bims-mitmed 2023-08-13 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–08–13
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Leigh syndrome: an adult presentation of a paediatric disease.
Mitochondrial integrated stress response controls lung epithelial cell fate.
Mitochondrial encephalomyopathy.
Mitochondrial fission fueled by fasting.
Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.
Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.
ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.
FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.
Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.
NME6: ribonucleotide salvage sustains mitochondrial transcription.
A combination of metformin and galantamine exhibits synergistic benefits in the treatment of sarcopenia.
Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.
Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.
Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes.
The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate.
The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.
Structure and dynamics of the mitochondrial DNA-compaction factor Abf2 from S. cerevisiae.
Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.
DELE1 oligomerization promotes integrated stress response activation.
The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore.
FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures.
Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene.
Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family.
iNOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway.
Genetic etiology of progressive pediatric neurological disorders.
Calculation of ATP production rates using the Seahorse XF Analyzer.
The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice.
Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Pract Neurol. 2023 Aug 11. pii: pn-2023-003862. [Epub ahead of print]

Leigh syndrome: an adult presentation of a paediatric disease.

Taylor Watson-Fargie, Victoria Marshall, Natasha E Fullerton, Veronica Leach, Daniela Pilz, Charlotte V Y Hemingbrough, Sila Hopton, Robert W Taylor, Yi S Ng, Andrew Schaefer, Gráinne S Gorman, Maria Elena Farrugia.

  A previously healthy 27-year-old man was admitted to the acute neurology ward with events involving his face, throat and upper limb, which video telemetry later confirmed were refractory focal seizures. He also had progressive pyramidal features, dysarthria and ataxia. MR scans of the brain identified progressive bilateral basal ganglia abnormalities, consistent with Leigh syndrome. However, extensive laboratory and genetic panels did not give a unifying diagnosis. A skeletal muscle biopsy showed no histopathological abnormalities on routine stains. Sequencing of the entire mitochondrial genome in skeletal muscle identified a well-characterised pathogenic variant (m.10191T>C in MT-ND3; NC_012920.1) at 85% heteroplasmy in skeletal muscle. We discuss the clinical and molecular diagnosis of an adult presenting with Leigh syndrome, which is more commonly a paediatric presentation of mitochondrial disease, and how early recognition of a mitochondrial cause is important to support patient care.

Keywords:  CLINICAL NEUROLOGY; METABOLIC DISEASE; MITOCHONDRIAL DISORDERS; NEUROGENETICS

DOI:  https://doi.org/10.1136/pn-2023-003862
Nature. 2023 Aug 09.

Mitochondrial integrated stress response controls lung epithelial cell fate.

SeungHye Han, Minho Lee, Youngjin Shin, Regina Giovanni, Ram P Chakrabarty, Mariana M Herrerias, Laura A Dada, Annette S Flozak, Paul A Reyfman, Basil Khuder, Colleen R Reczek, Lin Gao, José Lopéz-Barneo, Cara J Gottardi, G R Scott Budinger, Navdeep S Chandel.

Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.

DOI: https://doi.org/10.1038/s41586-023-06423-8
Handb Clin Neurol. 2023 ;pii: B978-0-323-98818-6.00025-X. [Epub ahead of print]195 563-585

Mitochondrial encephalomyopathy.

Yi Shiau Ng, Robert McFarland.

  Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.

Keywords:  Ataxia; CPEO; Leigh syndrome; MELAS; Mitochondrial DNA; Movement disorders; Myopathy; Neuropathy

DOI:  https://doi.org/10.1016/B978-0-323-98818-6.00025-X
Sci Signal. 2023 08 08. 16(797): eadk1008

Mitochondrial fission fueled by fasting.

Wei Wong.

Fasting activates mTORC2 to stimulate mitochondrial fission and support mitochondrial respiration.

DOI: https://doi.org/10.1126/scisignal.adk1008
Cells. 2023 Aug 07. pii: 2013. [Epub ahead of print]12(15):

Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy.

Hoda Shamsnajafabadi, Robert E MacLaren, Jasmina Cehajic-Kapetanovic.

  Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.

Keywords:  LHON; NADH dehydrogenase; gene therapy; idebenone; leber hereditary optic neuropathy; mitochondrial inheritance; retinal ganglion cells

DOI:  https://doi.org/10.3390/cells12152013
Nat Commun. 2023 Aug 10. 14(1): 4726

Brain mitochondrial diversity and network organization predict anxiety-like behavior in male mice.

Ayelet M Rosenberg, Manish Saggar, Anna S Monzel, Jack Devine, Peter Rogu, Aaron Limoges, Alex Junker, Carmen Sandi, Eugene V Mosharov, Dani Dumitriu, Christoph Anacker, Martin Picard.

The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied at a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in male mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity, and exhibited distinct molecular mitochondrial phenotype signatures. This work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the male mouse brain.

DOI: https://doi.org/10.1038/s41467-023-39941-0
Int J Mol Sci. 2023 Aug 07. pii: 12511. [Epub ahead of print]24(15):

ATAD3A: A Key Regulator of Mitochondria-Associated Diseases.

Liting Chen, Yuchang Li, Alexander Zambidis, Vassilios Papadopoulos.

  Mitochondrial membrane protein ATAD3A is a member of the AAA-domain-containing ATPases superfamily. It is important for the maintenance of mitochondrial DNA, structure, and function. In recent years, an increasing number of ATAD3A mutations have been identified in patients with neurological symptoms. Many of these mutations disrupt mitochondrial structure, function, and dynamics and are lethal to patients at a young age. Here, we summarize the current understanding of the relationship between ATAD3A and mitochondria, including the interaction of ATAD3A with mitochondrial DNA and mitochondrial/ER proteins, the regulation of ATAD3A in cholesterol mitochondrial trafficking, and the effect of known ATAD3A mutations on mitochondrial function. In the current review, we revealed that the oligomerization and interaction of ATAD3A with other mitochondrial/ER proteins are vital for its various functions. Despite affecting different domains of the protein, nearly all documented mutations observed in ATAD3A exhibit either loss-of-function or dominant-negative effects, potentially leading to disruption in the dimerization of ATAD3A; autophagy; mitophagy; alteration in mitochondrial number, size, and cristae morphology; and diminished activity of mitochondrial respiratory chain complexes I, IV, and V. These findings imply that ATAD3A plays a critical role in mitochondrial dynamics, which can be readily perturbed by ATAD3A mutation variants.

Keywords:  ATAD3A; cancer; cholesterol; mitochondria; mitochondrial respiration; mtDNA; mutation; neurological diseases

DOI:  https://doi.org/10.3390/ijms241512511
Cell Death Differ. 2023 Aug 11.

FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome.

Yingji Chen, Dongyue Jiao, Yang Liu, Xiayun Xu, Yilin Wang, Xiaona Luo, Hexige Saiyin, Yao Li, Kun Gao, Yucai Chen, Shi-Min Zhao, Lixiang Ma, Chenji Wang.

Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1FBXL4 complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1FBXL4 complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.

DOI: https://doi.org/10.1038/s41418-023-01205-1
NPJ Parkinsons Dis. 2023 Aug 08. 9(1): 120

Parkinson's disease neurons exhibit alterations in mitochondrial quality control proteins.

Chun Chen, David McDonald, Alasdair Blain, Emily Mossman, Kiera Atkin, Michael F Marusich, Roderick Capaldi, Laura Bone, Anna Smith, Andrew Filby, Daniel Erskine, Oliver Russell, Gavin Hudson, Amy E Vincent, Amy K Reeve.

Mitochondrial dysfunction has been suggested to contribute to Parkinson's disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson's patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson's neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson's neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson's neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.

DOI: https://doi.org/10.1038/s41531-023-00564-3
EMBO J. 2023 Aug 07. e114990

NME6: ribonucleotide salvage sustains mitochondrial transcription.

Paulina H Wanrooij, Andrei Chabes.

The building blocks for RNA and DNA are made in the cytosol, meaning mitochondria depend on the import and salvage of ribonucleoside triphosphates (rNTPs) and deoxyribonucleoside triphosphates (dNTPs) for the synthesis of their own genetic material. While extensive research has focused on mitochondrial dNTP homeostasis due to its defects being associated with various mitochondrial DNA (mtDNA) depletion and deletion syndromes, the investigation of mitochondrial rNTP homeostasis has received relatively little attention. In this issue of the EMBO Journal, Grotehans et al provide compelling evidence of a major role for NME6, a mitochondrial nucleoside diphosphate kinase, in the conversion of pyrimidine ribonucleoside diphosphates into the corresponding triphosphates. These data also suggest a significant physiological role for NME6, as its absence results in the depletion of mitochondrial transcripts and destabilization of the electron transport chain (Grotehans et al, 2023).

DOI: https://doi.org/10.15252/embj.2023114990
JCI Insight. 2023 08 08. pii: e168787. [Epub ahead of print]8(15):

A combination of metformin and galantamine exhibits synergistic benefits in the treatment of sarcopenia.

Caterina Tezze, Francesco Ivan Amendolagine, Leonardo Nogara, Martina Baraldo, Stefano Ciciliot, Diletta Arcidiacono, Alice Zaramella, Giulio Masiero, Giulia Ferrarese, Stefano Realdon, Bert Blaauw, Giel Detienne, Ann Tj Beliën, Marco Sandri, Evi M Mercken.

  Age-associated sarcopenia, characterized by a progressive loss in muscle mass and strength, is the largest cause of frailty and disability in the elderly worldwide. Current treatments involve nonpharmacological guidelines that few subjects can abide by, highlighting the need for effective drugs. Preclinical models were employed to test the benefits of RJx-01, a combination drug composed of metformin and galantamine, on sarcopenia. In worms, RJx-01 treatment improved lifespan, locomotion, pharyngeal pumping, and muscle fiber organization. The synergistic effects of RJx-01 were recapitulated in a transgenic mouse model that displays an exacerbated aging phenotype (Opa1-/-). In these mice, RJx-01 ameliorated physical performance, muscle mass and force, neuromuscular junction stability, and systemic inflammation. RJx-01 also improved physical performance and muscle strength in 22-month-old WT mice and also improved skeletal muscle ultrastructure, mitochondrial morphology, autophagy, lysosomal function, and satellite cell content. Denervation and myofiber damage were decreased in RJx-01-treated animals compared with controls. RJx-01 improved muscle quality rather than quantity, indicating that the improvement in quality underlies the beneficial effects of the combination drug. The studies herein indicate synergistic beneficial effects of RJx-01 in the treatment of sarcopenia and support the pursuit of RJx-01 in a human clinical trial as a therapeutic intervention for sarcopenia.

Keywords:  Aging; Drug therapy; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.168787
Brain Pathol. 2023 Aug 08. e13192

Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.

Allison R Hanaford, Asheema Khanna, Vivian Truong, Katerina James, Yihan Chen, Michael Mulholland, Bernhard Kayser, Ryan W Liao, Margaret Sedensky, Phil Morgan, Nathan Baerchst, Vandana Kalia, Surojit Sarkar, Simon C Johnson.

  Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.

Keywords:  CNS lesions; Leigh syndrome; microglia; mitochondrial disease; pediatric disease; subacute necrotizing encephalomyelopathy

DOI:  https://doi.org/10.1111/bpa.13192
Nat Commun. 2023 08 09. 14(1): 4794

Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition.

Bernhard Kuhle, Marscha Hirschi, Lili K Doerfel, Gabriel C Lander, Paul Schimmel.

Animal mitochondrial gene expression relies on specific interactions between nuclear-encoded aminoacyl-tRNA synthetases and mitochondria-encoded tRNAs. Their evolution involves an antagonistic interplay between strong mutation pressure on mtRNAs and selection pressure to maintain their essential function. To understand the molecular consequences of this interplay, we analyze the human mitochondrial serylation system, in which one synthetase charges two highly divergent mtRNASer isoacceptors. We present the cryo-EM structure of human mSerRS in complex with mtRNASer(UGA), and perform a structural and functional comparison with the mSerRS-mtRNASer(GCU) complex. We find that despite their common function, mtRNASer(UGA) and mtRNASer(GCU) show no constrain to converge on shared structural or sequence identity motifs for recognition by mSerRS. Instead, mSerRS evolved a bimodal readout mechanism, whereby a single protein surface recognizes degenerate identity features specific to each mtRNASer. Our results show how the mutational erosion of mtRNAs drove a remarkable innovation of intermolecular specificity rules, with multiple evolutionary pathways leading to functionally equivalent outcomes.

DOI: https://doi.org/10.1038/s41467-023-40354-2
Int J Mol Sci. 2023 Aug 06. pii: 12486. [Epub ahead of print]24(15):

Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.

Germán Plascencia-Villa, George Perry.

  The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer's and Parkinson's disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; mitochondrial dysfunction; neurodegeneration; neurons; oxidative stress

DOI:  https://doi.org/10.3390/ijms241512486
Int J Mol Sci. 2023 Aug 06. pii: 12488. [Epub ahead of print]24(15):

Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes.

Daniela Valenti, Rosa Anna Vacca.

  Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves regulated from a series of signaling proteins to achieve the best efficiency in producing energy, in establishing a network and in performing their own de novo synthesis or clearance. Dysfunctions in signaling processes that control mitochondrial biogenesis, dynamics and bioenergetics are increasingly associated with impairment in brain development and involved in a wide variety of neurodevelopmental disorders. Here, we review recent evidence proving the emerging role of mitochondria as master regulators of brain bioenergetics, highlighting their control skills in brain neurodevelopment and cognition. We analyze, from a mechanistic point of view, mitochondrial bioenergetic dysfunction as causally interrelated to the origins of typical genetic intellectual disability-related neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes. Finally, we discuss whether mitochondria can become therapeutic targets to improve brain development and function from a holistic perspective.

Keywords:  Down syndrome; Fragile X syndrome; Rett syndrome; brain mitochondrial bioenergetics; genetic neurodevelopmental disorders; neurogenesis; neuroplasticity

DOI:  https://doi.org/10.3390/ijms241512488
Int J Mol Sci. 2023 Jul 29. pii: 12181. [Epub ahead of print]24(15):

The Key Role of Mitochondria in Somatic Stem Cell Differentiation: From Mitochondrial Asymmetric Apportioning to Cell Fate.

Ilario Amato, Sébastien Meurant, Patricia Renard.

  The study of the mechanisms underlying stem cell differentiation is under intensive research and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has strengthened the interest in the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission, and mitophagy processes as well as emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate.

Keywords:  RISP; asymmetric; differentiation; epigenetic; metabolism; mitochondria; stem cell

DOI:  https://doi.org/10.3390/ijms241512181
Front Neurosci. 2023 ;17 1144896

The complexities of investigating mitochondria dynamics in multiple sclerosis and mouse models of MS.

Kelley C Atkinson, Marvellous Osunde, Seema K Tiwari-Woodruff.

  Multiple sclerosis (MS) is a demyelinating, degenerating disorder of the central nervous system (CNS) that is accompanied by mitochondria energy production failure. A loss of myelin paired with a deficit in energy production can contribute to further neurodegeneration and disability in patients in MS. Mitochondria are essential organelles that produce adenosine triphosphate (ATP) via oxidative phosphorylation in all cells in the CNS, including neurons, oligodendrocytes, astrocytes, and immune cells. In the context of demyelinating diseases, mitochondria have been shown to alter their morphology and undergo an initial increase in metabolic demand. This is followed by mitochondrial respiratory chain deficiency and abnormalities in mitochondrial transport that contribute to progressive neurodegeneration and irreversible disability. The current methodologies to study mitochondria are limiting and are capable of providing only a partial snapshot of the true mitochondria activity at a particular timepoint during disease. Mitochondrial functional studies are mostly performed in cell culture or whole brain tissue, which prevents understanding of mitochondrial pathology in distinct cell types in vivo. A true understanding of cell-specific mitochondrial pathophysiology of MS in mouse models is required. Cell-specific mitochondria morphology, mitochondria motility, and ATP production studies in animal models of MS will help us understand the role of mitochondria in the normal and diseased CNS. In this review, we present currently used methods to investigate mitochondria function in MS mouse models and discuss the current advantages and caveats with using each technique. In addition, we present recently developed mitochondria transgenic mouse lines expressing Cre under the control of CNS specific promoters to relate mitochondria to disease in vivo.

Keywords:  EAE; cuprizone; demyelination; inflammation; mitochondria; multiple sclerosis; myelin; remyelination

DOI:  https://doi.org/10.3389/fnins.2023.1144896
J Struct Biol. 2023 Aug 03. pii: S1047-8477(23)00071-0. [Epub ahead of print] 108008

Structure and dynamics of the mitochondrial DNA-compaction factor Abf2 from S. cerevisiae.

Jens Lidman, Ylber Sallova, Irena Matečko-Burmann, Björn M Burmann.

  Mitochondria are essential organelles that produce most of the energy via the oxidative phosphorylation (OXPHOS) system in all eukaryotic cells. Several essential subunits of the OXPHOS system are encoded by the mitochondrial genome (mtDNA) despite its small size. Defects in mtDNA maintenance and expression can lead to severe OXPHOS deficiencies and are amongst the most common causes of mitochondrial disease. The mtDNA is packaged as nucleoprotein structures, referred to as nucleoids. The conserved mitochondrial proteins, ARS-binding factor 2 (Abf2) in the budding yeast Saccharomyces cerevisiae (S. cerevisiae) and mitochondrial transcription factor A (TFAM) in mammals, are nucleoid associated proteins (NAPs) acting as condensing factors needed for packaging and maintenance of the mtDNA. Interestingly, gene knockout of Abf2 leads, in yeast, to the loss of mtDNA and respiratory growth, providing evidence for its crucial role. On a structural level, the condensing factors usually contain two DNA binding domains called high-mobility group boxes (HMG boxes). The co-operating mechanical activities of these domains are crucial in establishing the nucleoid architecture by bending the DNA strands. Here we used advanced solution NMR spectroscopy methods to characterize the dynamical properties of Abf2 together with its interaction with DNA. We find that the two HMG-domains react notably different to external cues like temperature and salt, indicating distinct functional properties. Biophysical characterizations show the pronounced difference of these domains upon DNA-binding, suggesting a refined picture of the Abf2 functional cycle.

Keywords:  ABF2; HMG-boxes; mitochondrial DNA packaging; protein dynamics

DOI:  https://doi.org/10.1016/j.jsb.2023.108008
Clin Sci (Lond). 2023 Aug 10. pii: CS20230048. [Epub ahead of print]

Maternal hepatic adaptations during obese pregnancy encompass lobe-specific mitochondrial alterations and oxidative stress.

Luís F Grilo, João D Martins, Mariana S Diniz, Carolina Tocantins, Chiara H Cavallaro, Inês Baldeiras, Teresa Cunha-Oliveira, Stephen Ford, Peter W Nathanielsz, Paulo J Oliveira, Susana P Pereira.

  Maternal obesity(MO) is rising worldwide, affecting half of all gestations, constituting a risk-factor for pregnancy-associated liver diseases (PALD) and hepatic diseases. PALD occur in approximately 3% of pregnancies and are characterized by maternal hepatic oxidative stress(OS) and mitochondrial dysfunction. Understanding the role of MO on liver function and pathophysiology could be crucial for understanding the altered pathways leading to PALD and liver disease. We investigated specific hepatic metabolic alterations in mitochondria and oxidative stress during MO at late-gestation. Maternal hepatic tissue was collected at 90% gestation in Control and MO ewes. Maternal hepatic redox state, mitochondrial Respiratory Chain(MRC) and OS markers were investigated. MO decreased MRC complex-II activity and SDHA and SDHB protein, increased complex-I and complex-IV activities despite reduced mtCO1 protein, and increased ATP5a protein. Hepatic MO-metabolic remodeling was characterized by decreased ANT-1/2 and VDAC protein expression and PKA activity, and augmented NAD+/NADH ratio due to reduced NADH levels. MO showed an altered redox state with increased OS, increased lipid peroxidation, decreased GSH/GSSG ratio, increased SOD and decreased catalase antioxidant enzymatic activities, lower catalase, glutathione peroxidase (Gpx)-4 and glutathione reductase protein expression, and increased Gpx-1 abundance. MO-related hepatic changes were more evident in the right lobe, corroborated by the integrative data analysis. Hepatic tissue from obese pregnant ewes showed alterations in the redox state, consistent with OS and MRC and metabolism remodeling. These are hallmarks of PALD and hepatic disease, supporting MO as a risk-factor and highlighting OS and mitochondrial dysfunction as mechanisms responsible for liver disease predisposition.

Keywords:  gestation; hepatic mitochondria; liver disease; maternal malnutrition; overnutrition; oxidative stress

DOI:  https://doi.org/10.1042/CS20230048
Nat Struct Mol Biol. 2023 Aug 07.

DELE1 oligomerization promotes integrated stress response activation.

Jie Yang, Kelsey R Baron, Daniel E Pride, Anette Schneemann, Xiaoyan Guo, Wenqian Chen, Albert S Song, Giovanni Aviles, Martin Kampmann, R Luke Wiseman, Gabriel C Lander.

Mitochondria are dynamic organelles that continually respond to cellular stress. Recent studies have demonstrated that mitochondrial stress is relayed from mitochondria to the cytosol by the release of a proteolytic fragment of DELE1 that binds to the eIF2α kinase HRI to initiate integrated stress response (ISR) signaling. We report the cryo-electron microscopy structure of the C-terminal cleavage product of human DELE1, which assembles into a high-order oligomer. The oligomer consists of eight DELE1 monomers that assemble with D4 symmetry via two sets of hydrophobic inter-subunit interactions. We identified the key residues involved in DELE1 oligomerization, and confirmed their role in stabilizing the octamer in vitro and in cells using mutagenesis. We further show that assembly-impaired DELE1 mutants are compromised in their ability to induce HRI-dependent ISR activation in cell culture models. Together, our findings provide molecular insights into the activity of DELE1 and how it signals to promote ISR activity following mitochondrial insult.

DOI: https://doi.org/10.1038/s41594-023-01061-0
Int J Mol Sci. 2023 Aug 01. pii: 12295. [Epub ahead of print]24(15):

The Reduction in the Mitochondrial Membrane Potential in Aging: The Role of the Mitochondrial Permeability Transition Pore.

Hagai Rottenberg.

  It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP. Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and mROS, and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively.

Keywords:  C. elegans; aging; membrane potential; mitochondria; permeability transition pore

DOI:  https://doi.org/10.3390/ijms241512295
Mol Genet Metab. 2023 Aug 02. pii: S1096-7192(23)00306-2. [Epub ahead of print]140(3): 107676

FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures.

Olivia Liu, Bhargava Kumar Chinni, Cedric Manlhiot, Hilary J Vernon.

  Barth Syndrome (BTHS) is a rare X-linked disorder that is caused by defects TAFAZZIN, which leads to an abnormal cardiolipin (CL) profile of the inner mitochondrial membrane and clinical features including cardiomyopathy, neutropenia and skeletal myopathy. The ratio of monolysocardiolipin (MLCL, the remodeling intermediate of cardiolipin) to remodeled CL is always abnormal in Barth Syndrome and 3-methylglutaconic acid is often elevated affected patients, however neither of these biomarkers has been shown to temporally correlate to clinical status. In this study, we measured plasma FGF21 and GDF15 levels in 16 individuals with Barth Syndrome and evaluated whether these biomarkers were correlated to the MLCL/CL ratio in patient bloodspots and clinical laboratory parameters indicative of organ involvement in Barth Syndrome including: neutrophil and monocyte counts, liver function, and cardiac function (NT-proBNP). We found that FGF21 and GDF15 were elevated in all 16 patients and that FGF21 was significantly correlated to AST, ALT GGT, percentage of neutrophils comprising total white blood cells, percent monocytes comprising total white blood cells, and NT-proBNP levels. GDF-15 was significantly positively associated with NT-proBNP. We conclude that clinical measurements of FGF21 and GDF-15 may be relevant in the monitoring multi-organ system involvement in Barth Syndrome.

Keywords:  Barth Syndrome; Cardiolipin; FGF21; GDF-15; Mitochondria

DOI:  https://doi.org/10.1016/j.ymgme.2023.107676
Am J Med Genet A. 2023 Aug 11.

Α rare case of myopathy, lactic acidosis, and severe rhabdomyolysis, due to a homozygous mutation of the ferredoxin-2 (FDX2) gene.

Nikolaos Gkiourtzis, Despoina Tramma, Kyriaki Papadopoulou-Legbelou, Maria Moutafi, Athanasios Evangeliou.

  Mitochondrial myopathy is a severe metabolic myopathy related to nuclear or mitochondrial DNA dysfunction. We present a rare case of mitochondrial myopathy, presented with multiple episodes of proximal muscle weakness, lactic acidosis, and severe rhabdomyolysis (CPK 319,990 U/L, lactic acid 22.31 mmol/L, and GFR 3.82 mL/min/1.73m2 ). She was hospitalized in the pediatric intensive care unit due to acute kidney injury, elevated blood pressure, and deterioration of respiratory and cardiac function. Investigation for inherited metabolic disorders showed elevated levels of ammonia, lactic acid to pyruvic acid ratio, and urine ketone bodies. Exome sequencing detected a homozygous pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) and a heterozygous variant of uncertain significance in MSTO1 (ENST00000538143:p.Leu137Pro/c.410 T > C). After Sanger sequencing, the p.Met4Leu pathogenic variant in FDX2 (ENST00000541276:p.Met4Leu/c.10A > T) was identified in a heterozygous state in both her parents and sister. Recently, pathogenic variants in the FDX2 gene have been associated with mitochondrial myopathy, lactic acidosis, optic atrophy, and leukoencephalopathy. Only four reports of FDX2-related rhabdomyolysis have been described before, but none of the previous patients had hyperammonemia. This is a rare case of severe mitochondrial myopathy in a pediatric patient related to a pathogenic FDX2 variant, suggesting the need for genetic analysis of the FDX2 gene in cases of suspicion of mitochondrial myopathies.

Keywords:  FDX2; children; ferredoxin; lactic acidosis; mitochondrial myopathy; rhabdomyolysis

DOI:  https://doi.org/10.1002/ajmg.a.63368
Front Genet. 2023 ;14 1235887

Case report: Asp194Ala variant in MFN2 is associated with ALS-FTD in an Italian family.

C Vinciguerra, A Di Fonzo, E Monfrini, D Ronchi, S Cuoco, G Piscosquito, P Barone, M T Pellecchia.

  Background:MFN2 gene encodes the protein Mitofusin 2, involved in essential mitochondrial functions such as fusion, trafficking, turnover, and cellular interactions. We describe a family carrying a novel MFN2 mutation associated with ALS-frontotemporal dementia (FTD) clinical phenotype in the mother and Charcot-Marie-Tooth disease type 2A (CMT2A) in her son. Case presentation: The mother, a 67-year-old woman, referred to us for a three year-history of mood disturbance and gait impairment, and a more recent hypophonia, dysarthria, dysphagia, and diffuse muscle wasting. Family history was positive for psychiatric disorders and gait disturbances. Brain 18F-FDG PET showed severe hypometabolism in the fronto-temporal brain cortex bilaterally. Electrodiagnostic studies (EDX) showed severe motor axonopathy in the bulbar, cervical and lumbosacral districts. Her 41-year-old son had a history of mood depression and sensory disturbances in the limbs, along with mild muscle wasting, weakness, and reduced reflexes. Nerve conduction studies revealed a moderate sensory-motor polyneuropathy, while brain MRI was normal. Whole exome sequencing of the patients' DNA identified the novel MFN2 (NM_014874.4) variant c.581A>C p.(Asp194Ala). Conclusion: Our findings provide evidence of heterogenous clinical manifestations in family members sharing the same MFN2 molecular defect. Additionally, we present the first documented case of ASL-FTD associated with an MFN2 mutation, thereby expanding the range of MFN-related disorders. Further research involving larger cohorts of patients will be needed to better understand the role of MFN2 as a contributing gene in the development of ALS-FTD.

Keywords:  amyotrophic lateral sclerosis (ALS); charcot marie tooth (CMT); frontotemporal dementia (FTD); mitofusin 2-gene (MFN2); whole exom sequencing

DOI:  https://doi.org/10.3389/fgene.2023.1235887
Theranostics. 2023 ;13(12): 4229-4246

iNOS aggravates pressure overload-induced cardiac dysfunction via activation of the cytosolic-mtDNA-mediated cGAS-STING pathway.

Yongzheng Guo, Yuehua You, Fei-Fei Shang, Xiaowen Wang, Bi Huang, Boying Zhao, Dingyi Lv, Shenglan Yang, Ming Xie, Lingwen Kong, Dingyuan Du, Suxin Luo, Xin Tian, Yong Xia.

  Background: Sterile inflammation contributes to the pathogenesis of cardiac dysfunction caused by various conditions including pressure overload in hypertension. Mitochondrial DNA (mtDNA) released from damaged mitochondria has been implicated in cardiac inflammation. However, the upstream mechanisms governing mtDNA release and how mtDNA activates sterile inflammation in pressure-overloaded hearts remain largely unknown. Here, we investigated the role of inducible NO synthase (iNOS) on pressure overload-induced cytosolic accumulation of mtDNA and whether mtDNA activated inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Methods: To investigate whether the cGAS-STING cascade was involved in sterile inflammation and cardiac dysfunction upon pressure overload, cardiomyocyte-specific STING depletion mice and mice injected with adeno-associated virus-9 (AAV-9) to suppress the cGAS-STING cascade in the heart were subjected to transverse aortic constriction (TAC). iNOS null mice were used to determine the role of iNOS in cGAS-STING pathway activation in pressure-stressed hearts. Results: iNOS knockout abrogated mtDNA release and alleviated cardiac sterile inflammation resulting in improved cardiac function. Conversely, activating the cGAS-STING pathway blunted the protective effects of iNOS knockout. Moreover, iNOS activated the cGAS-STING pathway in isolated myocytes and this was prevented by depleting cytosolic mtDNA. In addition, disruption of the cGAS-STING pathway suppressed inflammatory cytokine transcription and modulated M1/M2 macrophage polarization, and thus mitigated cardiac remodeling and improved heart function. Finally, increased iNOS expression along with cytosolic mtDNA accumulation and cGAS-STING activation were also seen in human hypertensive hearts. Conclusion: Our findings demonstrate that mtDNA is released into the cytosol and triggers sterile inflammation through the cGAS-STING pathway leading to cardiac dysfunction after pressure overload. iNOS controls mtDNA release and subsequent cGAS activation in pressure-stressed hearts.

Keywords:  Cardiac dysfunction; Sterile inflammation; cGAS; iNOS; mtDNA

DOI:  https://doi.org/10.7150/thno.84049
Pediatr Res. 2023 Aug 10.

Genetic etiology of progressive pediatric neurological disorders.

Juho Aaltio, Anna Etula, Simo Ojanen, Virginia Brilhante, Tuula Lönnqvist, Pirjo Isohanni, Anu Suomalainen.

BACKGROUND: The aim of the study was to characterize molecular diagnoses in patients with childhood-onset progressive neurological disorders of suspected genetic etiology.
METHODS: We studied 48 probands (age range from newborn to 17 years old) with progressive neurological disorders of unknown etiology from the largest pediatric neurology clinic in Finland. Phenotypes included encephalopathy (54%), neuromuscular disorders (33%), movement disorders (11%), and one patient (2%) with hemiplegic migraine. All patients underwent whole-exome sequencing and disease-causing genes were analyzed.
RESULTS: We found 20 (42%) of the patients to have variants in genes previously associated with disease. Of these, 12 were previously reported disease-causing variants, whereas eight patients had a novel variant on a disease-causing gene: ATP7A, CHD2, PURA, PYCR2, SLC1A4, SPAST, TRIT1, and UPF3B. Genetics also enabled us to define atypical clinical presentations of Rett syndrome (MECP2) and Menkes disease (ATP7A). Except for one deletion, all findings were single-nucleotide variants (missense 72%, truncating 22%, splice-site 6%). Nearly half of the variants were de novo.
CONCLUSIONS: The most common cause of childhood encephalopathies are de novo variants. Whole-exome sequencing, even singleton, proved to be an efficient tool to gain specific diagnoses and in finding de novo variants in a clinically heterogeneous group of childhood encephalopathies.
IMPACT: Whole-exome sequencing is useful in heterogeneous pediatric neurology cohorts. Our article provides further evidence for and novel variants in several genes. De novo variants are an important cause of childhood encephalopathies.

DOI: https://doi.org/10.1038/s41390-023-02767-z
EMBO Rep. 2023 Aug 07. e56380

Calculation of ATP production rates using the Seahorse XF Analyzer.

Brandon R Desousa, Kristen Ko Kim, Anthony E Jones, Andréa B Ball, Wei Y Hsieh, Pamela Swain, Danielle H Morrow, Alexandra J Brownstein, David A Ferrick, Orian S Shirihai, Andrew Neilson, David A Nathanson, George W Rogers, Brian P Dranka, Anne N Murphy, Charles Affourtit, Steven J Bensinger, Linsey Stiles, Natalia Romero, Ajit S Divakaruni.

  Oxidative phosphorylation and glycolysis are the dominant ATP-generating pathways in mammalian metabolism. The balance between these two pathways is often shifted to execute cell-specific functions in response to stimuli that promote activation, proliferation, or differentiation. However, measurement of these metabolic switches has remained mostly qualitative, making it difficult to discriminate between healthy, physiological changes in energy transduction or compensatory responses due to metabolic dysfunction. We therefore present a broadly applicable method to calculate ATP production rates from oxidative phosphorylation and glycolysis using Seahorse XF Analyzer data and empirical conversion factors. We quantify the bioenergetic changes observed during macrophage polarization as well as cancer cell adaptation to in vitro culture conditions. Additionally, we detect substantive changes in ATP utilization upon neuronal depolarization and T cell receptor activation that are not evident from steady-state ATP measurements. This method generates a single readout that allows the direct comparison of ATP produced from oxidative phosphorylation and glycolysis in live cells. Additionally, the manuscript provides a framework for tailoring the calculations to specific cell systems or experimental conditions.

Keywords:  ATP; ECAR; Seahorse XF Analyzer; glycolysis; oxidative phosphorylation

DOI:  https://doi.org/10.15252/embr.202256380
Placenta. 2023 Jul 08. pii: S0143-4004(23)00155-8. [Epub ahead of print]140 66-71

The MNRR1 activator nitazoxanide abrogates lipopolysaccharide-induced preterm birth in mice.

Neeraja Purandare, Nardhy Gomez-Lopez, Marcia Arenas-Hernandez, Jose Galaz, Roberto Romero, Yue Xi, Andrew M Fribley, Lawrence I Grossman, Siddhesh Aras.

  Intra-amniotic inflammation leading to preterm birth is one of the leading causes of neonatal morbidity and mortality. We recently reported that the mitochondrial levels of MNRR1 (Mitochondrial Nuclear Retrograde, Regulator 1; also called CHCHD2, AAG10, or PARK22), an important bi-organellar regulator of cellular function, are reduced in the context of inflammation and that genetic and pharmacological increases in MNRR1 levels can counter the inflammatory profile. Herein, we show that nitazoxanide, a clinically approved drug, is an activator of MNRR1 and abrogates preterm birth in a well-characterized murine model caused by intra-amniotic lipopolysaccharide (LPS) injection.

Keywords:  CHCHD2; Decidua; Intra-amniotic infection; Intra-amniotic inflammation; Nitazoxanide (Alinia); Prematurity; Preterm labor

DOI:  https://doi.org/10.1016/j.placenta.2023.07.005
Sci Transl Med. 2023 08 09. 15(708): eabq1533

Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts.

Joseph W Guarnieri, Joseph M Dybas, Hossein Fazelinia, Man S Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G Murdock, Alessia Angelin, Larry N Singh, Scott L Weiss, Sonja M Best, Marie T Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J Enguita, Peter Grabham, Nidia S Trovao, Urminder Singh, Jeffrey Haltom, Mark T Heise, Nathaniel J Moorman, Victoria K Baxter, Emily A Madden, Sharon A Taft-Benz, Elizabeth J Anderson, Wes A Sanders, Rebekah J Dickmander, Stephen B Baylin, Eve Syrkin Wurtele, Pedro M Moraes-Vieira, Deanne Taylor, Christopher E Mason, Jonathan C Schisler, Robert E Schwartz, Afshin Beheshti, Douglas C Wallace.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)-encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.

DOI: https://doi.org/10.1126/scitranslmed.abq1533