bims-mitmed 2024-04-28 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2024‒04‒28
thirty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.
Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.
Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.
Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.
Mitochondrial sites of contact with the nucleus.
Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.
Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.
Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.
Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.
Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
Telomere length determines the mitochondrial copy number in blastocyst-stage embryos.
Inflammation and mitophagy are mitochondrial checkpoints to aging.
Primary Coenzyme Q10 Deficiency-Related Ataxias.
The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
Regulation of mitochondrial fission by fatty acyl-coenzyme A.
The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.
Presenting metabolomics analyses: what is in a number?
Unleashing the potential of mRNA therapeutics for inherited neurological diseases.
Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.
A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.
Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.
Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.
Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.
Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.
Quercetin prevents methylmercury-induced mitochondrial dysfunction in the cerebral cortex of mice.
Unraveling the Pathogenetic Mechanisms Underlying the Association between Specific Mitochondrial DNA Haplogroups and Parkinson's Disease.
Mitochondrial Venus is more likely to have a lower birthweight.
Placental Nanoparticle-mediated IGF1 Gene Therapy Corrects Fetal Growth Restriction in a Guinea Pig Model.
Multimodal cell atlas of the ageing human skeletal muscle.
Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
Loss of AMPK activity induces organelle dysfunction and oxidative stress during oocyte aging.

Nature. 2024 Apr 24.

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.

Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.

Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.

DOI: https://doi.org/10.1038/s41586-024-07332-0
Genes (Basel). 2024 Apr 17. pii: 500. [Epub ahead of print]15(4):

Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome.

Doriana Misceo, Petter Strømme, Fatemeh Bitarafan, Maninder Singh Chawla, Ying Sheng, Sandra Monica Bach de Courtade, Lars Eide, Eirik Frengen.

  Oxidative phosphorylation involves a complex multi-enzymatic mitochondrial machinery critical for proper functioning of the cell, and defects herein cause a wide range of diseases called "primary mitochondrial disorders" (PMDs). Mutations in about 400 nuclear and 37 mitochondrial genes have been documented to cause PMDs, which have an estimated birth prevalence of 1:5000. Here, we describe a 4-year-old female presenting from early childhood with psychomotor delay and white matter signal changes affecting several brain regions, including the brainstem, in addition to lactic and phytanic acidosis, compatible with Leigh syndrome, a genetically heterogeneous subgroup of PMDs. Whole genome sequencing of the family trio identified a homozygous 12.9 Kb deletion, entirely overlapping the NDUFA4 gene. Sanger sequencing of the breakpoints revealed that the genomic rearrangement was likely triggered by Alu elements flanking the gene. NDUFA4 encodes for a subunit of the respiratory chain Complex IV, whose activity was significantly reduced in the patient's fibroblasts. In one family, dysfunction of NDUFA4 was previously documented as causing mitochondrial Complex IV deficiency nuclear type 21 (MC4DN21, OMIM 619065), a relatively mild form of Leigh syndrome. Our finding confirms the loss of NDUFA4 function as an ultra-rare cause of Complex IV defect, clinically presenting as Leigh syndrome.

Keywords:  Alu element; COX; Complex IV; Leigh syndrome; NDUFA4/COXFA4; WGS; encephalopathy; structural variant (SV)

DOI:  https://doi.org/10.3390/genes15040500
Biomolecules. 2024 Mar 28. pii: 411. [Epub ahead of print]14(4):

Mitochondrial and Nuclear DNA Variants in Amyotrophic Lateral Sclerosis: Enrichment in the Mitochondrial Control Region and Sirtuin Pathway Genes in Spinal Cord Tissue.

Sharon Natasha Cox, Claudio Lo Giudice, Anna Lavecchia, Maria Luana Poeta, Matteo Chiara, Ernesto Picardi, Graziano Pesole.

  Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS.

Keywords:  Amyotrophic Lateral Sclerosis; WES; WGS; bioinformatic pipeline; heteroplasmy; mtDNA; nDNA; variants

DOI:  https://doi.org/10.3390/biom14040411
Life Sci Alliance. 2024 Jul;pii: e202302473. [Epub ahead of print]7(7):

Lineage-specific changes in mitochondrial properties during neural stem cell differentiation.

Rita Soares, Diogo M Lourenço, Isa F Mota, Ana M Sebastião, Sara Xapelli, Vanessa A Morais.

Neural stem cells (NSCs) reside in discrete regions of the adult mammalian brain where they can differentiate into neurons, astrocytes, and oligodendrocytes. Several studies suggest that mitochondria have a major role in regulating NSC fate. Here, we evaluated mitochondrial properties throughout NSC differentiation and in lineage-specific cells. For this, we used the neurosphere assay model to isolate, expand, and differentiate mouse subventricular zone postnatal NSCs. We found that the levels of proteins involved in mitochondrial fusion (Mitofusin [Mfn] 1 and Mfn 2) increased, whereas proteins involved in fission (dynamin-related protein 1 [DRP1]) decreased along differentiation. Importantly, changes in mitochondrial dynamics correlated with distinct patterns of mitochondrial morphology in each lineage. Particularly, we found that the number of branched and unbranched mitochondria increased during astroglial and neuronal differentiation, whereas the area occupied by mitochondrial structures significantly reduced with oligodendrocyte maturation. In addition, comparing the three lineages, neurons revealed to be the most energetically flexible, whereas astrocytes presented the highest ATP content. Our work identified putative mitochondrial targets to enhance lineage-directed differentiation of mouse subventricular zone-derived NSCs.

DOI: https://doi.org/10.26508/lsa.202302473
Cell Death Dis. 2024 Apr 20. 15(4): 281

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.

Raquel Brañas Casas, Alessandro Zuppardo, Giovanni Risato, Alberto Dinarello, Rudy Celeghin, Camilla Fontana, Eleonora Grelloni, Alexandru Ionut Gilea, Carlo Viscomi, Andrea Rasola, Luisa Dalla Valle, Tiziana Lodi, Enrico Baruffini, Nicola Facchinello, Francesco Argenton, Natascia Tiso.

The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.

DOI: https://doi.org/10.1038/s41419-024-06622-9
J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):

Mitochondrial sites of contact with the nucleus.

Michelangelo Campanella, Brindha Kannan.

Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.

DOI: https://doi.org/10.1083/jcb.202305010
Biomolecules. 2024 Apr 18. pii: 493. [Epub ahead of print]14(4):

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.

Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, James D McCully, Maik Hüttemann, Moh H Malek.

  BACKGROUND: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity.METHODS: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex).
RESULTS: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.
CONCLUSIONS: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.

Keywords:  endurance; energy production; exercise physiology

DOI:  https://doi.org/10.3390/biom14040493
PLoS Biol. 2024 Apr 26. 22(4): e3002602

Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.

Cynthia Alsayyah, Manish K Singh, Maria Angeles Morcillo-Parra, Laetitia Cavellini, Nadav Shai, Christine Schmitt, Maya Schuldiner, Einat Zalckvar, Adeline Mallet, Naïma Belgareh-Touzé, Christophe Zimmer, Mickaël M Cohen.

Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

DOI: https://doi.org/10.1371/journal.pbio.3002602
Front Cell Dev Biol. 2024 ;12 1260496

Nucleoside supplements as treatments for mitochondrial DNA depletion syndrome.

Eszter Dombi, Tony Marinaki, Paolo Spingardi, Val Millar, Nastasia Hadjichristou, Janet Carver, Iain G Johnston, Carl Fratter, Joanna Poulton.

  Introduction: In mitochondrial DNA (mtDNA) depletion syndrome (MDS), patients cannot maintain sufficient mtDNA for their energy needs. MDS presentations range from infantile encephalopathy with hepatopathy (Alpers syndrome) to adult chronic progressive external ophthalmoplegia. Most are caused by nucleotide imbalance or by defects in the mtDNA replisome. There is currently no curative treatment available. Nucleoside therapy is a promising experimental treatment for TK2 deficiency, where patients are supplemented with exogenous deoxypyrimidines. We aimed to explore the benefits of nucleoside supplementation in POLG and TWNK deficient fibroblasts. Methods: We used high-content fluorescence microscopy with software-based image analysis to assay mtDNA content and membrane potential quantitatively, using vital dyes PicoGreen and MitoTracker Red CMXRos respectively. We tested the effect of 15 combinations (A, T, G, C, AT, AC, AG, CT, CG, GT, ATC, ATG, AGC, TGC, ATGC) of deoxynucleoside supplements on mtDNA content of fibroblasts derived from four patients with MDS (POLG1, POLG2, DGUOK, TWNK) in both a replicating (10% dialysed FCS) and quiescent (0.1% dialysed FCS) state. We used qPCR to measure mtDNA content of supplemented and non-supplemented fibroblasts following mtDNA depletion using 20 µM ddC and after 14- and 21-day recovery in a quiescent state. Results: Nucleoside treatments at 200 µM that significantly increased mtDNA content also significantly reduced the number of cells remaining in culture after 7 days of treatment, as well as mitochondrial membrane potential. These toxic effects were abolished by reducing the concentration of nucleosides to 50 µM. In POLG1 and TWNK cells the combination of ATGC treatment increased mtDNA content the most after 7 days in non-replicating cells. ATGC nucleoside combination significantly increased the rate of mtDNA recovery in quiescent POLG1 cells following mtDNA depletion by ddC. Conclusion: High-content imaging enabled us to link mtDNA copy number with key read-outs linked to patient wellbeing. Elevated G increased mtDNA copy number but severely impaired fibroblast growth, potentially by inhibiting purine synthesis and/or causing replication stress. Combinations of nucleosides ATGC, T, or TC, benefited growth of cells harbouring POLG mutations. These combinations, one of which reflects a commercially available preparation, could be explored further for treatment of POLG patients.

Keywords:  POLG; TWNK; alpers syndrome; heavy isotope labelling mass spectroscopy; high-content imaging; mitochondrial DNA; mitochondrial DNA depletion syndrome; nucleoside bypass therapy

DOI:  https://doi.org/10.3389/fcell.2024.1260496
Biomolecules. 2024 Mar 28. pii: 415. [Epub ahead of print]14(4):

Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.

Emanuele Marzetti, Biliana Lozanoska-Ochser, Riccardo Calvani, Francesco Landi, Hélio José Coelho-Júnior, Anna Picca.

  Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.

Keywords:  aging; cytokines; inflammation; mitochondrial dysfunction; mitochondrial-derived vesicles; muscle fibrosis; muscle injury; muscle satellite cells; muscle wasting; skeletal muscle fibers

DOI:  https://doi.org/10.3390/biom14040415
Science. 2024 Apr 26. 384(6694): 438-446

Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.

Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.

DOI: https://doi.org/10.1126/science.adk1005
Front Bioeng Biotechnol. 2024 ;12 1372211

Harnessing accurate mitochondrial DNA base editing mediated by DdCBEs in a predictable manner.

Jiaxin Qiu, Haibo Wu, Qin Xie, Yuxiao Zhou, Yining Gao, Junbo Liu, Xueyi Jiang, Lun Suo, Yanping Kuang.

  Introduction: Mitochondrial diseases caused by mtDNA have no effective cures. Recently developed DddA-derived cytosine base editors (DdCBEs) have potential therapeutic implications in rescuing the mtDNA mutations. However, the performance of DdCBEs relies on designing different targets or improving combinations of split-DddA halves and orientations, lacking knowledge of predicting the results before its application. Methods: A series of DdCBE pairs for wide ranges of aC or tC targets was constructed, and transfected into Neuro-2a cells. The mutation rate of targets was compared to figure out the potential editing rules. Results: It is found that DdCBEs mediated mtDNA editing is predictable: 1) aC targets have a concentrated editing window for mtDNA editing in comparison with tC targets, which at 5'C8-11 (G1333) and 5'C10-13 (G1397) for aC target, while 5'C4-13 (G1333) and 5'C5-14 (G1397) for tC target with 16bp spacer. 2) G1333 mediated C>T conversion at aC targets in DddA-half-specific manner, while G1333 and G1397 mediated C>T conversion are DddA-half-prefer separately for tC and aC targets. 3) The nucleotide adjacent to the 3' end of aC motif affects mtDNA editing. Finally, by the guidance of these rules, a cell model harboring a pathogenic mtDNA mutation was constructed with high efficiency and no bystander effects. Discussion: In summary, this discovery helps us conceive the optimal strategy for accurate mtDNA editing, avoiding time- and effort-consuming optimized screening jobs.

Keywords:  DdCBEs; gene editing; mitochondrial genome; mtDNA; predictability

DOI:  https://doi.org/10.3389/fbioe.2024.1372211
Curr Biol. 2024 Apr 17. pii: S0960-9822(24)00390-7. [Epub ahead of print]

Spaced training activates Miro/Milton-dependent mitochondrial dynamics in neuronal axons to sustain long-term memory.

Alice Pavlowsky, Typhaine Comyn, Julia Minatchy, David Geny, Philippe Bun, Lydia Danglot, Thomas Preat, Pierre-Yves Plaçais.

  Neurons have differential and fluctuating energy needs across distinct cellular compartments, shaped by brain electrochemical activity associated with cognition. In vitro studies show that mitochondria transport from soma to axons is key to maintaining neuronal energy homeostasis. Nevertheless, whether the spatial distribution of neuronal mitochondria is dynamically adjusted in vivo in an experience-dependent manner remains unknown. In Drosophila, associative long-term memory (LTM) formation is initiated by an early and persistent upregulation of mitochondrial pyruvate flux in the axonal compartment of neurons in the mushroom body (MB). Through behavior experiments, super-resolution analysis of mitochondria morphology in the neuronal soma and in vivo mitochondrial fluorescence recovery after photobleaching (FRAP) measurements in the axons, we show that LTM induction, contrary to shorter-lived memories, is sustained by the departure of some mitochondria from MB neuronal soma and increased mitochondrial dynamics in the axonal compartment. Accordingly, impairing mitochondrial dynamics abolished the increased pyruvate consumption, specifically after spaced training and in the MB axonal compartment, thereby preventing LTM formation. Our results thus promote reorganization of the mitochondrial network in neurons as an integral step in elaborating high-order cognitive processes.

Keywords:  3D-STED microscopy; Drosophila; brain energy metabolism; long-term memory; mitochondria motility; mushroom body

DOI:  https://doi.org/10.1016/j.cub.2024.03.050
Eur J Clin Invest. 2024 Apr 21. e14217

Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.

Kevin Aguilar, Patrycja Jakubek, Antonio Zorzano, Mariusz R Wieckowski.

  OBJECTIVES AND SCOPE: Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.INSIGHTS: The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.
SUMMARY: In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.

Keywords:  ETC; OXPHOS; bioenergetics; metabolism; mitochondria; mtDNA; nDNA; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1111/eci.14217
Mitochondrion. 2024 Apr 23. pii: S1567-7249(24)00045-X. [Epub ahead of print] 101887

Telomere length determines the mitochondrial copy number in blastocyst-stage embryos.

Yuki Inoue, Sogo Aoki, Jun Ito, Shun Hara, Komei Shirasuna, Hisataka Iwata.

  Telomere length (TL) and mitochondrial DNA copy number (mt-cn) are associated with embryonic development. Here, we investigated the correlation between TL and mt-cn in bovine embryos to determine whether TL regulates mt-cn. TL and mt-cn were closely correlated in embryos derived from six bulls. Treatment of embryos with a telomerase inhibitor (TMPyP) and siTERT shortened the TL and reduced mt-cn in blastocysts. RNA-sequencing of blastocysts developed with TMPyP revealed differentially expressed genes associated with transforming growth factor-β1 signaling and inflammation. In conclusion, TL regulates mt-cn in embryos.

Keywords:  Blastocyst; Cow; Mitochondrial DNA copy number; Telomerase; Telomere length

DOI:  https://doi.org/10.1016/j.mito.2024.101887
Nat Commun. 2024 Apr 20. 15(1): 3375

Inflammation and mitophagy are mitochondrial checkpoints to aging.

Emma Guilbaud, Kristopher A Sarosiek, Lorenzo Galluzzi.

DOI: https://doi.org/10.1038/s41467-024-47840-1
J Clin Med. 2024 Apr 19. pii: 2391. [Epub ahead of print]13(8):

Primary Coenzyme Q10 Deficiency-Related Ataxias.

Piervito Lopriore, Marco Vista, Alessandra Tessa, Martina Giuntini, Elena Caldarazzo Ienco, Michelangelo Mancuso, Gabriele Siciliano, Filippo Maria Santorelli, Daniele Orsucci.

  Cerebellar ataxia is a neurological syndrome characterized by the imbalance (e.g., truncal ataxia, gait ataxia) and incoordination of limbs while executing a task (dysmetria), caused by the dysfunction of the cerebellum or its connections. It is frequently associated with other signs of cerebellar dysfunction, including abnormal eye movements, dysmetria, kinetic tremor, dysarthria, and/or dysphagia. Among the so-termed mitochondrial ataxias, variants in genes encoding steps of the coenzyme Q10 biosynthetic pathway represent a common cause of autosomal recessive primary coenzyme Q10 deficiencies (PCoQD)s. PCoQD is a potentially treatable condition; therefore, a correct and timely diagnosis is essential. After a brief presentation of the illustrative case of an Italian woman with this condition (due to a novel homozygous nonsense mutation in COQ8A), this article will review ataxias due to PCoQD.

Keywords:  ataxia; cerebellum; coenzyme Q10; mitochondrial diseases; primary coenzyme Q10 deficiencies

DOI:  https://doi.org/10.3390/jcm13082391
Mitochondrion. 2024 Apr 21. pii: S1567-7249(24)00043-6. [Epub ahead of print]76 101885

The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.

Priyanka Biswal, Manas Ranjan Sahu, Mir Hilal Ahmad, Amal Chandra Mondal.

  Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.

Keywords:  Apoptosis; Hippo signaling; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.mito.2024.101885
Nat Cell Biol. 2024 Apr 23.

Regulation of mitochondrial fission by fatty acyl-coenzyme A.

DOI: https://doi.org/10.1038/s41556-024-01406-x
Autophagy. 2024 Apr 23. 1-12

The Wolfram-like variant WFS1E864K destabilizes MAM and compromises autophagy and mitophagy in human and mice.

Simone Patergnani, Méghane S Bataillard, Alberto Danese, Stacy Alves, Chantal Cazevieille, René Valéro, Lisbeth Tranebjærg, Tangui Maurice, Paolo Pinton, Benjamin Delprat, Elodie M Richard.

  Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that in human fibroblasts and murine neuronal cultures the WLS protein WFS1E864K leads to decreases in mitochondria bioenergetics and Ca2+ uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in the Wfs1E864K mouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM's integrity and functionality. It may open new treatment perspectives for patients with WLS.Abbreviations: BafA1: bafilomycin A1; ER: endoplasmic reticulum; HSPA9/GRP75: heat shock protein family A (Hsp70) member 9; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; MAM: mitochondria-associated endoplasmic reticulum membrane; MCU: mitochondrial calcium uniporter; MFN2: mitofusin 2; OCR: oxygen consumption rate; ROS: reactive oxygen species; ROT/AA: rotenone+antimycin A; VDAC1: voltage dependent anion channel 1; WLS: Wolfram-like syndrome; WS: Wolfram syndrome; WT: wild-type.

Keywords:  Autophagy; WFS1; Wolfram-like syndrome; mitochondria-associated endoplasmic reticulum membrane; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2341588
EMBO J. 2024 Apr 25.

Presenting metabolomics analyses: what is in a number?

Johannes Meiser, Christian Frezza.

DOI: https://doi.org/10.1038/s44318-024-00098-1
Brain. 2024 Apr 25. pii: awae135. [Epub ahead of print]

Unleashing the potential of mRNA therapeutics for inherited neurological diseases.

Edoardo Monfrini, Giacomo Baso, Dario Ronchi, Megi Meneri, Delia Gagliardi, Lorenzo Quetti, Federico Verde, Nicola Ticozzi, Antonia Ratti, Alessio Di Fonzo, Giacomo P Comi, Linda Ottoboni, Stefania Corti.

  Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing COVID-19 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the central nervous system, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present, and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders.

Keywords:  mRNA; monogenic disorders; neurological diseases; personalized medicine

DOI:  https://doi.org/10.1093/brain/awae135
Acta Physiol (Oxf). 2024 Apr 26. e14150

Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.

Charlotte A Hoogstraten, Tom J J Schirris, Frans G M Russel.

  A disturbed mitochondrial function contributes to the pathology of many common diseases. These organelles are therefore important therapeutic targets. On the contrary, many adverse effects of drugs can be explained by a mitochondrial off-target effect, in particular, due to an interaction with carrier proteins in the inner membrane. Yet this class of transport proteins remains underappreciated and understudied. The aim of this review is to provide a deeper understanding of the role of mitochondrial carriers in health and disease and their significance as drug targets. We present literature-based evidence that mitochondrial carrier proteins are associated with prevalent diseases and emphasize their potential as drug (off-)target sites by summarizing known mitochondrial drug-transporter interactions. Studying these carriers will enhance our knowledge of mitochondrial drug on- and off-targets and provide opportunities to further improve the efficacy and safety of drugs.

Keywords:  carrier proteins; drugs; efficacy and safety; inner mitochondrial membrane; mitochondria; on‐ and off‐target

DOI:  https://doi.org/10.1111/apha.14150
Brain. 2024 Apr 25. pii: awae134. [Epub ahead of print]

A new type of blood-brain barrier aminoacidopathy underlies metabolic microcephaly associated with SLC1A4 mutations.

Maali Odeh, Clara Sajrawi, Adam Majcher, Salman Zubedat, Lihi Shaulov, Alex Radzishevsky, Liron Mizrahi, Wendy K Chung, Avi Avital, Thorsten Hornemann, Daniel J Liebl, Inna Radzishevsky, Herman Wolosker.

  Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum, and microcephaly in children. SLC1A4 catalyzes obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models, including a constitutive Slc1a4-KO mouse, a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E), and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L-serine transporter at the BBB and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L-serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids in the brain, neurodegeneration, synaptic and mitochondrial abnormalities, and behavioral impairments. Prenatal and early postnatal oral administration of L-serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioral changes. Administration of L-serine till the second postnatal week also normalized brain weight in Slc1a4-E256 K mice. Our observations suggest that the transport of "non-essential" amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We proposed that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB required for optimal brain growth and leads to a metabolic microcephaly, which may be amenable to treatment with L-serine.

Keywords:  d-serine; mitochondria; mitophagy; serine metabolism; synaptopathy

DOI:  https://doi.org/10.1093/brain/awae134
Diabetes. 2024 Apr 24. pii: db230432. [Epub ahead of print]

Inhibitory regulation of FoxO1 in PPARδ expression drives mitochondria dysfunction and insulin resistance.

Soyoung Park, Hye-Na Cha, Min-Gyeong Shin, Sanghee Park, Yeongmin Kim, Min-Seob Kim, Kyung-Hoon Shin, Themis Thoudam, Eun Ju Lee, Robert R Wolfe, Jinmyoung Dan, Jin-Ho Koh, Il-Young Kim, Inho Choi, In-Kyu Lee, Hoon-Ki Sung, So-Young Park.

Forkhead box protein O1 (FoxO1) regulates muscle growth, but the metabolic role of FoxO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FoxO1 in skeletal muscle, we generated skeletal muscle-specific FoxO1 inducible knockout (mFoxO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFoxO1 iKO mice, and assessed the correlation between FoxO1 and mitochondrial-related protein in the skeletal muscle of diabetic patients. Obese mFoxO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FoxO1 in peroxisome proliferator-activated receptor δ (PPARδ) expression was confirmed in skeletal muscle and deletion of PPARδ abolished the beneficial effects of FoxO1 deficiency. FoxO1 protein levels were higher in the skeletal muscle of diabetic patients and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FoxO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FoxO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ.

DOI: https://doi.org/10.2337/db23-0432
Res Sq. 2024 Apr 10. pii: rs.3.rs-4178088. [Epub ahead of print]

Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.

Chunling Chen, Ronald A Merrill, Chian Ju Jong, Stefan Strack.

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion ( B β 2 KO) nor fission ( Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

DOI: https://doi.org/10.21203/rs.3.rs-4178088/v1
J Clin Invest. 2024 Apr 23. pii: e167371. [Epub ahead of print]

Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism.

Piyarat Siripoksup, Guoshen Cao, Ahmad A Cluntun, J Alan Maschek, Quentinn Pearce, Marisa J Lang, Mi-Young Jeong, Hiroaki Eshima, Patrick J Ferrara, Precious C Opurum, Ziad S Mahmassani, Alek D Peterlin, Shinya Watanabe, Maureen A Walsh, Eric B Taylor, James E Cox, Micah J Drummond, Jared Rutter, Katsuhiko Funai.

  Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.

Keywords:  Metabolism; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI167371
Nat Commun. 2024 Apr 24. 15(1): 3468

Functional synergy of a human-specific and an ape-specific metabolic regulator in human neocortex development.

Lei Xing, Vasiliki Gkini, Anni I Nieminen, Hui-Chao Zhou, Matilde Aquilino, Ronald Naumann, Katrin Reppe, Kohichi Tanaka, Peter Carmeliet, Oskari Heikinheimo, Svante Pääbo, Wieland B Huttner, Takashi Namba.

Metabolism has recently emerged as a major target of genes implicated in the evolutionary expansion of human neocortex. One such gene is the human-specific gene ARHGAP11B. During human neocortex development, ARHGAP11B increases the abundance of basal radial glia, key progenitors for neocortex expansion, by stimulating glutaminolysis (glutamine-to-glutamate-to-alpha-ketoglutarate) in mitochondria. Here we show that the ape-specific protein GLUD2 (glutamate dehydrogenase 2), which also operates in mitochondria and converts glutamate-to-αKG, enhances ARHGAP11B's ability to increase basal radial glia abundance. ARHGAP11B + GLUD2 double-transgenic bRG show increased production of aspartate, a metabolite essential for cell proliferation, from glutamate via alpha-ketoglutarate and the TCA cycle. Hence, during human evolution, a human-specific gene exploited the existence of another gene that emerged during ape evolution, to increase, via concerted changes in metabolism, progenitor abundance and neocortex size.

DOI: https://doi.org/10.1038/s41467-024-47437-8
Drug Chem Toxicol. 2024 Apr 22. 1-15

Quercetin prevents methylmercury-induced mitochondrial dysfunction in the cerebral cortex of mice.

Haihui Liu, Liujiangshan Jiang, Si Xu, Chen Wang, Jingyi Sun.

  Methylmercury (MeHg) exposure can cause nerve damage and mitochondrial dysfunction. Mitochondrial dysfunction is mainly mediated by mitochondrial biogenesis and mitochondrial dynamics disorders. Quercetin (QE) plays an important role in activating silencing information regulator 2 related enzyme 1 (SIRT1), and SIRT1 activates peroxisome-proliferator-activated receptor-γ co-activator 1α (PGC-1α), which can regulate mitochondrial biogenesis and mitochondrial dynamics. The main purpose of this study was to explore the alleviating effects of QE on MeHg-induced nerve damage and mitochondrial dysfunction. The results showed that QE could reduce the excessive production of reactive oxygen species (ROS) and the loss of membrane potential induced by MeHg. Meanwhile, QE activated SIRT1 activity and SIRT1/PGC-1α signaling pathway, improved mitochondrial biogenesis and fusion and reduced mitochondrial fission. In summary, we hypothesized that QE prevents MeHg-induced mitochondrial dysfunction by activating SIRT1/PGC-1α signaling pathway.

Keywords:  MeHg; PGC-1α; SIRT1; mitochondrial dysfunction; quercetin

DOI:  https://doi.org/10.1080/01480545.2024.2341888
Cells. 2024 Apr 17. pii: 694. [Epub ahead of print]13(8):

Unraveling the Pathogenetic Mechanisms Underlying the Association between Specific Mitochondrial DNA Haplogroups and Parkinson's Disease.

Min-Yu Lan, Tsu-Kung Lin, Baiba Lace, Algirdas Utkus, Birute Burnyte, Kristina Grigalioniene, Yu-Han Lin, Inna Inashkina, Chia-Wei Liou.

  Variants of mitochondrial DNA (mtDNA) have been identified as risk factors for the development of Parkinson's disease (PD). However, the underlying pathogenetic mechanisms remain unclear. Cybrid models carrying various genotypes of mtDNA variants were tested for resistance to PD-simulating MPP+ treatment. The most resistant line was selected for transcriptome profiling, revealing specific genes potentially influencing the resistant characteristic. We then conducted protein validation and molecular biological studies to validate the related pathways as the influential factor. Cybrids carrying the W3 mtDNA haplogroup demonstrated the most resistance to the MPP+ treatment. In the transcriptome study, PPP1R15A was identified, while further study noted elevated expressions of the coding protein GADD34 across all cybrids. In the study of GADD34-related mitochondrial unfolding protein response (mtUPR), we found that canonical mtUPR, launched by the phosphate eIF2a, is involved in the resistant characteristic of specific mtDNA to MPP+ treatment. Our study suggests that a lower expression of GADD34 in the late phase of mtUPR may prolong the mtUPR process, thereby benefitting protein homeostasis and facilitating cellular resistance to PD development. We herein demonstrate that GADD34 plays an important role in PD development and should be further investigated as a target for the development of therapies for PD.

Keywords:  Parkinson’s disease; cybrid; mitochondrial haplogroup; transcriptome; unfolding protein response

DOI:  https://doi.org/10.3390/cells13080694
Trends Endocrinol Metab. 2024 Apr 24. pii: S1043-2760(24)00094-8. [Epub ahead of print]

Mitochondrial Venus is more likely to have a lower birthweight.

Elina Aleksejeva, Masoud Zamani Esteki, Andres Salumets.

  Assisted reproductive technologies (ART) are associated with a moderately higher risk of preterm birth and low birthweight, but the causes are unknown. A recent study by Mertens et al. reveals a link between being born through ART, ovarian stimulation, and an increased incidence of mitochondrial heteroplasmic variants that correlate with lower birthweight.

Keywords:  assisted reproduction; birthweight; mitochondria; ovarian aging; ovarian stimulation; preterm birth

DOI:  https://doi.org/10.1016/j.tem.2024.04.011
bioRxiv. 2024 Apr 10. pii: 2024.04.05.587765. [Epub ahead of print]

Placental Nanoparticle-mediated IGF1 Gene Therapy Corrects Fetal Growth Restriction in a Guinea Pig Model.

Baylea N Davenport, Rebecca L Wilson, Alyssa A Williams, Helen N Jones.

Fetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific human insulin-like 1 growth factor ( IGF1 ) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using the guinea pig maternal nutrient restriction model of FGR, nanoparticle-mediated IGF1 treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR animals compared to control, improved fetal physiology and no negative maternal side-effects. Overall, we show for the first time a therapy capable of improving the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at both mid pregnancy and in numerous cell and animal models demonstrate the plausibility of this therapy for future human translation to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.

DOI: https://doi.org/10.1101/2024.04.05.587765
Nature. 2024 Apr 22.

Multimodal cell atlas of the ageing human skeletal muscle.

Yiwei Lai, Ignacio Ramírez-Pardo, Joan Isern, Juan An, Eusebio Perdiguero, Antonio L Serrano, Jinxiu Li, Esther García-Domínguez, Jessica Segalés, Pengcheng Guo, Vera Lukesova, Eva Andrés, Jing Zuo, Yue Yuan, Chuanyu Liu, José Viña, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Yancheng Song, Longqi Liu, Xun Xu, Pura Muñoz-Cánoves, Miguel A Esteban.

Muscle atrophy and functional decline (sarcopenia) are common manifestations of frailty and are critical contributors to morbidity and mortality in older people1. Deciphering the molecular mechanisms underlying sarcopenia has major implications for understanding human ageing2. Yet, progress has been slow, partly due to the difficulties of characterizing skeletal muscle niche heterogeneity (whereby myofibres are the most abundant) and obtaining well-characterized human samples3,4. Here we generate a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals aged 15 to 99 years with distinct fitness and frailty levels. We describe how cell populations change during ageing, including the emergence of new populations in older people, and the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) associated with these changes. On the basis of cross-comparison with genetic data, we also identify key elements of chromatin architecture that mark susceptibility to sarcopenia. Our study provides a basis for identifying targets in the skeletal muscle that are amenable to medical, pharmacological and lifestyle interventions in late life.

DOI: https://doi.org/10.1038/s41586-024-07348-6
Am J Physiol Cell Physiol. 2024 Apr 22.

Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.

Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.

  We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.

Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase

DOI:  https://doi.org/10.1152/ajpcell.00576.2023
Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.

  Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2024.03.030
Biol Direct. 2024 Apr 23. 19(1): 29

Loss of AMPK activity induces organelle dysfunction and oxidative stress during oocyte aging.

Lin-Lin Hu, Mei-Hua Liao, Ya-Xi Liu, Chun-Hua Xing, Lan-Lan Nong, Feng-Lian Yang, Shao-Chen Sun.

  BACKGROUND: Oocyte quality is critical for the mammalian reproduction due to its necessity on fertilization and early development. During aging, the declined oocytes showing with organelle dysfunction and oxidative stress lead to infertility. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase which is important for energy homeostasis for metabolism. Little is known about the potential relationship between AMPK with oocyte aging.RESULTS: In present study we reported that AMPK was related with low quality of oocytes under post ovulatory aging and the potential mechanism. We showed the altered AMPK level during aging and inhibition of AMPK activity induced mouse oocyte maturation defect. Further analysis indicated that similar with its upstream regulator PKD1, AMPK could reduce ROS level to avoid oxidative stress in oocytes, and this might be due to its regulation on mitochondria function, since loss of AMPK activity induced abnormal distribution, reduced ATP production and mtDNA copy number of mitochondria. Besides, we also found that the ER and Golgi apparatus distribution was aberrant after AMPK inhibition, and enhanced lysosome function was also observed.
CONCLUSIONS: Taken together, these data indicated that AMPK is important for the organelle function to reduce oxidative stress during oocyte meiotic maturation.

Keywords:  AMPK; Meiosis; Mitochondria; Oocyte; Oxidative stress

DOI:  https://doi.org/10.1186/s13062-024-00471-4