bims-mitmed 2024-05-12 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024–05–12
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
Charcot-Marie-Tooth type 2A in vivo models: Current updates.
Dendrite architecture determines mitochondrial distribution patterns in vivo.
Mitochondrial transplantation: A promising therapy for mitochondrial disorders.
An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
How to treat a "sweetheart" in mitochondrial cardiomyopathy.
Mitochondrial retinopathies and optic neuropathies: The impact of retinal imaging on modern understanding of pathogenesis, diagnosis, and management.
Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.
Gene therapy trials deliver double win.
Newborn Genetic Screening: Significance in Early Diagnosis of an Infant with Mitochondrial DNA Depletion Syndrome-6.
Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.
Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC).
Metabolic contribution to age-related chromosome missegregation in mammalian oocytes.
Regulation of placental amino acid transport in health and disease.
Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
Whole-body muscle magnetic resonance imaging in inflammatory myopathy with mitochondrial pathology.

Nat Metab. 2024 May 08.

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.

DOI: https://doi.org/10.1038/s42255-024-01039-2
J Cell Mol Med. 2024 May;28(9): e18293

Charcot-Marie-Tooth type 2A in vivo models: Current updates.

Elena Abati, Mafalda Rizzuti, Alessia Anastasia, Giacomo Pietro Comi, Stefania Corti, Federica Rizzo.

  Charcot-Marie-Tooth type 2A (CMT2A) is an inherited sensorimotor neuropathy associated with mutations within the Mitofusin 2 (MFN2) gene. These mutations impair normal mitochondrial functioning via different mechanisms, disturbing the equilibrium between mitochondrial fusion and fission, of mitophagy and mitochondrial axonal transport. Although CMT2A disease causes a significant disability, no resolutive treatment for CMT2A patients to date. In this context, reliable experimental models are essential to precisely dissect the molecular mechanisms of disease and to devise effective therapeutic strategies. The most commonly used models are either in vitro or in vivo, and among the latter murine models are by far the most versatile and popular. Here, we critically revised the most relevant literature focused on the experimental models, providing an update on the mammalian models of CMT2A developed to date. We highlighted the different phenotypic, histopathological and molecular characteristics, and their use in translational studies for bringing potential therapies from the bench to the bedside. In addition, we discussed limitations of these models and perspectives for future improvement.

Keywords:  Charcot–Marie‐Tooth type 2A; animal model; mitofusin 2; mouse models

DOI:  https://doi.org/10.1111/jcmm.18293
Cell Rep. 2024 May 06. pii: S2211-1247(24)00518-7. [Epub ahead of print]43(5): 114190

Dendrite architecture determines mitochondrial distribution patterns in vivo.

Eavan J Donovan, Anamika Agrawal, Nicole Liberman, Jordan I Kalai, Avi J Adler, Adam M Lamper, Hailey Q Wang, Nicholas J Chua, Elena F Koslover, Erin L Barnhart.

  Neuronal morphology influences synaptic connectivity and neuronal signal processing. However, it remains unclear how neuronal shape affects steady-state distributions of organelles like mitochondria. In this work, we investigated the link between mitochondrial transport and dendrite branching patterns by combining mathematical modeling with in vivo measurements of dendrite architecture, mitochondrial motility, and mitochondrial localization patterns in Drosophila HS (horizontal system) neurons. In our model, different forms of morphological and transport scaling rules-which set the relative thicknesses of parent and daughter branches at each junction in the dendritic arbor and link mitochondrial motility to branch thickness-predict dramatically different global mitochondrial localization patterns. We show that HS dendrites obey the specific subset of scaling rules that, in our model, lead to realistic mitochondrial distributions. Moreover, we demonstrate that neuronal activity does not affect mitochondrial transport or localization, indicating that steady-state mitochondrial distributions are hard-wired by the architecture of the neuron.

Keywords:  CP: Cell biology; CP: Neuroscience; dendrite scaling; in vivo imaging; mitochondrial motility; neuronal morphology

DOI:  https://doi.org/10.1016/j.celrep.2024.114190
Int J Pharm. 2024 May 02. pii: S0378-5173(24)00428-9. [Epub ahead of print] 124194

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

Qiangqiang Jiao, Li Xiang, Yuping Chen.

  As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trial for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Keywords:  Artificial mitochondria; Clinical trials; Mitochondrial medicine; Mitochondrial transplantation

DOI:  https://doi.org/10.1016/j.ijpharm.2024.124194
Nat Commun. 2024 May 07. 15(1): 3793

An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.

Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.

Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.

DOI: https://doi.org/10.1038/s41467-024-48189-1
EMBO Mol Med. 2024 May 09.

How to treat a "sweetheart" in mitochondrial cardiomyopathy.

Hsin-Pin Lin, Derek P Narendra.

DOI: https://doi.org/10.1038/s44321-024-00070-w
Prog Retin Eye Res. 2024 May 03. pii: S1350-9462(24)00029-6. [Epub ahead of print]101 101264

Mitochondrial retinopathies and optic neuropathies: The impact of retinal imaging on modern understanding of pathogenesis, diagnosis, and management.

Enrico Borrelli, Francesco Bandello, Camiel J F Boon, Valerio Carelli, Guy Lenaers, Michele Reibaldi, Srinivas R Sadda, Alfredo A Sadun, David Sarraf, Patrick Yu-Wai-Man, Piero Barboni.

  Advancements in ocular imaging have significantly broadened our comprehension of mitochondrial retinopathies and optic neuropathies by examining the structural and pathological aspects of the retina and optic nerve in these conditions. This article aims to review the prominent imaging characteristics associated with mitochondrial retinopathies and optic neuropathies, aiming to deepen our insight into their pathogenesis and clinical features. Preceding this exploration, the article provides a detailed overview of the crucial genetic and clinical features, which is essential for the proper interpretation of in vivo imaging. More importantly, we will provide a critical analysis on how these imaging modalities could serve as biomarkers for characterization and monitoring, as well as in guiding treatment decisions. However, these imaging methods have limitations, which will be discussed along with potential strategies to mitigate them. Lastly, the article will emphasize the potential advantages and future integration of imaging techniques in evaluating patients with mitochondrial eye disorders, considering the prospects of emerging gene therapies.

Keywords:  Fundus autofluorescence; Imaging; Mitochondria; Optic neuropathy; Optical coherence tomography; Optical coherence tomography angiography; Retinal dystrophy

DOI:  https://doi.org/10.1016/j.preteyeres.2024.101264
Elife. 2024 May 07. pii: RP92178. [Epub ahead of print]12

Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms.

Mohammad Alfatah, Jolyn Jia Jia Lim, Yizhong Zhang, Arshia Naaz, Trishia Yi Ning Cheng, Sonia Yogasundaram, Nashrul Afiq Faidzinn, Jovian Jing Lin, Birgit Eisenhaber, Frank Eisenhaber.

  Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared genesets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralog RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Furthermore, we find that genetic- or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.

Keywords:  S. cerevisiae; cellular aging; genetics; genomics; human; lifespan; mitochondria; nutrient signaling; target of rapamycin complex 1; uncharacterized genes

DOI:  https://doi.org/10.7554/eLife.92178
Nat Med. 2024 May 09.

Gene therapy trials deliver double win.

Karen O'Leary.



Keywords:  Clinical trials; Gene therapy

DOI:  https://doi.org/10.1038/d41591-024-00033-1
J Obstet Gynaecol India. 2024 Apr;74(2): 176-178

Newborn Genetic Screening: Significance in Early Diagnosis of an Infant with Mitochondrial DNA Depletion Syndrome-6.

Sanjay A Gupte, Manju Kurup, Shweta M Jangam, Preeti Arora, Sarjan S Shah.

DOI: https://doi.org/10.1007/s13224-023-01770-y
Ann Clin Transl Neurol. 2024 May 08.

Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

Pamela J Yao, Apostolos Manolopoulos, Erden Eren, Susan Michelle Rivera, David R Hessl, Randi Hagerman, Veronica Martinez-Cerdeno, Flora Tassone, Dimitrios Kapogiannis.

OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum.
METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls.
RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity.
INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

DOI: https://doi.org/10.1002/acn3.52040
Front Genet. 2024 ;15 1375467

Human induced pluripotent stem cells (hiPSCs) derived cells reflect tissue specificity found in patients with Leigh syndrome French Canadian variant (LSFC).

Roselle Gélinas, Chloé Lévesque, Julie Thompson Legault, Marie-Eve Rivard, Louis Villeneuve, Catherine Laprise, John D Rioux.

  Leigh syndrome French Canadian type (LSFC) is a recessive neurodegenerative disease characterized by tissue-specific deficiency in cytochrome c oxidase (COX), the fourth complex in the oxidative phosphorylation system. LSFC is caused by mutations in the leucine rich pentatricopeptide repeat containing gene (LRPPRC). Most LSFC patients in Quebec are homozygous for an A354V substitution that causes a decrease in the expression of the LRPPRC protein. While LRPPRC is ubiquitously expressed and is involved in multiple cellular functions, tissue-specific expression of LRPPRC and COX activity is correlated with clinical features. In this proof-of-principle study, we developed human induced pluripotent stem cell (hiPSC)-based models from fibroblasts taken from a patient with LSFC, homozygous for the LRPPRC*354V allele, and from a control, homozygous for the LRPPRC*A354 allele. Specifically, for both of these fibroblast lines we generated hiPSC, hiPSC-derived cardiomyocytes (hiPSC-CMs) and hepatocyte-like cell (hiPSC-HLCs) lines, as well as the three germ layers. We observed that LRPPRC protein expression is reduced in all cell lines/layers derived from LSFC patient compared to control cells, with a reduction ranging from ∼70% in hiPSC-CMs to undetectable levels in hiPSC-HLC, reflecting tissue heterogeneity observed in patient tissues. We next performed exploratory analyses of these cell lines and observed that COX protein expression was reduced in all cell lines derived from LSFC patient compared to control cells. We also observed that mutant LRPPRC was associated with altered expression of key markers of endoplasmic reticulum stress response in hiPSC-HLCs but not in other cell types that were tested. While this demonstrates feasibility of the approach to experimentally study genotype-based differences that have tissue-specific impacts, this study will need to be extended to a larger number of patients and controls to not only validate the current observations but also to delve more deeply in the pathogenic mechanisms of LSFC.

Keywords:  Leigh syndrome French Canadian type; cardiomyocyte cells; disease modeling; hepatocyte-like cells; induced pluripotent stem cells; three germ layers

DOI:  https://doi.org/10.3389/fgene.2024.1375467
Reproduction. 2024 May 01. pii: REP-23-0510. [Epub ahead of print]

Metabolic contribution to age-related chromosome missegregation in mammalian oocytes.

Bettina P Mihalas, Adele L Marston, Lindsay E Wu, Robert B Gilchrist.

Advanced maternal age is a major cause of infertility, miscarriage, and congenital abnormalities. This is principally caused by a decrease in oocyte quality and developmental competence with age. Oocyte ageing is characterised by an increase in chromosome missegregation and aneuploidy. However, the underlying mechanisms of age-related aneuploidy have not been fully elucidated and are still under active investigation. In addition to chromosome missegregation, oocyte ageing is also accompanied by metabolic dysfunction. In this review, we integrate old and new perspectives on oocyte ageing, chromosome segregation and metabolism in mammalian oocytes and make direct links between these processes. We consider age-related alterations to chromosome segregation machinery, including the loss of cohesion, microtubule stability and the integrity of the spindle assembly checkpoint. We focus on how metabolic dysfunction in the ageing oocyte disrupts chromosome segregation machinery to contribute to and exacerbate age-related aneuploidy. More specifically, we discuss how mitochondrial function, ATP production and the generation of free radicals are altered during ageing. We also explore recent developments in oocyte metabolic ageing, including altered redox reactions (NAD+ metabolism) and the interactions between oocytes and their somatic nurse cells. Throughout the review we integrate the mechanisms by which changes in oocyte metabolism influence age-related chromosome missegregation.

DOI: https://doi.org/10.1530/REP-23-0510
Acta Physiol (Oxf). 2024 May 06. e14157

Regulation of placental amino acid transport in health and disease.

Hiroshi Shimada, Theresa L Powell, Thomas Jansson.

  Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

Keywords:  fetal development; fetal growth restriction; fetal overgrowth; human; maternal–fetal exchange; prenatal; programming; syncytiotrophoblast

DOI:  https://doi.org/10.1111/apha.14157
Nat Commun. 2024 May 04. 15(1): 3767

Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.

Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam.

Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs' biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.

DOI: https://doi.org/10.1038/s41467-024-48086-7
Front Neurol. 2024 ;15 1386293

Whole-body muscle magnetic resonance imaging in inflammatory myopathy with mitochondrial pathology.

Wagner Cid Palmeira Cavalcante, André Macedo Serafim da Silva, Rodrigo de Holanda Mendonça, Cristiane de Araújo Martins Moreno, Bruna Moreira de Souza Proença, Júlio Brandão Guimarães, Alípio Gomes Ormond Filho, Edmar Zanoteli.

   Introduction: Inflammatory myopathy with mitochondrial pathology (IM-Mito) is a rare condition described in a few case series, and it is not clear whether it is a specific disease or a variant of Inclusion Body Myositis (IBM). Radiological data of IM-Mito patients has only been evaluated in one study.
Aim: To analyze whole-body muscle magnetic resonance imaging (MRI) features in patients with IM-Mito compared with individuals with IBM.
Methods: Fourteen IM-Mito and ten IBM patients were included. IM-Mito was defined by endomysial inflammatory infiltrate, presence of at least 1% of Cytochrome C Oxidase negative fibers, and absence of rimmed vacuoles in muscle biopsy; and IBM was defined by the presence of dystrophic muscular abnormalities, endomysial inflammatory infiltrate, and rimmed vacuoles. Patients underwent clinical evaluation and whole-body muscle MRI to determine the presence of edema, and fatty infiltration in various muscles.
Results: Muscle imaging abnormalities were asymmetric in most patients with IM-Mito and IBM. Muscles with the highest average degree of fatty infiltration in both conditions were the quadriceps and medial gastrocnemius. Most patients with IM-Mito and IBM showed imaging patterns of rectus femoris relatively spared compared to other quadriceps muscles. The flexor digitorum profundus was the most affected muscle of the upper limbs in both IBM and IM-Mito.
Discussion: Although the results suggest some similarities in muscle imaging features between IM-Mito and IBM, there remains uncertainty whether these two conditions are part of the same clinical spectrum.

Keywords:  inclusion body myositis; inflammatory myopathy; magnetic resonance imaging; mitochondria; polymyositis

DOI:  https://doi.org/10.3389/fneur.2024.1386293