bims-mitmed 2024-10-06 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–10–06
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Skeletal Muscle Involvement in Friedreich Ataxia.
Biogenesis of mitochondrial β-barrel membrane proteins.
The role of PINK1-Parkin in mitochondrial quality control.
Mitochondrial Dysfunctions: Genetic and Cellular Implications Revealed by Various Model Organisms.
Temporal alterations of the nascent proteome in response to mitochondrial stress.
Mitochondria: the beating heart of the eukaryotic cell.
Biallelic Variants in COQ4 Cause Childhood-Onset Pure Hereditary Spastic Paraplegia.
SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.
Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.
Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.
Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.
Mitochondrial Dynamics and mRNA Translation: A Local Synaptic Tale.
New Insights into Mitochondria in Health and Diseases.
Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
p38α kinase governs muscle strength through PGC1α in mice.
Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.
Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.
Reassessing kinetin's effect on PINK1 and mitophagy.
An atlas of small non-coding RNAs in human preimplantation development.
Early human development and stem cell-based human embryo models.
Metabolic impairments in neurodegeneration with brain iron accumulation.
Preservation of Mitochondrial Function by SkQ1 in Skin Fibroblasts Derived from Patients with Leber's Hereditary Optic Neuropathy Is Associated with the PINK1/PRKN-Mediated Mitophagy.
Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.
An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development.

Int J Mol Sci. 2024 Sep 13. pii: 9915. [Epub ahead of print]25(18):

Skeletal Muscle Involvement in Friedreich Ataxia.

Elisabetta Indelicato, Julia Wanschitz, Wolfgang Löscher, Sylvia Boesch.

  Friedreich Ataxia (FRDA) is an inherited neuromuscular disorder triggered by a deficit of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency results in insufficient iron-sulfur cluster biosynthesis and impaired mitochondrial function and adenosine triphosphate production. The main clinical manifestation is a progressive balance and coordination disorder which depends on the involvement of peripheral and central sensory pathways as well as of the cerebellum. Besides the neurological involvement, FRDA affects also the striated muscles. The most prominent manifestation is a hypertrophic cardiomyopathy, which also represents the major determinant of premature mortality. Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Keywords:  Friedreich Ataxia; biomarker; frataxin; mitochondria; proteomics; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.3390/ijms25189915
FEBS Open Bio. 2024 Oct;14(10): 1595-1609

Biogenesis of mitochondrial β-barrel membrane proteins.

Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.

  β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.

Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein

DOI:  https://doi.org/10.1002/2211-5463.13905
Nat Cell Biol. 2024 Oct 02.

The role of PINK1-Parkin in mitochondrial quality control.

Derek P Narendra, Richard J Youle.

Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.

DOI: https://doi.org/10.1038/s41556-024-01513-9
Genes (Basel). 2024 Sep 01. pii: 1153. [Epub ahead of print]15(9):

Mitochondrial Dysfunctions: Genetic and Cellular Implications Revealed by Various Model Organisms.

Monika Stańczyk, Natalia Szubart, Roman Maslanka, Renata Zadrag-Tecza.

  Mitochondria play a crucial role in maintaining the energy status and redox homeostasis of eukaryotic cells. They are responsible for the metabolic efficiency of cells, providing both ATP and intermediate metabolic products. They also regulate cell survival and death under stress conditions by controlling the cell response or activating the apoptosis process. This functional diversity of mitochondria indicates their great importance for cellular metabolism. Hence, dysfunctions of these structures are increasingly recognized as an element of the etiology of many human diseases and, therefore, an extremely promising therapeutic target. Mitochondrial dysfunctions can be caused by mutations in both nuclear and mitochondrial DNA, as well as by stress factors or replication errors. Progress in knowledge about the biology of mitochondria, as well as the consequences for the efficiency of the entire organism resulting from the dysfunction of these structures, is achieved through the use of model organisms. They are an invaluable tool for analyzing complex cellular processes, leading to a better understanding of diseases caused by mitochondrial dysfunction. In this work, we review the most commonly used model organisms, discussing both their advantages and limitations in modeling fundamental mitochondrial processes or mitochondrial diseases.

Keywords:  mitochondria; mitochondrial dysfunction; model organisms

DOI:  https://doi.org/10.3390/genes15091153
Cell Rep. 2024 Oct 02. pii: S2211-1247(24)01154-9. [Epub ahead of print]43(10): 114803

Temporal alterations of the nascent proteome in response to mitochondrial stress.

Tomasz M Stępkowski, Vanessa Linke, Dorota Stadnik, Maciej Zakrzewski, Anna E Zawada, Remigiusz A Serwa, Agnieszka Chacinska.

  Under stress, protein synthesis is attenuated to preserve energy and mitigate challenges to protein homeostasis. Here, we describe, with high temporal resolution, the dynamic landscape of changes in the abundance of proteins synthesized upon stress from transient mitochondrial inner membrane depolarization. This nascent proteome was altered when global translation was attenuated by stress and began to normalize as translation was recovering. This transition was associated with a transient desynchronization of cytosolic and mitochondrial translation and recovery of cytosolic and mitochondrial ribosomal proteins. Further, the elongation factor EEF1A1 was downregulated upon mitochondrial stress, and its silencing mimicked the stress-induced nascent proteome remodeling, including alterations in the nascent respiratory chain proteins. Unexpectedly, the stress-induced alterations in the nascent proteome were independent of physiological protein abundance and turnover. In summary, we provide insights into the physiological and pathological consequences of mitochondrial function and dysfunction.

Keywords:  CP: Cell biology; CP: Metabolism; EEF1A; EEF1A1; cellular stress; elongation factor; mass spectrometry; mitochondria; nascent chain; protein synthesis; proteomics; translation

DOI:  https://doi.org/10.1016/j.celrep.2024.114803
FEBS Open Bio. 2024 Oct;14(10): 1588-1590

Mitochondria: the beating heart of the eukaryotic cell.

Johannes M Herrmann.

Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.

DOI: https://doi.org/10.1002/2211-5463.13884
Mov Disord Clin Pract. 2024 Oct 05.

Biallelic Variants in COQ4 Cause Childhood-Onset Pure Hereditary Spastic Paraplegia.

Luca Schierbaum, Vicente Quiroz, Amy Tam, Umar Zubair, Laura Tochen, Rasha Srouji, Kathryn Yang, Darius Ebrahimi-Fakhari.



Keywords:  coenzyme Q; hereditary spastic paraplegia; inborn error of metabolism; mitochondrial disease; spastic paraplegia

DOI:  https://doi.org/10.1002/mdc3.14226
Sci Adv. 2024 Oct 04. 10(40): eadq6223

SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.

Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.

Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.

DOI: https://doi.org/10.1126/sciadv.adq6223
Biomedicines. 2024 Sep 09. pii: 2050. [Epub ahead of print]12(9):

Succinate Dehydrogenase and Human Disease: Novel Insights into a Well-Known Enzyme.

María J Esteban-Amo, Patricia Jiménez-Cuadrado, Pablo Serrano-Lorenzo, Miguel Á de la Fuente, María Simarro.

  Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations.

Keywords:  complex II; disease; mitochondria; succinate dehydrogenase

DOI:  https://doi.org/10.3390/biomedicines12092050
bioRxiv. 2024 Sep 22. pii: 2024.09.20.614152. [Epub ahead of print]

Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific and individualized regulatory mechanisms.

Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.

Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have high and others low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic activities in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mtDNA density were correlated between tissues (median r = -0.01-0.16), indicating that animals with high mitochondrial capacity in one tissue can have low capacity in other tissues. Similarly, the multi-tissue correlation structure of RNAseq-based indices of mitochondrial gene expression across 45 tissues from 948 women and men (GTEx) showed small to moderate coherence between only some tissues (regions of the same brain), but not between brain-body tissue pairs in the same person (median r = 0.01). Mitochondrial DNA copy number (mtDNAcn) also lacked coherence across organs and tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were attributable in part to i) tissue-specific activation of canonical energy sensing pathways including the transcriptional coactivator PGC-111 and the integrated stress response (ISR), and ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with high mitochondrial gene expression in some tissues (e.g., heart) but low expression in others (e.g., skeletal muscle) who display different clinical phenotypic patterns. Taken together, these data raise the possibility that tissue-specific energy sensing pathways may contribute to the idiosyncratic mitochondrial distribution patterns associated with the inter-organ heterogeneity and phenotypic diversity among individuals.

DOI: https://doi.org/10.1101/2024.09.20.614152
EMBO J. 2024 Oct 04.

Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.

Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.

  Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.

Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00241-y
Mitochondrion. 2024 Oct 01. pii: S1567-7249(24)00130-2. [Epub ahead of print] 101972

Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.

Keshari Sriwastawa, Ashutosh Kumar.

  Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction is reported as a key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes, as well as functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide stable and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.

Keywords:  Diabetes; Diabetic neuropathy; Inflammasome; Mitochondria; Mitochondrial dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.mito.2024.101972
Front Neurol. 2024 ;15 1466275

Recognizing Leber's Hereditary Optic Neuropathy to avoid delayed diagnosis and misdiagnosis.

Chiara La Morgia, Maria Lucia Cascavilla, Anna Maria De Negri, Marcello Romano, Fabrizio Canalini, Silvia Rossi, Diego Centonze, Massimo Filippi.

  Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited optic nerve disease primarily caused by mutations in mitochondrial DNA (mtDNA). The peak of onset is typically between 15 and 30 years, but variability exists. Misdiagnosis, often as inflammatory optic neuritis, delays treatment, compounded by challenges in timely genetic diagnosis. Given the availability of a specific treatment for LHON, its early diagnosis is imperative to ensure therapeutic appropriateness. This work gives an updated guidance about LHON differential diagnosis to clinicians dealing also with multiple sclerosi and neuromyelitis optica spectrtum disorders-related optic neuritis. LHON diagnosis relies on clinical signs and paraclinical evaluations. Differential diagnosis in the acute phase primarily involves distinguishing inflammatory optic neuropathies, considering clinical clues such as ocular pain, fundus appearance and visual recovery. Imaging analysis obtained with Optical Coherence Tomography (OCT) assists clinicians in early recognition of LHON and help avoiding misdiagnosis. Genetic testing for the three most common LHON mutations is recommended initially, followed by comprehensive mtDNA sequencing if suspicion persists despite negative results. We present and discuss crucial strategies for accurate diagnosis and management of LHON cases.

Keywords:  Leber’s Hereditary Optic Neuropathy; Optical Coherence Tomography; optic nerve; retinal ganglion cell; visual field

DOI:  https://doi.org/10.3389/fneur.2024.1466275
Biology (Basel). 2024 Sep 23. pii: 746. [Epub ahead of print]13(9):

Mitochondrial Dynamics and mRNA Translation: A Local Synaptic Tale.

Marta Zaninello, Pedro Baptista, Filipe V Duarte.

  Mitochondria are dynamic organelles that can adjust and respond to different stimuli within a cell. This plastic ability allows them to effectively coordinate several cellular functions in cells and becomes particularly relevant in highly complex cells such as neurons. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular function and ultimately to a range of diseases, including neurodegenerative disorders. Regulation of mRNA transport and local translation inside neurons is crucial for maintaining the proteome of distal mitochondria, which is vital for energy production and synaptic function. A significant portion of the axonal transcriptome is dedicated to mRNAs for mitochondrial proteins, emphasizing the importance of local translation in sustaining mitochondrial function in areas far from the cell body. In neurons, local translation and the regulation of mRNAs encoding mitochondrial-shaping proteins could be essential for synaptic plasticity and neuronal health. The dynamics of these mRNAs, including their transport and local translation, may influence the morphology and function of mitochondria, thereby affecting the overall energy status and responsiveness of synapses. Comprehending the mitochondria-related mRNA regulation and local translation, as well as its influence on mitochondrial morphology near the synapses will help to better understand neuronal physiology and neurological diseases where mitochondrial dysfunction and impaired synaptic plasticity play a central role.

Keywords:  mRNA; mRNA trafficking; mitochondria; mitochondrial morphology; neuron; synapse

DOI:  https://doi.org/10.3390/biology13090746
Int J Mol Sci. 2024 Sep 16. pii: 9975. [Epub ahead of print]25(18):

New Insights into Mitochondria in Health and Diseases.

Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Ziyuan Wen, Mohan Su, Bing Li, Lina Yang.

  Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.

Keywords:  ROS; aging; bioenergetics; mitochondrial; mitochondrial dysfunction; mitochondrial targeted therapy; mtDNA; mutations

DOI:  https://doi.org/10.3390/ijms25189975
J Cachexia Sarcopenia Muscle. 2024 Oct 02.

Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.

Juan Diego Hernández-Camacho, Cristina Vicente-García, Lorena Ardila-García, Ana Padilla-Campos, Guillermo López-Lluch, Carlos Santos-Ocaña, Peter S Zammit, Jaime J Carvajal, Plácido Navas, Daniel J M Fernández-Ayala.

   BACKGROUND: ADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.
METHODS: We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.
RESULTS: We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).
CONCLUSIONS: Our work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.

Keywords:  ageing; coenzyme Q; development; mitochondria; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13574
Acta Physiol (Oxf). 2024 Oct 03. e14234

p38α kinase governs muscle strength through PGC1α in mice.

Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A Dumesic, Sarah E Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio.

   AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; muscle strength; p38α; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14234
Brain Sci. 2024 Sep 05. pii: 899. [Epub ahead of print]14(9):

Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases.

Adaleiz Ore, James M Angelastro, Cecilia Giulivi.

  The role of mitochondria in neurodegenerative diseases is crucial, and recent developments have highlighted its significance in cell therapy. Mitochondrial dysfunction has been implicated in various neurodegenerative disorders, including Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and Huntington's diseases. Understanding the impact of mitochondrial biology on these conditions can provide valuable insights for developing targeted cell therapies. This mini-review refocuses on mitochondria and emphasizes the potential of therapies leveraging mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, stem cell-derived secretions, and extracellular vesicles. Mesenchymal stem cell-mediated mitochondria transfer is highlighted for restoring mitochondrial health in cells with dysfunctional mitochondria. Additionally, attention is paid to gene-editing techniques such as mito-CRISPR, mitoTALENs, mito-ZNFs, and DdCBEs to ensure the safety and efficacy of stem cell treatments. Challenges and future directions are also discussed, including the possible tumorigenic effects of stem cells, off-target effects, disease targeting, immune rejection, and ethical issues.

Keywords:  cell therapy; ethical concerns; exosomes; extracellular vesicles; mitochondrial dysfunction; mitochondrial medicine; neurodegenerative diseases; stem cells

DOI:  https://doi.org/10.3390/brainsci14090899
EMBO Mol Med. 2024 Oct 02.

Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.

Jessica P Wiseman, Joseph M Scarrott, João Alves-Cruzeiro, Afshin Saffari, Cedric Böger, Evangelia Karyka, Emily Dawes, Alexandra K Davies, Paolo M Marchi, Emily Graves, Fiona Fernandes, Zih-Liang Yang, Ian Coldicott, Jennifer Hirst, Christopher P Webster, J Robin Highley, Neil Hackett, Adrienn Angyal, Thushan de Silva, Adrian Higginbottom, Pamela J Shaw, Laura Ferraiuolo, Darius Ebrahimi-Fakhari, Mimoun Azzouz.

  Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 β1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.

Keywords:  AAV; AP4B1; Gene Therapy; HSP; SPG47

DOI:  https://doi.org/10.1038/s44321-024-00148-5
Autophagy. 2024 Sep 29. 1-2

Reassessing kinetin's effect on PINK1 and mitophagy.

Zhong Yan Gan, David Komander, Sylvie Callegari.

  Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.

Keywords:  Mitophagy; PINK1; parkin; parkinson’s disease; protein kinase; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2024.2395144
Nat Commun. 2024 Oct 05. 15(1): 8634

An atlas of small non-coding RNAs in human preimplantation development.

Stewart J Russell, Cheng Zhao, Savana Biondic, Karen Menezes, Michael Hagemann-Jensen, Clifford L Librach, Sophie Petropoulos.

Understanding the molecular circuitries that govern early embryogenesis is important, yet our knowledge of these in human preimplantation development remains limited. Small non-coding RNAs (sncRNAs) can regulate gene expression and thus impact blastocyst formation, however, the expression of specific biotypes and their dynamics during preimplantation development remains unknown. Here we identify the abundance of and kinetics of piRNA, rRNA, snoRNA, tRNA, and miRNA from embryonic day (E)3-7 and isolate specific miRNAs and snoRNAs of particular importance in blastocyst formation and pluripotency. These sncRNAs correspond to specific genomic hotspots: an enrichment of the chromosome 19 miRNA cluster (C19MC) in the trophectoderm (TE), and the chromosome 14 miRNA cluster (C14MC) and MEG8-related snoRNAs in the inner cell mass (ICM), which may serve as 'master regulators' of potency and lineage. Additionally, we observe a developmental transition with 21 isomiRs and in tRNA fragment (tRF) codon usage and identify two novel miRNAs. Our analysis provides a comprehensive measure of sncRNA biotypes and their corresponding dynamics throughout human preimplantation development, providing an extensive resource. Better understanding the sncRNA regulatory programmes in human embryogenesis will inform strategies to improve embryo development and outcomes of assisted reproductive technologies. We anticipate broad usage of our data as a resource for studies aimed at understanding embryogenesis, optimising stem cell-based models, assisted reproductive technology, and stem cell biology.

DOI: https://doi.org/10.1038/s41467-024-52943-w
Cell Stem Cell. 2024 Oct 03. pii: S1934-5909(24)00316-3. [Epub ahead of print]31(10): 1398-1418

Early human development and stem cell-based human embryo models.

Marta N Shahbazi, Vincent Pasque.

  The use of stem cells to model the early human embryo promises to transform our understanding of developmental biology and human reproduction. In this review, we present our current knowledge of the first 2 weeks of human embryo development. We first focus on the distinct cell lineages of the embryo and the derivation of stem cell lines. We then discuss the intercellular crosstalk that guides early embryo development and how this crosstalk is recapitulated in vitro to generate stem cell-based embryo models. We highlight advances in this fast-developing field, discuss current limitations, and provide a vision for the future.

Keywords:  human embryos; pluripotent stem cells; stem cell-based embryo models

DOI:  https://doi.org/10.1016/j.stem.2024.09.002
Biochim Biophys Acta Bioenerg. 2024 Oct 02. pii: S0005-2728(24)00487-0. [Epub ahead of print] 149517

Metabolic impairments in neurodegeneration with brain iron accumulation.

Agata Wydrych, Barbara Pakuła, Justyna Janikiewicz, Aneta M Dobosz, Patrycja Jakubek-Olszewska, Marta Skowrońska, Iwona Kurkowska-Jastrzębska, Maciej Cwyl, Mariola Popielarz, Paolo Pinton, Barbara Zavan, Agnieszka Dobrzyń, Magdalena Lebiedzińska-Arciszewska, Mariusz R Więckowski.

  Neurodegeneration with brain iron accumulation (NBIA) is a broad, heterogeneous group of rare inherited diseases (1-3 patients/1,000,000 people) characterized by progressive symptoms associated with excessive abnormal iron deposition in the brain. Approximately 15,000-20,000 individuals worldwide are estimated to be affected by NBIA. NBIA is usually associated with slowly progressive pyramidal and extrapyramidal symptoms, axonal motor neuropathy, optic nerve atrophy, cognitive impairment and neuropsychiatric disorders. To date, eleven subtypes of NBIA have been described and the most common ones include pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), mitochondrial membrane protein-associated neurodegeneration (MPAN) and beta-propeller protein-associated neurodegeneration (BPAN). We present a comprehensive overview of the evidence for disturbed cellular homeostasis and metabolic alterations in NBIA variants, with a careful focus on mitochondrial bioenergetics and lipid metabolism which drives a new perspective in understanding the course of this infrequent malady.

Keywords:  Bioenergetics; Iron accumulation in the brain; Lipid metabolism; Mitochondria; NBIA; Rare disease

DOI:  https://doi.org/10.1016/j.bbabio.2024.149517
Biomedicines. 2024 Sep 04. pii: 2020. [Epub ahead of print]12(9):

Preservation of Mitochondrial Function by SkQ1 in Skin Fibroblasts Derived from Patients with Leber's Hereditary Optic Neuropathy Is Associated with the PINK1/PRKN-Mediated Mitophagy.

Jin Xu, Yan Li, Shun Yao, Xiuxiu Jin, Mingzhu Yang, Qingge Guo, Ruiqi Qiu, Bo Lei.

  Increased or altered mitochondrial ROS production in the retinal ganglion cells is regarded as the chief culprit of the disease-causing Leber's hereditary optic neuropathy (LHON). SkQ1 is a rechargeable mitochondria-targeted antioxidant with high specificity and efficiency. SkQ1 has already been used to treat LHON patients, and a phase 2a randomized clinical trial of SkQ1 has demonstrated improvements in eyesight. However, the underlying mechanism of SkQ1 in LHON remains unclear. This study aimed to assess the effects and molecular mechanism of SkQ1 in the preservation of mitochondrial function using skin fibroblasts derived from LHON patients. Our study found that SkQ1 could reduce ROS production and stabilize the mitochondrial membrane. Mechanistically, through network pharmacology and molecular docking, we identified the key targets of SkQ1 as SOD2 and PINK1, which play crucial roles in redox and mitophagy. SkQ1 interacted with PINK1 and downregulated its expression to balance mitochondrial homeostasis. Collectively, the findings of our study reveal that by regulating PINK1/PRKN-mediated mitophagy, SkQ1 preserves mitochondrial function in LHON fibroblasts. The data indicate that SkQ1 may be a novel therapeutic intervention to prevent the progression of LHON.

Keywords:  Leber’s hereditary optic neuropathy; ROS; SkQ1; mitochondria function; mitophagy

DOI:  https://doi.org/10.3390/biomedicines12092020
Sci Rep. 2024 10 03. 14(1): 22965

Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.

Alexander Schaiter, Andreas Hentschel, Felix Kleefeld, Julia Schuld, Vincent Umathum, Tara Procida-Kowalski, Christopher Nelke, Angela Roth, Andreas Hahn, Heidrun H Krämer, Tobias Ruck, Rita Horvath, Peter F M van der Ven, Marek Bartkuhn, Andreas Roos, Anne Schänzer.

  To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC-MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4-28 months and adults aged 19-65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

Keywords:  Bioinformatics in omics; Mitochondria in aging; Muscle proteomics; Muscle transcriptomics

DOI:  https://doi.org/10.1038/s41598-024-74913-4
Exp Mol Med. 2024 Oct 03.

An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development.

Seoyeon Kim, Jihae Lee, In Gyeong Koh, Jungeun Ji, Hyun Jung Kim, Eunha Kim, Jihwan Park, Jong-Eun Park, Joon-Yong An.

Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. Lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage's influence on disease determination. Our findings facilitate unbiased comparisons of cell type‒disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders.

DOI: https://doi.org/10.1038/s12276-024-01328-6