Moreno, Emilio Siendones, Maria J Barrero, Beatriz Martínez-Delgado, Carlos Santos-Ocaña, Isabel Liste, M V Cascajo-Almenara.

  Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.

Keywords:  3D cultures; drug repurposing; high-throughput screening; mitochondrial diseases; neurodevelopmental disorders; organoid; spheroids

DOI:  https://doi.org/10.3389/fncel.2024.1403734
Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.

  Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster

DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
bioRxiv. 2024 Jun 24. pii: 2024.05.12.593764. [Epub ahead of print]

The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.

Sijie Tan, Alisa Susan Dengler, Rami Zahi Darawsheh, Nora Kory.

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.

DOI: https://doi.org/10.1101/2024.05.12.593764
EMBO J. 2024 Jul 08.

The caspase-activated DNase promotes cellular senescence.

Aladin Haimovici, Valentin Rupp, Tarek Amer, Abdul Moeed, Arnim Weber, Georg Häcker.

  Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence.

Keywords:  Ageing; Apoptosis; Caspase-activated DNase; Senescence

DOI:  https://doi.org/10.1038/s44318-024-00163-9
Nat Commun. 2024 Jul 10. 15(1): 5818

Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.

Kazuhiro Yamada, Claudette St Croix, Donna B Stolz, Yulia Y Tyurina, Vladimir A Tyurin, Laura R Bradley, Alexander A Kapralov, Yanhan Deng, Xiuxia Zhou, Qi Wei, Bo Liao, Nobuhiko Fukuda, Mara Sullivan, John Trudeau, Anuradha Ray, Valerian E Kagan, Jinming Zhao, Sally E Wenzel.

A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death. However, in this report we identify a lipoxygenase orchestrated, compartmentally-targeted ferroptosis-associated peroxidation process which occurs in a subpopulation of dysfunctional mitochondria, without promoting cell death. Rather, this mitochondrial peroxidation process tightly couples with PTEN-induced kinase (PINK)-1(PINK1)-Parkin-Optineurin mediated mitophagy in an effort to preserve the pool of functional mitochondria and prevent cell death. These combined peroxidation processes lead to altered epithelial cell phenotypes and loss of ciliated cells which associate with worsened asthma severity. Ferroptosis-targeted interventions of this process could preserve healthy mitochondria, reverse cell phenotypic changes and improve disease outcomes.

DOI: https://doi.org/10.1038/s41467-024-50222-2
Int J Mol Sci. 2024 Jun 22. pii: 6878. [Epub ahead of print]25(13):

Lipid Droplet-Mitochondria Contacts in Health and Disease.

Hongjun Fan, Yanjie Tan.

  The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.

Keywords:  disease; lipid droplet; metabolism; mitochondria; redox

DOI:  https://doi.org/10.3390/ijms25136878
Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00385-X. [Epub ahead of print]

GRP75-dependent mitochondria-ER contacts ensure cell survival during early mouse thymocyte development.

Fan Zhao, Zejin Cui, Pengfei Wang, Zhishan Zhao, Kaixiang Zhu, Yadan Bai, Xuexiao Jin, Lie Wang, Linrong Lu.

  Mitochondria and endoplasmic reticulum contacts (MERCs) control multiple cellular processes, including cell survival and differentiation. Based on the observations that MERCs were specifically enriched in the CD4-CD8- double-negative (DN) stage, we studied their role in early mouse thymocyte development. We found that T cell-specific knockout of Hspa9, which encodes GRP75, a protein that mediates MERC formation by assembling the IP3R-GRP75-VDAC complex, impaired DN3 thymocyte viability and resulted in thymocyte developmental arrest at the DN3-DN4 transition. Mechanistically, GRP75 deficiency induced mitochondrial stress, releasing mitochondrial DNA (mtDNA) into the cytosol and triggering the type I interferon (IFN-I) response. The IFN-I pathway contributed to both the impairment of cell survival and DN3-DN4 transition blockage, while increased lipid peroxidation (LPO) played a major role downstream of IFN-I. Thus, our study identifies the essential role of GRP75-dependent MERCs in early thymocyte development and the governing facts of cell survival and differentiation in the DN stage.

Keywords:  GRP75; IFN-I; cell survival; mitochondria-ER contacts; thymocyte development

DOI:  https://doi.org/10.1016/j.devcel.2024.06.007
Nat Struct Mol Biol. 2024 Jul 11.

A roadmap for ribosome assembly in human mitochondria.

Elena Lavdovskaia, Elisa Hanitsch, Andreas Linden, Martin Pašen, Venkatapathi Challa, Yehor Horokhovskyi, Hanna P Roetschke, Franziska Nadler, Luisa Welp, Emely Steube, Marleen Heinrichs, Mandy Mong-Quyen Mai, Henning Urlaub, Juliane Liepe, Ricarda Richter-Dennerlein.

Mitochondria contain dedicated ribosomes (mitoribosomes), which synthesize the mitochondrial-encoded core components of the oxidative phosphorylation complexes. The RNA and protein components of mitoribosomes are encoded on two different genomes (mitochondrial and nuclear) and are assembled into functional complexes with the help of dedicated factors inside the organelle. Defects in mitoribosome biogenesis are associated with severe human diseases, yet the molecular pathway of mitoribosome assembly remains poorly understood. Here, we applied a multidisciplinary approach combining biochemical isolation and analysis of native mitoribosomal assembly complexes with quantitative mass spectrometry and mathematical modeling to reconstitute the entire assembly pathway of the human mitoribosome. We show that, in contrast to its bacterial and cytosolic counterparts, human mitoribosome biogenesis involves the formation of ribosomal protein-only modules, which then assemble on the appropriate ribosomal RNA moiety in a coordinated fashion. The presence of excess protein-only modules primed for assembly rationalizes how mitochondria cope with the challenge of forming a protein-rich ribonucleoprotein complex of dual genetic origin. This study provides a comprehensive roadmap of mitoribosome biogenesis, from very early to late maturation steps, and highlights the evolutionary divergence from its bacterial ancestor.

DOI: https://doi.org/10.1038/s41594-024-01356-w
Int J Mol Sci. 2024 Jul 05. pii: 7406. [Epub ahead of print]25(13):

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment.

Tonie Farris, Salvador González-Ochoa, Muna Mohammed, Harshana Rajakaruna, Jane Tonello, Thanigaivelan Kanagasabai, Olga Korolkova, Akiko Shimamoto, Alla Ivanova, Anil Shanker.

  Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4+ T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, the data suggest that dysregulation of Ca2+-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca2+- signaling pathways in the brain should be explored to improve cognitive health.

Keywords:  Fus1; Tusc2; aging; brain immune populations; calcium; cognitive impairment; mitochondria; neuroinflammation; sex-dependent changes

DOI:  https://doi.org/10.3390/ijms25137406
Int J Mol Sci. 2024 Jun 30. pii: 7240. [Epub ahead of print]25(13):

Creation of an Isogenic Human iPSC-Based RGC Model of Dominant Optic Atrophy Harboring the Pathogenic Variant c.1861C>T (p.Gln621Ter) in the OPA1 Gene.

Marta García-López, Lydia Jiménez-Vicente, Raquel González-Jabardo, Helena Dorado, Irene Gómez-Manjón, Miguel Ángel Martín, Carmen Ayuso, Joaquín Arenas, María Esther Gallardo.

  Autosomal dominant optic atrophy (ADOA) is a rare progressive disease mainly caused by mutations in OPA1, a nuclear gene encoding for a mitochondrial protein that plays an essential role in mitochondrial dynamics, cell survival, oxidative phosphorylation, and mtDNA maintenance. ADOA is characterized by the degeneration of retinal ganglion cells (RGCs). This causes visual loss, which can lead to legal blindness in many cases. Nowadays, there is no effective treatment for ADOA. In this article, we have established an isogenic human RGC model for ADOA using iPSC technology and the genome editing tool CRISPR/Cas9 from a previously generated iPSC line of an ADOA plus patient harboring the pathogenic variant NM_015560.3: c.1861C>T (p.Gln621Ter) in heterozygosis in OPA1. To this end, a protocol based on supplementing the iPSC culture media with several small molecules and defined factors trying to mimic embryonic development has been employed. Subsequently, the created model was validated, confirming the presence of a defect of intergenomic communication, impaired mitochondrial respiration, and an increase in apoptosis and ROS generation. Finally, we propose the analysis of OPA1 expression by qPCR as an easy read-out method to carry out future drug screening studies using the created RGC model. In summary, this model provides a useful platform for further investigation of the underlying pathophysiological mechanisms of ADOA plus and for testing compounds with potential pharmacological action.

Keywords:  ADOA; CRISPR/Cas9; OPA1; RGCs; autosomal dominant optic atrophy; disease modeling; iPSCs; isogenic control; retinal ganglion cells

DOI:  https://doi.org/10.3390/ijms25137240
Front Ophthalmol (Lausanne). 2022 ;2 1077395

Leber's hereditary optic neuropathy: Update on current diagnosis and treatment.

Ali Esmaeil, Ali Ali, Raed Behbehani.

  Leber's hereditary optic neuropathy (LHON) is a fairly prevalent mitochondrial disorder (1:50,000) arising from the dysfunction of the mitochondrial respiratory chain, which eventually leads to apoptosis of retinal ganglion cells. The usual presentation is that of a young male with a sequential reduction in visual acuity. OCT has been used to study the pattern of optic nerve involvement in LHON, showing early thickening of the inferior and superior retinal nerve fibre layer and ganglion cell layer thinning corresponding with the onset of symptoms. Of the three primary mutations for LHON, the m.14484T>C mutation has the best visual prognosis. Recent emerging therapeutic options for LHON include idebenone and the introduction of genetic vector therapy, which is currently in phase III clinical trials. Screening of family members and adequate advice to avoid environmental triggers, such as smoking and alcohol consumption, are also cornerstones in the management of LHON.

Keywords:  Leber’s hereditary optic neuropathy; diagnostics; genetic vector therapy; idebenone; mitochondrial disorder

DOI:  https://doi.org/10.3389/fopht.2022.1077395
Stem Cell Rev Rep. 2024 Jul 08.

Extracellular Microvesicles vs. Mitochondria: Competing for the Top Spot in Cardiovascular Regenerative Medicine.

David M Smadja.

  Regenerative medicine aims to restore, replace, and regenerate human cells, tissues, and organs. Despite significant advancements, many cell therapy trials for cardiovascular diseases face challenges like cell survival and immune compatibility, with benefits largely stemming from paracrine effects. Two promising therapeutic tools have been recently emerged in cardiovascular diseases: extracellular vesicles (EVs) and mitochondrial transfer. Concerning EVs, the first pivotal study with EV-enriched secretome derived from cardiovascular progenitor cells has been done treating heart failure. This first in man demonstrated the safety and feasibility of repeated intravenous infusions and highlighted significant clinical improvements, including enhanced cardiac function and reduced symptoms in heart failure patients. The second study uncovered a novel mechanism of endothelial regeneration through mitochondrial transfer via tunneling nanotubes (TNTs). This research showed that mesenchymal stromal cells (MSCs) transfer mitochondria to endothelial cells, significantly enhancing their bioenergetics and vessel-forming capabilities. This mitochondrial transfer was crucial for endothelial cell engraftment and function, offering a new strategy for vascular regeneration without the need for additional cell types. Combining EV and mitochondrial strategies presents new clinical opportunities. These approaches could revolutionize regenerative medicine, offering new hope for treating cardiovascular and other degenerative diseases. Continued research and clinical trials will be crucial in optimizing these therapies, potentially leading to personalized medicine approaches that enhance patient outcomes.

Keywords:  ECFCs; Extracellular vesicles; Heart failure; Mitochondria; Regeneration; Stem cells

DOI:  https://doi.org/10.1007/s12015-024-10758-8
Pharmacol Rep. 2024 Jul 09.

Mitochondrial targeted antioxidants as potential therapy for huntington's disease.

Shubham Upadhayay, Puneet Kumar.

  Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion in CAG repeat on huntington (Htt) gene, leading to a degeneration of GABAergic medium spiny neurons (MSNs) in the striatum, resulting in the generation of reactive oxygen species, and decrease antioxidant activity. These pathophysiological alterations impair mitochondrial functions, leading to an increase in involuntary hyperkinetic movement. However, researchers investigated the neuroprotective effect of antioxidants using various animal models. Still, their impact is strictly limited to curtailing oxidative stress and increasing the antioxidant enzyme in the brain, which is less effective in HD. Meanwhile, researchers discovered Mitochondria-targeted antioxidants (MTAXs) that can improve mitochondrial functions and antioxidant activity through the modulation of mitochondrial signaling pathways, including peroxisome proliferator-activated receptor (PPAR)-coactivator 1 (PGC-1α), dynamin-related protein 1 (Drp1), mitochondrial fission protein 1 (Fis1), and Silent mating type information regulation 2 homolog 1 (SIRT-1), showing neuroprotective effects in HD. The present review discusses the clinical and preclinical studies that investigate the neuroprotective effect of MTAXs (SS31, XJB-5-131, MitoQ, bezafibrate, rosiglitazone, meldonium, coenzyme Q10, etc.) in HD. This brief literature review will help to understand the relevance of MTAXs in HD and enlighten the importance of MTAXs in future drug discovery and development.

Keywords:  Huntington’s disease; Mitochondria targeted antioxidants; Mitochondrial dysfunction; Neuroprotection; Oxidative stress

DOI:  https://doi.org/10.1007/s43440-024-00619-z
Nat Cell Biol. 2024 Jul 08.

A single-cell atlas of chromatin accessibility in mouse organogenesis.

Keyong Sun, Xin Liu, Xun Lan.

Organogenesis is a highly complex and precisely regulated process. Here we profiled the chromatin accessibility in >350,000 cells derived from 13 mouse embryos at four developmental stages from embryonic day (E) 10.5 to E13.5 by SPATAC-seq in a single experiment. The resulting atlas revealed the status of 830,873 candidate cis-regulatory elements in 43 major cell types. By integrating the chromatin accessibility atlas with the previous transcriptomic dataset, we characterized cis-regulatory sequences and transcription factors associated with cell fate commitment, such as Nr5a2 in the development of gastrointestinal tract, which was preliminarily supported by the in vivo experiment in zebrafish. Finally, we integrated this atlas with the previous single-cell chromatin accessibility dataset from 13 adult mouse tissues to delineate the developmental stage-specific gene regulatory programmes within and across different cell types and identify potential molecular switches throughout lineage development. This comprehensive dataset provides a foundation for exploring transcriptional regulation in organogenesis.

DOI: https://doi.org/10.1038/s41556-024-01435-6
J Clin Transl Hepatol. 2024 Jun 28. 12(6): 539-550

Mitochondrial GRIM19 Loss Induces Liver Fibrosis through NLRP3/IL33 Activation via Reactive Oxygen Species/NF-кB Signaling.

Xiaohui Xu, Jinmei Feng, Xin Wang, Xin Zeng, Ying Luo, Xinyu He, Meihua Yang, Tiewei Lv, Zijuan Feng, Liming Bao, Li Zhao, Daochao Huang, Yi Huang.

  Background and Aims: Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis.Methods: GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF.
Results: Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo.
Conclusions: The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Keywords:  GRIM19; IL33; Liver fibrosis; NF-кB; NLRP3 inflammasome; Reactive Oxygen Species

DOI:  https://doi.org/10.14218/JCTH.2023.00562
Reprod Sci. 2024 Jul 09.

Mitochondrial Quality Control in Ovarian Function: From Mechanisms to Therapeutic Strategies.

Xiaomei Wang, Yuxin Liu, Jinzheng Wang, Xueyi Lu, Zhipeng Guo, Shenmin Lv, Zhenyu Sun, Tan Gao, Fei Gao, Jinxiang Yuan.

  Mitochondrial quality control plays a critical role in cytogenetic development by regulating various cell-death pathways and modulating the release of reactive oxygen species (ROS). Dysregulated mitochondrial quality control can lead to a broad spectrum of diseases, including reproductive disorders, particularly female infertility. Ovarian insufficiency is a significant contributor to female infertility, given its high prevalence, complex pathogenesis, and profound impact on women's health. Understanding the pathogenesis of ovarian insufficiency and devising treatment strategies based on this understanding are crucial. Oocytes and granulosa cells (GCs) are the primary ovarian cell types, with GCs regulated by oocytes, fulfilling their specific energy requirements prior to ovulation. Dysregulation of mitochondrial quality control through gene knockout or external stimuli can precipitate apoptosis, inflammatory responses, or ferroptosis in both oocytes and GCs, exacerbating ovarian insufficiency. This review aimed to delineate the regulatory mechanisms of mitochondrial quality control in GCs and oocytes during ovarian development. This study highlights the adverse consequences of dysregulated mitochondrial quality control on GCs and oocyte development and proposes therapeutic interventions for ovarian insufficiency based on mitochondrial quality control. These insights provide a foundation for future clinical approaches for treating ovarian insufficiency.

Keywords:  Apoptosis; Granulosa cells; Mitochondrial dynamics; Mitophagy; Oocyte; Ovarian insufficiency

DOI:  https://doi.org/10.1007/s43032-024-01634-4
Trends Endocrinol Metab. 2024 Jul 06. pii: S1043-2760(24)00168-1. [Epub ahead of print]

Interorganelle phospholipid communication, a house not so divided.

Richard G Lee, Danielle L Rudler, Oliver Rackham, Aleksandra Filipovska.

  The presence of membrane-bound organelles with specific functions is one of the main hallmarks of eukaryotic cells. Organelle membranes are composed of specific lipids that govern their function and interorganelle communication. Discoveries in cell biology using imaging and omic technologies have revealed the mechanisms that drive membrane remodeling, organelle contact sites, and metabolite exchange. The interplay between multiple organelles and their interdependence is emerging as the next frontier for discovery using 3D reconstruction of volume electron microscopy (vEM) datasets. We discuss recent findings on the links between organelles that underlie common functions and cellular pathways. Specifically, we focus on the metabolism of ether glycerophospholipids that mediate organelle dynamics and their communication with each other, and the new imaging techniques that are powering these discoveries.

Keywords:  metabolic diseases; mitochondria; organelles; volume electron microscopy

DOI:  https://doi.org/10.1016/j.tem.2024.06.008
Pharmacol Res. 2024 Jul 04. pii: S1043-6618(24)00241-X. [Epub ahead of print] 107296

Discovery and characterization of a new class of NAD+-independent SIRT1 activators.

S Della Torre, G Dell'Omo, J Dellavedova, L Palazzolo, E Scanziani, Eberini, A Pinto, N Mitro, P Conti, A Villa, P Ciana.

  The activity of sirtuin 1 (SIRT1, a member of the NAD+-dependent deacetylases family) decreases during aging as NAD+ levels naturally decline, thus increasing the risk of several age-associated diseases. Several sirtuin-activating compounds (STACs) have been developed to counteract the age-associated reduction in SIRT1 activity, and some of them are currently under development in clinical trials. STACs induce SIRT1 activation, either through allosteric activation of the enzyme in the presence of NAD+, or by increasing NAD+ levels by inhibiting its degradation or by supplying a key precursor in biosynthesis. In this study, we have identified (E)-2'-des-methyl sulindac analogues as a novel class of STACs that act also in the absence of NAD+, a peculiar behavior demonstrated through enzymatic and mass spectrometry experiments, both in vitro and in cell lines. The activation of the SIRT1 pathway was confirmed in vivo through gene expression and metabolomics analysis. Our data suggest that these compounds could serve as candidate leads for a novel therapeutic strategy aimed at addressing a key metabolic deficiency that may contribute to metabolic and age-associated diseases.

Keywords:  NAD(+)-dependent deacetylases; ageing-associated diseases; metabolic diseases; sirtuin-activating compounds; sulindac analogues

DOI:  https://doi.org/10.1016/j.phrs.2024.107296
Front Transplant. 2022 ;1 1044551

Recovery from cold-induced mitochondrial fission in endothelial cells requires reconditioning temperatures of ≥ 25◦C.

Leonard Quiring, Luisa Caponi, Dhanusha Schwan, Anja Rech, Ursula Rauen.

  Mitochondrial integrity and function constitute a prerequisite for cellular function and repair processes. We have previously shown that mitochondria of different cell types exhibit pronounced fragmentation under hypothermic conditions. This fission, accompanied by a decline of cellular ATP content, showed reversibility at 37◦C. However, it is unclear whether other temperatures as currently discussed for reconditioning of organs allow this reconstitution of mitochondria. Therefore, we here study in a model of cultured porcine aortic endothelial cells how different rewarming temperatures affect mitochondrial re-fusion and function. After 48 h cold incubation of endothelial cells in Krebs-Henseleit buffer with glucose (5 mM) and deferoxamine (1 mM) at 4◦C pronounced mitochondrial fission was observed. Following 2 h rewarming in cell culture medium, marked fission was still present after rewarming at 10◦ or 15◦C. At 21◦C some re-fusion was visible, which became more marked at 25◦C. Networks of tubular mitochondria similar to control cells only re-appeared at 37◦C. ATP content decreased at 4◦C from 3.6 ± 0.4 to 1.6 ± 0.4 nmol/106 cells and decreased even further when rewarming cells to 10◦ and 15◦C. Values after rewarming at 21◦C were similar to the values before rewarming while ATP gradually increased at higher rewarming temperatures. Metabolic activity dropped to 5 ± 11% of control values during 4◦C incubation and recovered with increasing temperatures to 36 ± 10% at 25◦C and 78 ± 17% at 37◦C. Integrity of monolayers, largely disturbed at 4◦C (large gaps between endothelial cells; cell injury ≤ 1%), showed partial recovery from 15◦C upwards, complete recovery at 37◦C. Endothelial repair processes (scratch assay) at 25◦C were clearly inferior to those at 37◦C. These data suggest that reconditioning temperatures below 21◦C are not optimal with regard to reconstitution of mitochondrial integrity and function. For this goal, temperatures of at least 25◦C appear required, with 30◦C being superior and 37◦C yielding the best results.

Keywords:  endothelium; machine perfusion; mitochondria; mitochondrial dynamics; mitochondrial fragmentation; mitochondrial fusion; transplantation

DOI:  https://doi.org/10.3389/frtra.2022.1044551
Sci Transl Med. 2024 Jul 10. 16(755): eadn0689

Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human microRNA mutation.

Wenliang Zhu, Wan Du, Arun Prabhu Rameshbabu, Ariel Miura Armstrong, Stewart Silver, Yehree Kim, Wei Wei, Yilai Shu, Xuezhong Liu, Morag A Lewis, Karen P Steel, Zheng-Yi Chen.

Mutations in microRNA-96 (MIR96) cause autosomal dominant deafness-50 (DFNA50), a form of delayed-onset hearing loss. Genome editing has shown efficacy in hearing recovery through intervention in neonatal mice, yet editing in the adult inner ear is necessary for clinical applications, which has not been done. Here, we developed a genome editing therapy for the MIR96 mutation 14C>A by screening different CRISPR systems and optimizing Cas9 expression and the sgRNA scaffold for efficient and specific mutation editing. AAV delivery of the KKH variant of Staphylococcus aureus Cas9 (SaCas9-KKH) and sgRNA to the cochleae of presymptomatic (3-week-old) and symptomatic (6-week-old) adult Mir9614C>A/+ mutant mice improved hearing long term, with efficacy increased by injection at a younger age. Adult inner ear delivery resulted in transient Cas9 expression without evidence of AAV genomic integration, indicating the good safety profile of our in vivo genome editing strategy. We developed a dual-AAV system, including an AAV-sgmiR96-master carrying sgRNAs against all known human MIR96 mutations. Because mouse and human MIR96 sequences share 100% homology, our approach and sgRNA selection for efficient and specific hair cell editing for long-term hearing recovery lay the foundation for the development of treatment for patients with DFNA50 caused by MIR96 mutations.

DOI: https://doi.org/10.1126/scitranslmed.adn0689
Trends Biochem Sci. 2024 Jul 06. pii: S0968-0004(24)00154-3. [Epub ahead of print]

Ubiquitin system mutations in neurological diseases.

Colin Zenge, Alban Ordureau.

  Neuronal ubiquitin balance impacts the fate of countless cellular proteins, and its disruption is associated with various neurological disorders. The ubiquitin system is critical for proper neuronal cell state transitions and the clearance of misfolded or aggregated proteins that threaten cellular integrity. This article reviews the state of and recent advancements in our understanding of the disruptions to components of the ubiquitin system, in particular E3 ligases and deubiquitylases, in neurodevelopmental and neurodegenerative diseases. Specific focus is on enzymes with recent progress in their characterization, including identifying enzyme-substrate pairs, the use of stem cell and animal models, and the development of therapeutics for ubiquitin-related diseases.

Keywords:  E3 ubiquitin ligases; deubiquitylase (DUB); neurodegeneration; neurodevelopment; neuropathologies

DOI:  https://doi.org/10.1016/j.tibs.2024.06.011
Birth Defects Res. 2024 Jul;116(7): e2380

Prenatal diagnosis of SLC25A24 Fontaine progeroid syndrome: description of the fetal phenotype, genotype and detection of parental mosaicism.

Emmanuelle Pannier, Abel Sekri, Nathalie Roux, Alexandre Vasiljevic, Laïla El Khattabi, Nicolas Chatron, Sarah Grotto, Delphine Menzella, Gilles Grangé, Florent Thébault, Jérôme Massardier, Cécile Fourrage, Laurence Lohmann, Vassilis Tsatsaris, Audrey Putoux, Lucile Boutaud, Tania Attié-Bitach.

  BACKGROUND: Fontaine progeroid syndrome (FPS, OMIM 612289) is a recently identified genetic disorder stemming from pathogenic variants in the SLC25A24 gene, encoding a mitochondrial carrier protein. It encompasses Gorlin-Chaudry-Moss syndrome and Fontaine-Farriaux syndrome, primarily manifesting as craniosynostosis with brachycephaly, distinctive dysmorphic facial features, hypertrichosis, severe prenatal and postnatal growth restriction, limb shortening, and early aging with characteristic skin changes, phalangeal anomalies, and genital malformations.CASES: All known occurrences of FPS have been postnatally observed until now. Here, we present the first two prenatal cases identified during the second trimester of pregnancy. While affirming the presence of most postnatal abnormalities in prenatal cases, we note the absence of a progeroid appearance in young fetuses. Notably, our reports introduce new phenotypic features like encephalocele and nephromegaly, which were previously unseen postnatally. Moreover, paternal SLC25A24 mosaicism was detected in one case.
CONCLUSIONS: We present the initial two fetal instances of FPS, complemented by thorough phenotypic and genetic assessments. Our findings expand the phenotypical spectrum of FPS, unveiling new fetal phenotypic characteristics. Furthermore, one case underscores a potential novel inheritance pattern in this disorder. Lastly, our observations emphasize the efficacy of exome/genome sequencing in both prenatal and postmortem diagnosis of rare polymalformative syndromes with a normal karyotype and array-based comparative genomic hybridization (CGH).

Keywords:  2D/3D ultrasound; Fontaine progeroid syndrome; SLC25A24; craniofacial dysostosis; dysmorphic facial features; fetal growth restriction; fetus; mitochondrial disease; mosaicism

DOI:  https://doi.org/10.1002/bdr2.2380
J Inherit Metab Dis. 2024 Jul 08.

New variants expand the neurological phenotype of COQ7 deficiency.

María Alcázar Fabra, Abraham J Paredes-Fuentes, Manuel Torralba Carnerero, Daniel J Moreno Férnandez de Ayala, Antonio Arroyo Luque, Ana Sánchez Cuesta, Carmine Staiano, Paula Sanchez-Pintos, María Luz Couce, Miguel Tomás, Ana Victoria Marco-Hernández, Carmen Orellana, Francisco Martínez, Mónica Roselló, Alfonso Caro, Juan Silvestre Oltra Soler, Sandra Monfort, Alejandro Sánchez, Dolores Rausell, Isidro Vitoria, Mireia Del Toro, Angels Garcia-Cazorla, Natalia A Julia-Palacios, Cristina Jou, Delia Yubero, Luis Carlos López, Juan Diego Hernández Camacho, Guillermo López Lluch, Manuel Ballesteros Simarro, Juan Carlos Rodríguez Aguilera, Gloria Brea Calvo, María Victoria Cascajo Almenara, Rafael Artuch, Carlos Santos-Ocaña.

  The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.

Keywords:  COQ7; CoQ10; mitochondrial diseases; neurological disorders

DOI:  https://doi.org/10.1002/jimd.12776