bims-mitmed 2024-11-17 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–11–17
thirty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Opposing roles for AMPK in regulating distinct mitophagy pathways.
CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.
Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.
POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.
Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.
Mitochondria: great balls of fire.
The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.
Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.
A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.
FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.
Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia.
Mitochondrial disorders are associated with morphological neuromuscular junction defects.
Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.
Expanding the genetic and clinical spectrum of SLC25A42-associated disorders and testing of pantothenic acid to improve CoA level in vitro.
Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.
The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.
Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.
Metabolic Phenotyping of Synaptic Mitochondria Using MitoPlates™ and Synaptoneurosomes.
A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain.
KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain.
Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey.
Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters.
Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.
NAD+ enhancers as therapeutic agents in the cardiorenal axis.
Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease.
TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.
Metabolomic signatures associated with fetal growth restriction and small for gestational age: a systematic review.
Deep learning-based models for preimplantation mouse and human embryos based on single-cell RNA sequencing.
Precision medicine and Friedreich ataxia: promoting equity, beneficence, and informed consent for novel gene therapies.
A proteolytic AAA+ machine poised to unfold protein substrates.

Mol Cell. 2024 Nov 05. pii: S1097-2765(24)00865-7. [Epub ahead of print]

Opposing roles for AMPK in regulating distinct mitophagy pathways.

Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G Ganley.

  Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.

Keywords:  14-3-3; AMPK; NIX; Parkin; ULK1; autophagy; liver; mito-QC; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1016/j.molcel.2024.10.025
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 13. pii: S0925-4439(24)00563-5. [Epub ahead of print] 167569

CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency.

Shivani Goolab, Karin Terburgh, Charl du Plessis, Janine Scholefield, Roan Louw.

  Mitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of NDUFS4-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the NDUFS4 gene, generating isogenic NDUFS4 knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in NDUFS4 KO iPSCs, predominantly associated with an elevated NADH/NAD+ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD+ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen in vivo, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.

Keywords:  CI deficiency; CRISPR-Cas9; Mitochondrial disease; iPSC

DOI:  https://doi.org/10.1016/j.bbadis.2024.167569
EMBO J. 2024 Nov 08.

Structural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.

Genís Valentín Gesé, B Martin Hällberg.

  Maturation of human mitochondrial tRNA is essential for cellular energy production, yet the underlying mechanisms remain only partially understood. Here, we present several cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to different maturation states of mitochondrial tRNAHis, showing the molecular basis for tRNA-substrate selection and catalysis. Our structural insights provide a molecular rationale for the 5'-to-3' tRNA processing order in mitochondria, the 3'-CCA antideterminant effect, and the basis for sequence-independent recognition of mitochondrial tRNA substrates. Furthermore, our study links mutations in ELAC2 to clinically relevant mitochondrial diseases, offering a deeper understanding of the molecular defects contributing to these conditions.

Keywords:  Cryo-EM; ELAC2; Mitochondria; RNA Processing; RNase Z

DOI:  https://doi.org/10.1038/s44318-024-00297-w
Physiol Res. 2024 Nov 15. 73(5): 801-808

POLG p.A962T Mutation Leads to Neuronal Mitochondrial Dysfunction That is Restored After Mitochondrial Transplantation.

W Hu, C Shi, H Guo, B Zhang.

Mutations in DNA polymerase gamma (POLG) are known as the predominant cause of inherited mitochondrial disorders. But how these POLG mutations disturb mitochondrial function remains to be determined. Furthermore, no effective therapy, to date, has been reported for POLG diseases. Using differentiated SH-SY5Y cells, a human neuronal model cell line, the current study investigated whether the novel POLG variant p.A962T impairs mitochondrial function. This involved quantifying mitochondrial DNA (mtDNA) content using PCR and assessing the expression levels of the subunits of complex IV (COXI-IV), a complex I subunit NDUFV1 and Cytochrome C (Cyto C) release using Western blotting. Activities of mitochondrial complex I, II, and IV were measured using colorimetric assays. Mitochondrial membrane potential (delta Psim) and ATP were evaluated using fluorescence assays and luminescent assays, respectively. In addition, we investigated whether mitochondrial transplantation (MT) using Pep-1-conjugated mitochondria could compensate for mitochondrial defects caused by the variant in cells carrying mutant POLG. The results of this study showed that POLG p.A962T mutation resulted in mitochondrial defects, including mitochondrial DNA (mtDNA) depletion, membrane potential (delta Psim) depolarization and adenosine triphosphate (ATP) reduction. Mechanistically, POLG mutation-caused mtDNA depletion led to the loss of mtDNA-encoded subunits of complex I and IV and thus compromised their activities. POLG p.A962T mutation is a pathogenic mutation leading to mitochondrial malfunction and mtDNA depletion in neurons. Cell-penetrating peptide Pep-1-mediated MT treatment compensated for mitochondrial defects induced by these POLG variants, suggesting the therapeutic application of this method in POLG diseases.
Sci Rep. 2024 11 08. 14(1): 27182

Mitochondrial complex I inhibition enhances astrocyte responsiveness to pro-inflammatory stimuli.

Lena Wischhof, Amal John Mathew, Lorenzo Bonaguro, Marc Beyer, Dan Ehninger, Pierluigi Nicotera, Daniele Bano.

  Inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) system can lead to metabolic disorders and neurodegenerative diseases. In primary mitochondrial disorders, reactive astrocytes often accompany neuronal degeneration and may contribute to neurotoxic inflammatory cascades that elicit brain lesions. The influence of mitochondria to astrocyte reactivity as well as the underlying molecular mechanisms remain elusive. Here we report that mitochondrial Complex I dysfunction promotes neural progenitor cell differentiation into astrocytes that are more responsive to neuroinflammatory stimuli. We show that the SWItch/Sucrose Non-Fermentable (SWI/SNF/BAF) chromatin remodeling complex takes part in the epigenetic regulation of astrocyte responsiveness, since its pharmacological inhibition abrogates the expression of inflammatory genes. Furthermore, we demonstrate that Complex I deficient human iPSC-derived astrocytes negatively influence neuronal physiology upon cytokine stimulation. Together, our data describe the SWI/SNF/BAF complex as a sensor of altered mitochondrial OXPHOS and a downstream epigenetic regulator of astrocyte-mediated neuroinflammation.

Keywords:  ATP-dependent chromatin remodeling SWI/SNF/BAF complex; Mitochondria; Reactive astrocytes

DOI:  https://doi.org/10.1038/s41598-024-78434-y
FEBS J. 2024 Nov 14.

Mitochondria: great balls of fire.

Howard T Jacobs, Pierre Rustin, Paule Bénit, Dan Davidi, Mügen Terzioglu.

  Recent experimental studies indicate that mitochondria in mammalian cells are maintained at temperatures of at least 50 °C. While acknowledging the limitations of current experimental methods and their interpretation, we here consider the ramifications of this finding for cellular functions and for evolution. We consider whether mitochondria as heat-producing organelles had a role in the origin of eukaryotes and in the emergence of homeotherms. The homeostatic responses of mitochondrial temperature to externally applied heat imply the existence of a molecular heat-sensing system in mitochondria. While current findings indicate high temperatures for the innermost compartments of mitochondria, those of the mitochondrial surface and of the immediately surrounding cytosol remain to be determined. We ask whether some aspects of mitochondrial dynamics and motility could reflect changes in the supply and demand for mitochondrial heat, and whether mitochondrial heat production could be a factor in diseases and immunity.

Keywords:  cold‐shock; eukaryote origins; heat‐shock; homeothermy; immunity; mitochondria; mitochondrial disease; mitochondrial dynamics; temperature gradients; thermogenesis

DOI:  https://doi.org/10.1111/febs.17316
Nat Commun. 2024 Nov 13. 15(1): 9826

The mitochondrial mRNA-stabilizing protein SLIRP regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms.

Tang Cam Phung Pham, Steffen Henning Raun, Essi Havula, Carlos Henriquez-Olguín, Diana Rubalcava-Gracia, Emma Frank, Andreas Mæchel Fritzen, Paulo R Jannig, Nicoline Resen Andersen, Rikke Kruse, Mona Sadek Ali, Andrea Irazoki, Jens Frey Halling, Stine Ringholm, Elise J Needham, Solvejg Hansen, Anders Krogh Lemminger, Peter Schjerling, Maria Houborg Petersen, Martin Eisemann de Almeida, Thomas Elbenhardt Jensen, Bente Kiens, Morten Hostrup, Steen Larsen, Niels Ørtenblad, Kurt Højlund, Michael Kjær, Jorge L Ruas, Aleksandra Trifunovic, Jørgen Frank Pind Wojtaszewski, Joachim Nielsen, Klaus Qvortrup, Henriette Pilegaard, Erik Arne Richter, Lykke Sylow.

Decline in mitochondrial function is linked to decreased muscle mass and strength in conditions like sarcopenia and type 2 diabetes. Despite therapeutic opportunities, there is limited and equivocal data regarding molecular cues controlling muscle mitochondrial plasticity. Here we uncovered that the mitochondrial mRNA-stabilizing protein SLIRP, in complex with LRPPRC, is a PGC-1α target that regulates mitochondrial structure, respiration, and mtDNA-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracts mitochondrial defects caused by genetically-induced LRPPRC/SLIRP loss, despite sustained low mtDNA-encoded-mRNA pools, by increasing mitoribosome translation capacity and mitochondrial quality control. In humans, exercise training robustly increases muscle SLIRP and LRPPRC protein across exercise modalities and sexes, yet less prominently in individuals with type 2 diabetes. SLIRP muscle loss reduces Drosophila lifespan. Our data points to a mechanism of post-transcriptional mitochondrial regulation in muscle via mitochondrial mRNA stabilization, offering insights into how exercise enhances mitoribosome capacity and mitochondrial quality control to alleviate defects.

DOI: https://doi.org/10.1038/s41467-024-54183-4
J Mol Neurosci. 2024 Nov 08. 74(4): 107

Mitophagy Unveiled: Exploring the Nexus of Mitochondrial Health and Neuroendocrinopathy.

Mega Obukohwo Oyovwi, Emeka Williams Ugwuishi, Onoriode Andrew Udi, Gregory Joseph Uchechukwu.

  Mitochondria play a pivotal role in cellular metabolism, energy production, and apoptotic signaling, making mitophagy, the selective degradation of damaged mitochondria, crucial for mitochondrial health. Dysregulation of mitophagy has been implicated in various neuroendocrinopathies, yet the mechanisms linking these processes remain poorly understood. This review aims to explore the intersection between mitophagy and neuroendocrinopathy, addressing the critical gaps in knowledge regarding how mitochondrial dysfunction may contribute to the pathophysiology of neuroendocrine disorders. We conducted a comprehensive literature review of studies published on mitophagy and neuroendocrinopathies, focusing on data that elucidate the pathways involved and the clinical implications of mitochondrial health in neuroendocrine contexts. Our findings indicate that altered mitophagy may lead to the accumulation of dysfunctional mitochondria, contributing to neuroendocrine dysregulation. We present evidence linking impaired mitochondrial clearance to disease models of conditions such as metabolic syndrome, depression, and stress-related disorders, highlighting the potential for therapeutic interventions targeting mitophagy. While significant advances have been made in understanding mitochondrial biology, the direct interplay between mitophagy and neuroendocrinopathies remains underexplored. This review underscores the necessity for further research to elucidate these connections, which may offer novel insights into disease mechanisms and therapeutic strategies for treating maladaptive neuroendocrine responses.

Keywords:  Cellular resilience; Mitochondrial dynamics; Mitochondrial health; Mitophagy; Neuroendocrinopathy; Oxidative stress; Therapeutic interventions

DOI:  https://doi.org/10.1007/s12031-024-02280-w
Autophagy. 2024 Nov 09.

A PRKN-independent Mechanism Regulating Cardiac Mitochondrial Quality Control.

Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su.

  PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of Rnf7 in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.

Keywords:  Heart failure; RBX2/SAG; mitophagy; parkin; ubiquitination

DOI:  https://doi.org/10.1080/15548627.2024.2423329
Nat Cell Biol. 2024 Nov 15.

FMRP regulates MFF translation to locally direct mitochondrial fission in neurons.

Adam R Fenton, Ruchao Peng, Charles Bond, Siewert Hugelier, Melike Lakadamyali, Yi-Wei Chang, Erika L F Holzbaur, Thomas A Jongens.

Fragile X messenger ribonucleoprotein (FMRP) is a critical regulator of translation, whose dysfunction causes fragile X syndrome. FMRP dysfunction disrupts mitochondrial health in neurons, but it is unclear how FMRP supports mitochondrial homoeostasis. Here we demonstrate that FMRP granules are recruited to the mitochondrial midzone, where they mark mitochondrial fission sites in axons and dendrites. Endolysosomal vesicles contribute to FMRP granule positioning around mitochondria and facilitate FMRP-associated fission via Rab7 GTP hydrolysis. Cryo-electron tomography and real-time translation imaging reveal that mitochondria-associated FMRP granules are ribosome-rich structures that serve as sites of local protein synthesis. Specifically, FMRP promotes local translation of mitochondrial fission factor (MFF), selectively enabling replicative fission at the mitochondrial midzone. Disrupting FMRP function dysregulates mitochondria-associated MFF translation and perturbs fission dynamics, resulting in increased peripheral fission and an irregular distribution of mitochondrial nucleoids. Thus, FMRP regulates local translation of MFF in neurons, enabling precise control of mitochondrial fission.

DOI: https://doi.org/10.1038/s41556-024-01544-2
Placenta. 2024 Nov 02. pii: S0143-4004(24)00742-2. [Epub ahead of print]158 253-262

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia.

Jessica L Faulkner, Mayumi Takano, Safia Ogbi, Wen Tong, Masahiko Nakata, Desmond Moronge, Tereza Cindrova-Davies, Dino A Giussani.

   INTRODUCTION: Preeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown.
METHODS: In the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPRer) and mitochondrial (UPRmt) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice.
RESULTS: The data show that mid-late gestation leptin infusion induced activation of indices of placental UPRer and UPRmt, while reducing placental repair mechanisms to UPRmt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPRmt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice.
DISCUSSION: Collectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia.

Keywords:  Leptin; Oxidative stress; Placenta; Unfolded protein response

DOI:  https://doi.org/10.1016/j.placenta.2024.11.001
Neuromuscul Disord. 2024 Oct 25. pii: S0960-8966(24)01731-0. [Epub ahead of print]45 105235

Mitochondrial disorders are associated with morphological neuromuscular junction defects.

Lola E R Lessard, Emmanuelle Girard, Nathalie Streichenberger, Philippe Petiot, Cécile Acquaviva, Cécile Pagan, Peter Mulligan, Françoise Bouhour, Laurent Schaeffer, Arnaud Jacquier.

  We aimed to evaluate whether inherited mitochondrial dysfunction is associated with neuromuscular junction remodeling in patients with mitochondrial disorders. Muscle biopsies from 15 patients with mitochondrial disorders and 10 control patients were analyzed through immunostaining for various neuromuscular junction components. The patient group, with a mean age of 49.9 years, exhibited various mitochondrial disorders including chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes. Patients with mitochondrial disorders had a high percentage of remodeled (p= 0.0001), neoformed (p= 0.0049) and dilated (p= 0.016) endplates. There was a trend toward an increased proportion of neuromuscular junctions with terminal Schwann cell extension in these patients (p= 0.052). No significant difference was found in myofiber diameter between the groups. The observed neuromuscular junction defects varied widely across different mitochondrial disorder phenotypes and were present even without accompanying muscle weakness or neuropathy. This suggest that mitochondrial disorders are associated with a primary NMJ remodeling independent of muscle structural damage. Pathomechanisms underpinning this remodeling of the neuromuscular junction, as well as clinical factors predictive of this remodeling, remain to be fully characterized.

Keywords:  Confocal microscopy; Denervation; Fatigability; Ptosis; Reinnervation; Remodeling

DOI:  https://doi.org/10.1016/j.nmd.2024.105235
Cells. 2024 Oct 26. pii: 1773. [Epub ahead of print]13(21):

Mitochondrial Dynamics Drive Muscle Stem Cell Progression from Quiescence to Myogenic Differentiation.

Olivia Sommers, Rholls A Tomsine, Mireille Khacho.

  From quiescence to activation and myogenic differentiation, muscle stem cells (MuSCs) experience drastic alterations in their signaling activity and metabolism. Through balanced cycles of fission and fusion, mitochondria alter their morphology and metabolism, allowing them to affect their decisive role in modulating MuSC activity and fate decisions. This tightly regulated process contributes to MuSC regulation by mediating changes in redox signaling pathways, cell cycle progression, and cell fate decisions. In this review, we discuss the role of mitochondrial dynamics as an integral modulator of MuSC activity, fate, and maintenance. Understanding the influence of mitochondrial dynamics in MuSCs in health and disease will further the development of therapeutics that support MuSC integrity and thus may aid in restoring the regenerative capacity of skeletal muscle.

Keywords:  DRP1; OPA1; differentiation; glutathione; metabolism; mitochondria; mitochondrial dynamics; muscle stem cells; myogenesis; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cells13211773
JIMD Rep. 2024 Nov;65(6): 417-425

Expanding the genetic and clinical spectrum of SLC25A42-associated disorders and testing of pantothenic acid to improve CoA level in vitro.

Katharina Heckmann, Arcangela Iuso, Janine Reunert, Marianne Grüneberg, Anja Seelhöfer, Stephan Rust, Giuseppe Fiermonte, Eleonora Paradies, Carmela Piazzolla, Manoj Mannil, Thorsten Marquardt.

  SLC25A42 encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty-one patients have been described so far. In the current study, we report on the identification of new biallelic variants in SLC25A42 in three siblings. Patients presented with symmetrical T2 hyperintensity of the putamen with minor volume depression at the brain MRI, elevated lactate, reduced oxygen consumption rates in muscle and fibroblasts, and reduced CoA levels in fibroblasts. Administration of pantothenic acid led to clinical stabilization and increased CoA levels in fibroblasts, thus confirming a role for SLC25A42 in energy metabolism and CoA homeostasis.

Keywords:  SLC25A42; cellular CoA; mitochondrial coenzyme transporter; mitochondrial respiration; pantothenic acid

DOI:  https://doi.org/10.1002/jmd2.12441
ACS Nano. 2024 Nov 15.

Mitophagy-Enhanced Nanoparticle-Engineered Mitochondria Restore Homeostasis of Mitochondrial Pool for Alleviating Pulmonary Fibrosis.

Yi Wang, Li-Fan Hu, Na-Hui Liu, Jing-Song Yang, Lei Xing, Jee-Heon Jeong, Ling Li, Hu-Lin Jiang.

  Pulmonary fibrosis (PF) is an interstitial lung disease tightly associated with the disruption of mitochondrial pool homeostasis, a delicate balance influenced by functional and dysfunctional mitochondria within lung cells. Mitochondrial transfer is an emerging technology to increase functional mitochondria via exogenous mitochondrial delivery; however, the therapeutic effect on mitochondrial transfer is hampered during the PF process by the persistence of dysfunctional mitochondria, which is attributed to impaired mitophagy. Herein, we reported engineering mitochondria mediated by mitophagy-enhanced nanoparticle (Mito-MEN), which promoted synchronal regulation of functional and dysfunctional mitochondria for treating PF. Mitophagy-enhanced nanoparticles (MENs) were fabricated through the encapsulation of Parkin mRNA, and the electrostatic interaction favored MENs to anchor isolated healthy mitochondria for the construction of Mito-MEN. Mito-MEN increased the load of functional exogenous mitochondria by enhancing mitochondrial delivery efficiency and promoted mitophagy of dysfunctional endogenous mitochondria. In a bleomycin (BLM)-induced PF mouse model, Mito-MEN repaired mitochondrial function and efficiently relieved PF-related phenotypes. This study provides a powerful tool for synchronal adjustment of mitochondrial pool homeostasis and offers a translational approach for pan-mitochondrial disease therapies.

Keywords:  alveolar epithelial cells; mitophagy; nanoengineered mitochondria; nanoparticle; pulmonary fibrosis

DOI:  https://doi.org/10.1021/acsnano.4c10328
Front Cell Dev Biol. 2024 ;12 1464773

The impact of cannabinoid receptor 1 absence on mouse liver mitochondria homeostasis: insight into mitochondrial unfolded protein response.

Rosalba Senese, Giuseppe Petito, Elena Silvestri, Maria Ventriglia, Nicola Mosca, Nicoletta Potenza, Aniello Russo, Sara Falvo, Francesco Manfrevola, Gilda Cobellis, Teresa Chioccarelli, Veronica Porreca, Vincenza Grazia Mele, Rosanna Chianese, Pieter de Lange, Giulia Ricci, Federica Cioffi, Antonia Lanni.

   Introduction: The contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes.
Methods: We used CB1-/- and CB1+/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis.
Results and discussion: In the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1-/- mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPRmt). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPRmt and UPRER pathways.

Keywords:  cannabinoid receptor 1; homeostasis; mitochondrial quality control; mitochondrial unfolded protein response; oxidative stress; respiratory chain supercomplexes

DOI:  https://doi.org/10.3389/fcell.2024.1464773
J Clin Invest. 2024 Nov 12. pii: e163648. [Epub ahead of print]

Nicotinamide and pyridoxine stimulate muscle stem cell expansion and enhance regenerative capacity during aging.

Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N Feige.

  Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

Keywords:  Adult stem cells; Epidemiology; Muscle biology; Skeletal muscle; Stem cells

DOI:  https://doi.org/10.1172/JCI163648
Sci Adv. 2024 Nov 15. 10(46): eadp7423

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval-functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

DOI: https://doi.org/10.1126/sciadv.adp7423
Hum Mol Genet. 2024 Nov 13. pii: ddae152. [Epub ahead of print]

Stem cell models of TAFAZZIN deficiency reveal novel tissue-specific pathologies in Barth syndrome.

Olivia Sniezek Carney, Kodi W Harris, Yvonne Wohlfarter, Kyuna Lee, Grant Butschek, Arianna F Anzmann, Anne Hamacher-Brady, Markus A Keller, Hilary J Vernon.

  Barth syndrome (BTHS) is a rare mitochondrial disease caused by pathogenic variants in the gene TAFAZZIN, which leads to abnormal cardiolipin (CL) metabolism on the inner mitochondrial membrane. Although TAFAZZIN is ubiquitously expressed, BTHS involves a complex combination of tissue specific phenotypes including cardiomyopathy, neutropenia, skeletal myopathy, and growth delays, with a relatively minimal neurological burden. To understand both the developmental and functional effects of TAZ-deficiency in different tissues, we generated isogenic TAZ knockout (TAZ-KO) and WT cardiomyocytes (CMs) and neural progenitor cells (NPCs) from CRISPR-edited induced pluripotent stem cells (iPSCs). In TAZ-KO CMs we discovered evidence of dysregulated mitophagy including dysmorphic mitochondria and mitochondrial cristae, differential expression of key autophagy-associated genes, and an inability of TAZ-deficient CMs to properly initiate stress-induced mitophagy. In TAZ-deficient NPCs we identified novel phenotypes including a reduction in CIV abundance and CIV activity in the CIII2&CIV2 intermediate complex. Interestingly, while CL acyl chain manipulation was unable to alter mitophagy defects in TAZ-KO CMs, we found that linoleic acid or oleic acid supplementation was able to partially restore CIV abundance in TAZ-deficient NPCs. Taken together, our results have implications for understanding the tissue-specific pathology of BTHS and potential for tissue-specific therapeutic targeting. Moreover, our results highlight an emerging role for mitophagy in the cardiac pathophysiology of BTHS and reveal a potential neuron-specific bioenergetic phenotype.

Keywords:  Barth syndrome; TAFAZZIN; cardiomyopathy; mitophagy

DOI:  https://doi.org/10.1093/hmg/ddae152
Methods Mol Biol. 2025 ;2878 67-74

Metabolic Phenotyping of Synaptic Mitochondria Using MitoPlates™ and Synaptoneurosomes.

Aleksandra Stawikowska, Magdalena Dziembowska, Bozena Kuzniewska.

  Mitochondrial functional assays using MitoPlates™ S-1 allow us to characterize mitochondria in terms of substrate metabolism. MitoPlates™ are 96-well microplates pre-coated with a diverse set of substrates. The electron flow from NADH and FADH2 producing mitochondrial substrates is measured based on the reduction of redox dye, that acts as a terminal electron acceptor. Here, we describe the application of MitoPlates™ to characterize the metabolism of synaptic mitochondria enclosed in isolated pre- and postsynaptic terminals (synaptoneurosomes).

Keywords:  MitoPlates™; Mitochondrial substrate metabolism; Synaptic mitochondria; Synaptoneurosomes

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_4
J Biol Eng. 2024 Nov 14. 18(1): 67

A rotenone organotypic whole hemisphere slice model of mitochondrial abnormalities in the neonatal brain.

Brendan Butler, Malcolm Renney, Kristin Bennett, Gisele Charpentier, Elizabeth Nance.

  Mitochondrial abnormalities underscore a variety of neurologic injuries and diseases and are well-studied in adult populations. Clinical studies identify critical roles of mitochondria in a wide range of developmental brain injuries, but models that capture mitochondrial abnormalities in systems representative of the neonatal brain environment are lacking. Here, we develop an organotypic whole-hemisphere (OWH) brain slice model of mitochondrial dysfunction in the neonatal brain. We extended the utility of complex I inhibitor rotenone (ROT), canonically used in models of adult neurodegenerative diseases, to inflict mitochondrial damage in OWH slices from term-equivalent rats. We quantified whole-slice health over 6 days of exposure for a range of doses represented in ROT literature. We identified 50 nM ROT as a suitable exposure level for OWH slices to inflict injury without compromising viability. At the selected exposure level, we confirmed exposure- and time-dependent mitochondrial responses showing differences in mitochondrial fluorescence and nuclear localization using MitoTracker imaging in live OWH slices and dysregulated mitochondrial markers via RT-qPCR screening. We leveraged the regional structures present in OWH slices to quantify cell density and cell death in the cortex and the midbrain regions, observing higher susceptibilities to damage in the midbrain as a function of exposure and culture time. We supplemented these findings with analysis of microglia and mature neurons showing time-, region-, and exposure-dependent differences in microglial responses. We demonstrated changes in tissue microstructure as a function of region, culture time, and exposure level using live-video epifluorescence microscopy of extracellularly diffusing nanoparticle probes in live OWH slices. Our results highlight severity-, time-, and region-dependent responses and establish a complimentary model system of mitochondrial abnormalities for high-throughput or live-tissue experimental needs.

Keywords:  Cellular metabolism; Confocal microscopy; Ex vivo model; Nanoparticle tracking; Neurodevelopment

DOI:  https://doi.org/10.1186/s13036-024-00465-w
Life Sci Alliance. 2025 Feb;pii: e202402969. [Epub ahead of print]8(2):

KAT6B is required for histone 3 lysine 9 acetylation and SOX gene expression in the developing brain.

Maria I Bergamasco, Waruni Abeysekera, Alexandra L Garnham, Yifang Hu, Connie Sn Li-Wai-Suen, Bilal N Sheikh, Gordon K Smyth, Tim Thomas, Anne K Voss.

Heterozygous mutations in the histone lysine acetyltransferase gene KAT6B (MYST4/MORF/QKF) underlie neurodevelopmental disorders, but the mechanistic roles of KAT6B remain poorly understood. Here, we show that loss of KAT6B in embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, and neurite outgrowth. Mechanistically, loss of KAT6B resulted in reduced acetylation at histone H3 lysine 9 and reduced expression of key nervous system development genes in NSPCs and the developing cortex, including the SOX gene family, in particular Sox2, which is a key driver of neural progenitor proliferation, multipotency and brain development. In the fetal cortex, KAT6B occupied the Sox2 locus. Loss of KAT6B caused a reduction in Sox2 promoter activity in NSPCs. Sox2 overexpression partially rescued the proliferative defect of Kat6b -/- NSPCs. Collectively, these results elucidate molecular requirements for KAT6B in brain development and identify key KAT6B targets in neural precursor cells and the developing brain.

DOI: https://doi.org/10.26508/lsa.202402969
J Inherit Metab Dis. 2024 Nov 11.

Current global vitamin and cofactor prescribing practices for primary mitochondrial diseases: Results of a European reference network survey.

MetabERN PM‐MD Consortium authors

  Primary mitochondrial diseases (PMD) account for a group of approximately 400 different genetic disorders with diverse clinical presentations and pathomechanisms. Although each individual disorder is rare, collectively they represent one of the largest groups in the field of inherited metabolic disorders. The complexity of PMD results in a continued lack of therapeutic options, necessitating a predominantly symptomatic treatment approach for affected patients. While a subset of diseases responds exceptionally well to treatment with specific vitamins or cofactors, for most PMD systematic reviews were not able to show significant benefit. This is in discrepancy to their continued frequent use among specialists. To gain further insight into the current clinical practice of vitamin and cofactor supplementation among clinicians treating children and adults affected by PMD, we conducted a worldwide cross-sectional questionnaire study exploring the choice of substances and the specific diseases where they are applied. To our knowledge, this is the first global study exploring this topic and featuring a high response rate from paediatricians. The vast majority (95%, 106/112) of responding specialists recommended the use of vitamins and cofactors, either in an agnostic approach irrespective of the specific PMD or directed to the treatment of specific diseases or phenotypes. Our study highlights significant regional and specialty-specific differences in supplementation practices. We provide some preliminary insights into specialist-based opinions regarding the use of vitamins and cofactors in PMD and highlight the need for more rigorous clinical and preclinical investigations and/or clear consensus statements.

Keywords:  cofactors; cross sectional study; inherited metabolic disease; primary mitochondrial disease; survey; treatment; vitamins

DOI:  https://doi.org/10.1002/jimd.12805
Int J Mol Sci. 2024 Oct 29. pii: 11615. [Epub ahead of print]25(21):

Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters.

Sara Petrillo, Alessia Perna, Andrea Quatrana, Gabriella Silvestri, Enrico Bertini, Fiorella Piemonte, Massimo Santoro.

  Friedreich ataxia (FRDA) is the most common inherited ataxia, primarily impacting the nervous system and the heart. It is characterized by GAA repeat expansion in the FXN gene, leading to reduced mitochondrial frataxin levels. Previously, we described a family displaying two expanded GAA alleles, not only in the proband affected by late-onset FRDA but also in the younger asymptomatic sister. The molecular characterization of the expanded repeats showed that the affected sister carried two canonical uninterrupted GAA expended repeats, whereas the asymptomatic sister had a compound heterozygous for a canonical GAA repeat and an expanded GAAGGA motif. Therefore, we decided to perform RNA sequencing (RNA-seq) on fibroblasts from both sisters in order to understand whether some genes and/or pathways might be differently involved in the occurrence of FRDA clinical manifestation. The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention.

Keywords:  Friedreich’s ataxia; RNA-seq; TLR4; differentially expressed genes (DEGs); inflammation; neurodegenerative disease; transcriptomic analysis

DOI:  https://doi.org/10.3390/ijms252111615
Methods Mol Biol. 2025 ;2878 211-221

Understanding Mitochondrial and Lysosomal Dynamics by Fluorescent Microscopy.

Pedro A Dionísio, Vilma A Sardão, Nuno Raimundo.

  Live cell imaging is a robust method to visualize dynamic cellular structures, especially organelles with network-like structures such as mitochondria. In this regard, mitochondrial dynamics, namely mitochondrial fission and fusion, are highly dynamic processes that regulate mitochondrial size and morphology depending on a plethora of cellular cues. Likewise, lysosome size and distribution may hint at their function and state.Here, we describe how to perform live cell confocal imaging using commercially available organelle dyes (MitoTracker, LysoTracker), followed by either 2D or 3D analyses of mitochondrial morphology/network connectivity and lysosomal morphology using the freely available Mitochondria Analyzer plugin for ImageJ/Fiji.

Keywords:  Cell imaging; Fluorescent probes; LysoTracker; Lysosomes; Microscopy; MitoTracker; Mitochondria; Mitochondrial dynamics

DOI:  https://doi.org/10.1007/978-1-0716-4264-1_11
Cell Commun Signal. 2024 Nov 08. 22(1): 537

NAD+ enhancers as therapeutic agents in the cardiorenal axis.

Mariano Marín-Blázquez, Jordi Rovira, María José Ramírez-Bajo, Rubén Zapata-Pérez, Rubén Rabadán-Ros.

  Cardiorenal diseases represent a complex interplay between heart failure and renal dysfunction, being clinically classified as cardiorenal syndromes (CRS). Recently, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism, through deficient NAD+ synthesis and/or elevated consumption, have proved to be decisive in the onset and progress of cardiorenal disease. NAD+ is a pivotal coenzyme in cellular metabolism, being significant in various signaling pathways, such as energy metabolism, DNA damage repair, gene expression, and stress response. Convincing evidence suggests that strategies designed to boost cellular NAD+ levels are a promising therapeutic option to address cardiovascular and renal disorders. Here, we review and discuss the implications of NAD+ metabolism in cardiorenal diseases, focusing on the propitious NAD+ boosting therapeutic strategies, based on the use of NAD+ precursors, poly(ADP-ribose) polymerase inhibitors, sirtuin activators, and other alternative approaches, such as CD38 blockade, nicotinamide phosphoribosyltransferase activation and combined interventions.

Keywords:  AKI; Animal models; CD38; Cardiorenal syndrome; Clinical trial; Ischemia/reperfusion; NAD+ metabolism; NMNH; NRH; Niacin; Niacinamide; Nicotinamide; Nicotinamide mononucleotide; Nicotinamide riboside; Poly(ADP-ribose) polymerases; Sirtuins; Trigonelline

DOI:  https://doi.org/10.1186/s12964-024-01903-4
J Cereb Blood Flow Metab. 2024 Nov 14. 271678X241300223

Molecular and cellular mechanisms of mitochondria transfer in models of central nervous system disease.

Takafumi Nakano, Keiichi Irie, Koichi Matsuo, Kenichi Mishima, Yoshihiko Nakamura.

  In the central nervous system (CNS), neuronal function and dysfunction are critically dependent on mitochondrial integrity and activity. In damaged or diseased brains, mitochondrial dysfunction reduces adenosine triphosphate (ATP) levels and impairs ATP-dependent neural firing and neurotransmitter dynamics. Restoring mitochondrial capacity to generate ATP may be fundamental in restoring neuronal function. Recent studies in animals and humans have demonstrated that endogenous mitochondria may be released into the extracellular environment and transported or exchanged between cells in the CNS. Under pathological conditions in the CNS, intercellular mitochondria transfer contributes to new classes of signaling and multifunctional cellular activities, thereby triggering deleterious effects or promoting beneficial responses. Therefore, to take full advantage of the beneficial effects of mitochondria, it may be useful to transplant healthy and viable mitochondria into damaged tissues. In this review, we describe recent findings on the mechanisms of mitochondria transfer and provide an overview of experimental methodologies, including tissue sourcing, mitochondrial isolation, storage, and modification, aimed at optimizing mitochondria transplantation therapy for CNS disorders. Additionally, we examine the clinical relevance and potential strategies for the therapeutic application of mitochondria transplantation.

Keywords:  Central nervous system; experimental disease models; mitochondria transplantation; therapeutic strategies; transfer mechanism

DOI:  https://doi.org/10.1177/0271678X241300223
Cell Death Dis. 2024 Nov 08. 15(11): 807

TAp73 regulates mitochondrial dynamics and multiciliated cell homeostasis through an OPA1 axis.

Niall A Buckley, Andrew Craxton, Xiao-Ming Sun, Emanuele Panatta, Lucia Giraldez Pinon, Sina Beier, Lajos Kalmar, Jaime Llodrá, Nobuhiro Morone, Ivano Amelio, Gerry Melino, L Miguel Martins, Marion MacFarlane.

Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic Atrophy 1 (OPA1), a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy production via oxidative phosphorylation. Owing to the role of OPA1 in modulating cytochrome c release, TAp73-/- cells display an increased sensitivity to apoptotic cell death, e.g., via BH3-mimetics. We additionally show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells of Trp73-/- (global p73 knock-out) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this, Trp73 and OPA1 gene expression is decreased in chronic obstructive pulmonary disease (COPD) patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. Our findings also add to the growing body of evidence for growth-promoting roles of TAp73 isoforms.

DOI: https://doi.org/10.1038/s41419-024-07130-6
Nat Commun. 2024 Nov 11. 15(1): 9752

Metabolomic signatures associated with fetal growth restriction and small for gestational age: a systematic review.

Agustin Conde-Agudelo, Jose Villar, Milagros Risso, Aris T Papageorghiou, Lee D Roberts, Stephen H Kennedy.

The pathways involved in the pathophysiology of fetal growth restriction (FGR) and small for gestational age (SGA) are incompletely understood. We conduct a systematic review to identify metabolomic signatures in maternal and newborn tissues and body fluids samples associated with FGR/SGA. Here, we report that 825 non-duplicated metabolites were significantly altered across the 48 included studies using 10 different human biological samples, of which only 56 (17 amino acids, 12 acylcarnitines, 11 glycerophosphocholines, six fatty acids, two hydroxy acids, and eight other metabolites) were significantly and consistently up- or down-regulated in more than one study. Three amino acid metabolism-related pathways and one related with lipid metabolism are significantly associated with FGR and/or SGA: biosynthesis of unsaturated fatty acids in umbilical cord blood, and phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, and phenylalanine metabolism in newborn dried blood spot. Significantly enriched metabolic pathways were not identified in the remaining biological samples. Whether these metabolites are in the causal pathways or are biomarkers of fetal nutritional deficiency needs to be explored in large, well-phenotyped cohorts.

DOI: https://doi.org/10.1038/s41467-024-53597-4
Nat Methods. 2024 Nov 14.

Deep learning-based models for preimplantation mouse and human embryos based on single-cell RNA sequencing.

Martin Proks, Nazmus Salehin, Joshua M Brickman.

The rapid growth of single-cell transcriptomic technology has produced an increasing number of datasets for both embryonic development and in vitro pluripotent stem cell-derived models. This avalanche of data surrounding pluripotency and the process of lineage specification has meant it has become increasingly difficult to define specific cell types or states in vivo, and compare these with in vitro differentiation. Here we utilize a set of deep learning tools to integrate and classify multiple datasets. This allows the definition of both mouse and human embryo cell types, lineages and states, thereby maximizing the information one can garner from these precious experimental resources. Our approaches are built on recent initiatives for large-scale human organ atlases, but here we focus on material that is difficult to obtain and process, spanning early mouse and human development. Using publicly available data for these stages, we test different deep learning approaches and develop a model to classify cell types in an unbiased fashion at the same time as defining the set of genes used by the model to identify lineages, cell types and states. We used our models trained on in vivo development to classify pluripotent stem cell models for both mouse and human development, showcasing the importance of this resource as a dynamic reference for early embryogenesis.

DOI: https://doi.org/10.1038/s41592-024-02511-3
Int J Equity Health. 2024 Nov 08. 23(1): 230

Precision medicine and Friedreich ataxia: promoting equity, beneficence, and informed consent for novel gene therapies.

Faith A A Kwa, Evie Kendal.

Friedreich Ataxia (FA) is an incurable neurodegenerative disease with systemic consequences affecting vital organs including those of the central and peripheral nervous systems. This article will use FA as an example to explore some of the practical and ethical issues emerging in precision medicine for rare diseases. It will first describe the existing management strategies available for FA patients, before considering the potential impact of gene therapy trials on the prevention and treatment of disease symptoms. Finally, ethical considerations will be discussed, including equity of access and managing resource allocation dilemmas; balancing benefits, burdens and harms; and gaining informed consent for novel treatments.

DOI: https://doi.org/10.1186/s12939-024-02318-w
Nat Commun. 2024 Nov 08. 15(1): 9681

A proteolytic AAA+ machine poised to unfold protein substrates.

Alireza Ghanbarpour, Robert T Sauer, Joseph H Davis.

AAA+ proteolytic machines unfold proteins before degrading them. Here, we present cryoEM structures of ClpXP-substrate complexes that reveal a postulated but heretofore unseen intermediate in substrate unfolding/degradation. A ClpX hexamer draws natively folded substrates tightly against its axial channel via interactions with a fused C-terminal degron tail and ClpX-RKH loops that flexibly conform to the globular substrate. The specific ClpX-substrate contacts observed vary depending on the substrate degron and affinity tags, helping to explain ClpXP's ability to unfold/degrade a wide array of different cellular substrates. Some ClpX contacts with native substrates are enabled by upward movement of the seam subunit in the AAA+ spiral, a motion coupled to a rearrangement of contacts between the ClpX unfoldase and ClpP peptidase. Our structures additionally highlight ClpX's ability to translocate a diverse array of substrate topologies, including the co-translocation of two polypeptide chains.

DOI: https://doi.org/10.1038/s41467-024-53681-9