bims-mitmed 2022-07-17 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–07–17
twenty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Decreasing pdzd8-mediated mito-ER contacts improves organismal fitness and mitigates Aβ42 toxicity.
Comparing the mitochondrial signatures in ESCs and iPSCs and their neural derivations.
Base editing in human cells with monomeric DddA-TALE fusion deaminases.
Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases.
Fluctuating ataxia caused by mitochondrial tRNA (Lys) gene m.8363G > A variant.
Mitochondrial Transfusion Improves Mitochondrial Function Through Up-regulation of Mitochondrial Complex II Protein Subunit SDHB in the Hippocampus of Aged Mice.
The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity.
Cellular Senescence and Ageing: Mechanisms and Interventions.
Mitochondria in neurodegeneration.
Mitochondrial Stress Responses in Duchenne muscular dystrophy: Metabolic Dysfunction or Adaptive Reprogramming?
Age-related mitochondrial dysfunction in Parkinson's disease: new insights into the disease pathology.
Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.
Connecting aging biology and inflammation in the omics era.
Absence of lenadogene nolparvovec DNA in a brain tumor biopsy from a patient in the REVERSE clinical study, a case report.
Carriers of POLG1 variants require investigations for multisystem disease and for mtDNA variations.
Transcriptomic and epigenomic landscapes of Alzheimer's disease evidence mitochondrial-related pathways.
Mitochondrial heterogeneity and homeostasis through the lens of a neuron.
Tafazzin deficiency in mouse mesenchymal stem cells promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.
Developmental programming of mitochondrial substrate metabolism in skeletal muscle of adult sheep by cortisol exposure before birth.
Management of pregnancy in a patient with long-chain 3-hydroxyacyl CoA dehydrogenase deficiency.
Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.
Heterozygous POLG variant Ser1181Asn is associated with autosomal dominant neuro-myopathy in one family with no further specific manifestations of mitochondrial syndrome.
Somatic Mutations Detected in Parkinson Disease Could Affect Genes With a Role in Synaptic and Neuronal Processes.
Newborn screening for neurodevelopmental diseases: Are we there yet?
Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures.
The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.

Life Sci Alliance. 2022 Nov;pii: e202201531. [Epub ahead of print]5(11):

Decreasing pdzd8-mediated mito-ER contacts improves organismal fitness and mitigates Aβ42 toxicity.

Victoria L Hewitt, Leonor Miller-Fleming, Madeleine J Twyning, Simonetta Andreazza, Francesca Mattedi, Julien Prudent, Franck Polleux, Alessio Vagnoni, Alexander J Whitworth.

Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondrial quality control through mitophagy and mediating mitochondrial calcium uptake. Here, we identify and functionally characterize the Drosophila ortholog of the recently identified mammalian MERC protein, Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondrial toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer's disease expressing Amyloid β42 (Aβ42). Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.

DOI: https://doi.org/10.26508/lsa.202201531
Cell Cycle. 2022 Jul 10. 1-16

Comparing the mitochondrial signatures in ESCs and iPSCs and their neural derivations.

Cecilie Katrin Kristiansen, Anbin Chen, Lena Elise Høyland, Mathias Ziegler, Gareth John Sullivan, Laurence A Bindoff, Kristina Xiao Liang.

  Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have distinct origins: ESCs are derived from pre-implanted embryos while iPSCs are reprogrammed somatic cells. Both have their own characteristics and lineage specificity, and both are valuable tools for studying human neurological development and disease. Thus far, few studies have analyzed how differences between stem cell types influence mitochondrial function and mitochondrial DNA (mtDNA) homeostasis during differentiation into neural and glial lineages. In this study, we compared mitochondrial function and mtDNA replication in human ESCs and iPSCs at three different stages - pluripotent, neural progenitor and astrocyte. We found that while ESCs and iPSCs have a similar mitochondrial signature, neural and astrocyte derivations manifested differences. At the neural stem cell (NSC) stage, iPSC-NSCs displayed decreased ATP production and a reduction in mitochondrial respiratory chain (MRC) complex IV expression compared to ESC-NSCs. IPSC-astrocytes showed increased mitochondrial activity including elevated ATP production, MRC complex IV expression, mtDNA copy number and mitochondrial biogenesis relative to those derived from ESCs. These findings show that while ESCs and iPSCs are similar at the pluripotent stage, differences in mitochondrial function may develop during differentiation and must be taken into account when extrapolating results from different cell types.Abbreviation: BSA: Bovine serum albumin; DCFDA: 2',7'-dichlorodihydrofluorescein diacetate; DCX: Doublecortin; EAAT-1: Excitatory amino acid transporter 1; ESCs: Embryonic stem cells; GFAP: Glial fibrillary acidic protein; GS: Glutamine synthetase; iPSCs: Induced pluripotent stem cells; LC3B: Microtubule-associated protein 1 light chain 3β; LC-MS: Liquid chromatography-mass spectrometry; mito-ROS: Mitochondrial ROS; MMP: Mitochondrial membrane potential; MRC: Mitochondrial respiratory chain; mtDNA: Mitochondrial DNA; MTDR: MitoTracker Deep Red; MTG: MitoTracker Green; NSCs: Neural stem cells; PDL: Poly-D-lysine; PFA: Paraformaldehyde; PGC-1α: PPAR-γ coactivator-1 alpha; PPAR-γ: Peroxisome proliferator-activated receptor-gamma; p-SIRT1: Phosphorylated sirtuin 1; p-ULK1: Phosphorylated unc-51 like autophagy activating kinase 1; qPCR: Quantitative PCR; RT: Room temperature; RT-qPCR: Quantitative reverse transcription PCR; SEM: Standard error of the mean; TFAM: Mitochondrial transcription factor A; TMRE: Tetramethylrhodamine ethyl ester; TOMM20: Translocase of outer mitochondrial membrane 20.

Keywords:  ESCs; IPSCs; NSCs; astrocytes; mitochondrial biogenesis; mitochondrial function

DOI:  https://doi.org/10.1080/15384101.2022.2092185
Nat Commun. 2022 Jul 12. 13(1): 4038

Base editing in human cells with monomeric DddA-TALE fusion deaminases.

Young Geun Mok, Ji Min Lee, Eugene Chung, Jaesuk Lee, Kayeong Lim, Sung-Ik Cho, Jin-Soo Kim.

Inter-bacterial toxin DddA-derived cytosine base editors (DdCBEs) enable targeted C-to-T conversions in nuclear and organellar DNA. DddAtox, the deaminase catalytic domain derived from Burkholderia cenocepacia, is split into two inactive halves to avoid its cytotoxicity in eukaryotic cells, when fused to transcription activator-like effector (TALE) DNA-binding proteins to make DdCBEs. As a result, DdCBEs function as pairs, which hampers gene delivery via viral vectors with a small cargo size. Here, we present non-toxic, full-length DddAtox variants to make monomeric DdCBEs (mDdCBEs), enabling mitochondrial DNA editing with high efficiencies of up to 50%, when transiently expressed in human cells. We demonstrate that mDdCBEs expressed via AAV in cultured human cells can achieve nearly homoplasmic C-to-T editing in mitochondrial DNA. Interestingly, mDdCBEs often produce mutation patterns different from those obtained with conventional dimeric DdCBEs. Furthermore, mDdCBEs allow base editing at sites for which only one TALE protein can be designed. We also show that transfection of mDdCBE-encoding mRNA, rather than plasmid, can reduce off-target editing in human mitochondrial DNA.

DOI: https://doi.org/10.1038/s41467-022-31745-y
Neurol Genet. 2022 Aug;8(4): e200007

Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases.

Guido Primiano, Alessandra Torraco, Daniela Verrigni, Andrea Sabino, Enrico Bertini, Rosalba Carrozzo, Gabriella Silvestri, Serenella Servidei.

Objectives: Topoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the TOP3A gene have been associated with the Bloom syndrome-like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the TOP3A-related diseases and clarify the role of this gene in primary mitochondrial disorders.
Methods: A 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed.
Results: A histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the TOP3A gene associated with multiple mtDNA deletions.
Discussion: This case suggests that TOP3A is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome-like disorder to canonical mitochondrial syndromes.

DOI: https://doi.org/10.1212/NXG.0000000000200007
Neurol Sci. 2022 Jul 12.

Fluctuating ataxia caused by mitochondrial tRNA (Lys) gene m.8363G > A variant.

Ying Zhao, Bing Zhao, Kunqian Ji, Chuanzhu Yan.

DOI: https://doi.org/10.1007/s10072-022-06246-x
Mol Neurobiol. 2022 Jul 14.

Mitochondrial Transfusion Improves Mitochondrial Function Through Up-regulation of Mitochondrial Complex II Protein Subunit SDHB in the Hippocampus of Aged Mice.

A Adlimoghaddam, T Benson, B C Albensi.

  The mitochondrial theory of aging is characterized by mitochondrial electron transport chain dysfunction. As a hallmark of aging, an increasing number of investigations have attempted to improve mitochondrial function in both aging and age-related disease. Emerging from these attempts, methods involving mitochondrial isolation, transfusion, and transplantation have taken center stage. In particular, mitochondrial transfusion refers to the administration of mitochondria from healthy tissue into the bloodstream or into tissues affected by injury, disease, or aging. In this study, methods of mitochondrial isolation and transfusion were developed and utilized. First, we found a significant decrease (p < 0.05) in the expression of mitochondrial complex proteins (I-V) in aged (12 months old) mouse brain tissue (C57BL/6 mice) in comparison to healthy young brain tissue (1 month old). To investigate whether healthy young mitochondria taken from the liver could improve mitochondrial function in older animals, we intravenously injected mitochondria isolated from young C57BL/6 mice into aged mice from the same strain. This study, for the first time, demonstrates that mitochondrial transfusion significantly (p < 0.05) improves mitochondrial function via the up-regulation of the mitochondrial complex II protein subunit SDHB in the hippocampus of aged mice. This result has identified a role for mitochondrial complex II in the aging process. Therefore, mitochondrial complex II could serve as a putative target for therapeutic interventions against aging. However, more importantly, methods of mitochondrial transfusion should be further tested to treat a variety of human diseases or disorders and to slow down or reverse processes of aging.

Keywords:  Age-related disease; Aging; Bioenergetics; Brain; Complex II; Mitochondrial dysfunction; Mitochondrial transfusion; Neuroscience

DOI:  https://doi.org/10.1007/s12035-022-02937-w
Mitochondrion. 2022 Jul 08. pii: S1567-7249(22)00056-3. [Epub ahead of print]

The MitoAging Project: Single nucleotide polymorphisms (SNPs) in mitochondrial genes and their association to longevity.

Verónica Castañedaa, Alissen Haro-Vinueza, Ivonne Salinas, Andrés Caicedod, Miguel Angel Mendez.

  Mitochondrial dysfunction is a major hallmark of aging. Mitochondrial DNA (mtDNA) mutations (inherited or acquired) may cause a malfunction of the respiratory chain (RC), and thus negatively affect cell metabolism and function. In contrast, certain mtDNA single nucleotide polymorphisms (SNPs) may be beneficial to mitochondrial electron transport chain function and the extension of cellular health as well as lifespan. The goal of the MitoAging project is to detect key physiological characteristics and mechanisms that improve mitochondrial function and use them to develop therapies to increase longevity and a healthy lifespan. We chose to perform a systematic literature review (SLR) as a tool to collect key mtDNA SNPs associated with an increase in lifespan. Then validated our results by comparing them to the MitoMap database. Next, we assessed the effect of relevant SNPs on protein stability. A total of 28 SNPs were found in protein coding regions. These SNPs were reported in Japan, China, Turkey, and India. Among the studied SNPs, the C5178A mutation in the ND2 gene of Complex I of the RC was detected in all the reviewed reports except in Uygur Chinese centenarians. Then, we found that G9055A (ATP6 gene) and A10398G (ND3 gene) polymorphisms have been associated with a protective effect against Parkinson's disease (PD). Additionally, C8414T in ATP8 was significantly associated with longevity in three Japanese reports. Interestingly, using MitoMap we found that G9055A (ATP6 gene) was the only SNP promoting longevity not associated with any pathology. The identification of SNPs associated with an increase in lifespan opens the possibility to better understand individual differences regarding a decrease in illness susceptibility and find strategies that contribute to healthy aging.

Keywords:  Mitochondria; SNP; aging; longevity; mitochondrial DNA; mitochondrial protein

DOI:  https://doi.org/10.1016/j.mito.2022.06.008
Front Aging. 2022 ;3 866718

Cellular Senescence and Ageing: Mechanisms and Interventions.

Andreas Mylonas, Ana O'Loghlen.

  The influence of the activation of a cellular phenotype termed senescence and it's importance in ageing and age-related diseases is becoming more and more evident. In fact, there is a huge effort to tackle these diseases via therapeutic drugs targeting senescent cells named senolytics. However, a clearer understanding of how senescence is activated and the influence it has on specific cellular types and tissues is needed. Here, we describe general triggers and characteristics of senescence. In addition, we describe the influence of senescent cells in ageing and different age-related diseases.

Keywords:  SASP; age-related disease; ageing; extracellular vesicles; hallmarks; senescence; senolytics; senomorphics

DOI:  https://doi.org/10.3389/fragi.2022.866718
Curr Opin Physiol. 2022 Apr;pii: 100532. [Epub ahead of print]26

Mitochondria in neurodegeneration.

Charleen T Chu.

  The brain is one of the most energetically demanding tissues in the human body, and mitochondrial pathology is strongly implicated in chronic neurodegenerative diseases. In contrast to acute brain injuries in which bioenergetics and cell death play dominant roles, studies modeling familial neurodegeneration implicate a more complex and nuanced relationship involving the entire mitochondrial life cycle. Recent literature on mitochondrial mechanisms in Parkinson's disease, Alzheimer's disease, frontotemporal dementia, Huntington's disease, and amyotrophic lateral sclerosis is reviewed with an emphasis on mitochondrial quality control, transport and synaptodendritic calcium homeostasis. Potential neuroprotective interventions include targeting the mitochondrial kinase PTEN-induced kinase 1 (PINK1), which plays a role in regulating not only multiple facets of mitochondrial biology, but also neuronal morphogenesis and dendritic arborization.

Keywords:  Alzheimer disease; PTEN-induced kinase 1 (PINK1); Parkinson disease; drug discovery; mitochondrial calcium; mitochondrial proteases; mitophagy; synaptic degeneration

DOI:  https://doi.org/10.1016/j.cophys.2022.100532
Am J Physiol Cell Physiol. 2022 Jul 11.

Mitochondrial Stress Responses in Duchenne muscular dystrophy: Metabolic Dysfunction or Adaptive Reprogramming?

Catherine A Bellissimo, Madison C Garibotti, Christopher G R Perry.

  Mitochondrial stress may be a secondary contributor to muscle weakness in inherited muscular dystrophies. Duchenne muscular dystrophy has received the majority of attention whereby most discoveries suggest mitochondrial ATP synthesis may be reduced. However, not all studies support this finding. Furthermore, some studies have reported increased mitochondrial reactive oxygen species and propensity for permeability transition pore formation as an inducer of apoptosis, although divergent findings have also been described. A closer examination of the literature suggests the degree and direction of mitochondrial stress responses may depend on the progression of the disease, the muscle type examined, the mouse model employed with regards to pre-clinical research, the precise metabolic pathways in consideration, and in some cases the in vitro technique used to assess a given mitochondrial bioenergetic function. One intent of this review is to provide careful considerations for future experimental designs to resolve the heterogeneous nature of mitochondrial stress during the progression of Duchenne muscular dystrophy. Such considerations have implications for other muscular dystrophies as well which are addressed briefly herein. A renewed perspective of the term 'mitochondrial dysfunction' is presented whereby stress responses might be re-explored in future investigations as direct contributors to myopathy vs an adaptive 'reprogramming' intended to maintain homeostasis in the face of disease stressors themselves. In so doing, the prospective development of mitochondrial enhancement therapies can be driven by advances in perspectives as much as experimental approaches when resolving the precise relationships between mitochondrial remodelling and muscle weakness in Duchenne and, indeed, other muscular dystrophies.

Keywords:  Duchenne muscular dystrophy; bioenergetics; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.1152/ajpcell.00249.2022
Neuroscience. 2022 Jul 12. pii: S0306-4522(22)00350-5. [Epub ahead of print]

Age-related mitochondrial dysfunction in Parkinson's disease: new insights into the disease pathology.

Linchi Rani, Manas Ranjan Sahu, Amal Chandra Mondal.

  Aging is a progressive loss of physiological function that increases risk of disease and death. Among the many factors that contribute to human aging, mitochondrial dysfunction has emerged as one of the most prominent features of the aging process. It has been linked to the development of various age-related pathologies, including Parkinson's disease (PD). Mitochondria has a complex quality control system that ensures mitochondrial integrity and function. Perturbations in these mitochondrial mechanisms have long been linked to various age-related neurological disorders. Even though research has shed light on several aspects of the disease pathology, the underlying mechanism of age-related factors responsible for individuals developing this disease is still unknown. This review article aims to discuss the role of mitochondria in the transition from normal brain aging to pathological brain aging, which leads to the progression of PD. We have discussed the emerging evidence on how age-related disruption of mitochondrial quality control mechanisms contributes to the development of PD-related pathophysiology.

Keywords:  Aging; Mitochondrial aberrations; Mitochondrial quality control mechanism; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.neuroscience.2022.07.007
Front Aging. 2021 ;2 681428

Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.

Lauren A Callender, Elizabeth C Carroll, Conor Garrod-Ketchley, Johannes Schroth, Jonas Bystrom, Victoria Berryman, Melanie Pattrick, Desiree Campbell-Richards, Gillian A Hood, Graham A Hitman, Sarah Finer, Sian M Henson.

  Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.

Keywords:  T cell; ageing; inflammation; metabolism; mitochondria; senescence; type 2 diabetes

DOI:  https://doi.org/10.3389/fragi.2021.681428
J Clin Invest. 2022 Jul 15. pii: e158448. [Epub ahead of print]132(14):

Connecting aging biology and inflammation in the omics era.

Keenan A Walker, Nathan Basisty, David M Wilson, Luigi Ferrucci.

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging - and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

DOI: https://doi.org/10.1172/JCI158448
BMC Neurol. 2022 Jul 12. 22(1): 257

Absence of lenadogene nolparvovec DNA in a brain tumor biopsy from a patient in the REVERSE clinical study, a case report.

Nancy J Newman, Matthew Schniederjan, Pia R Mendoza, David J Calkins, Patrick Yu-Wai-Man, Valérie Biousse, Valerio Carelli, Magali Taiel, Francois Rugiero, Pramila Singh, Alexandra Rogue, José-Alain Sahel, Philippe Ancian.

   BACKGROUND: Leber Hereditary Optic Neuropathy (LHON) is a rare, maternally-inherited mitochondrial disease that primarily affects retinal ganglion cells (RGCs) and their axons in the optic nerve, leading to irreversible, bilateral severe vision loss. Lenadogene nolparvovec gene therapy was developed as a treatment for patients with vision loss from LHON caused by the most prevalent m.11778G > A mitochondrial DNA point mutation in the MT-ND4 gene. Lenadogene nolparvovec is a replication-defective recombinant adeno-associated virus vector 2 serotype 2 (AAV2/2), encoding the human wild-type MT-ND4 protein. Lenadogene nolparvovec was administered by intravitreal injection (IVT) in LHON patients harboring the m.11778G > A ND4 mutation in a clinical development program including one phase 1/2 study (REVEAL), three phase 3 pivotal studies (REVERSE, RESCUE, REFLECT), and one long-term follow-up study (RESTORE, the follow-up of REVERSE and RESCUE patients).
CASE PRESENTATION: A 67-year-old woman with MT-ND4 LHON, included in the REVERSE clinical study, received a unilateral IVT of lenadogene nolparvovec in the right eye and a sham injection in the left eye in May 2016, 11.4 months and 8.8 months after vision loss in her right and left eyes, respectively. The patient had a normal brain magnetic resonance imaging with contrast at the time of diagnosis of LHON. Two years after treatment administration, BCVA had improved in both eyes. The product was well tolerated with mild and resolutive anterior chamber inflammation in the treated eye. In May 2019, the patient was diagnosed with a right temporal lobe glioblastoma, IDH-wildtype, World Health Organization grade 4, based on histological analysis of a tumor excision. The brain tumor was assessed for the presence of vector DNA by using a sensitive validated qPCR assay targeting the ND4 sequence of the vector.
CONCLUSION: ND4 DNA was not detected (below 15.625 copies/μg of genomic DNA) in DNA extracted from the brain tumor, while a housekeeping gene DNA was detected at high levels. Taken together, this data shows the absence of detection of lenadogene nolparvovec in a brain tumor (glioblastoma) of a treated patient in the REVERSE clinical trial 3 years after gene therapy administration, supporting the long-term favorable safety of lenadogene nolparvovec.

Keywords:  Case report; Leber hereditary optic neuropathy; Lenadogene nolparvovec; ND4; Recombinant adeno-associated virus vector 2 serotype 2; Viral vector transduction; qPCR assay

DOI:  https://doi.org/10.1186/s12883-022-02787-y
Neurol Res Pract. 2022 Jul 11. 4(1): 33

Carriers of POLG1 variants require investigations for multisystem disease and for mtDNA variations.

Josef Finsterer, Sinda Zarrouk.



Keywords:  Lactate; Mitochondrial; Multisystem disease; POLG1; mtDNA

DOI:  https://doi.org/10.1186/s42466-022-00195-8
Biochim Biophys Acta Mol Cell Res. 2022 Jul 12. pii: S0167-4889(22)00118-5. [Epub ahead of print] 119326

Transcriptomic and epigenomic landscapes of Alzheimer's disease evidence mitochondrial-related pathways.

Alejandro Marmolejo-Garza, Tiago Medeiros-Furquim, Ramya Rao, Bart J L Eggen, Erik Boddeke, Amalia M Dolga.

  Alzheimer's Disease (AD) is the main cause of dementia and it is defined by cognitive decline coupled to extracellular deposit of amyloid-beta protein and intracellular hyperphosphorylation of tau protein. Historically, efforts to target such hallmarks have failed in numerous clinical trials. In addition to these hallmark-targeted approaches, several clinical trials focus on other AD pathological processes, such as inflammation, mitochondrial dysfunction, and oxidative stress. Mitochondria and mitochondrial-related mechanisms have become an attractive target for disease-modifying strategies, as mitochondrial dysfunction prior to clinical onset has been widely described in AD patients and AD animal models. Mitochondrial function relies on both the nuclear and mitochondrial genome. Findings from omics technologies have shed light on AD pathophysiology at different levels (e.g., epigenome, transcriptome and proteome). Most of these studies have focused on the nuclear-encoded components. The first part of this review provides an updated overview of the mechanisms that regulate mitochondrial gene expression and function. The second part of this review focuses on evidence of mitochondrial dysfunction in AD. We have focused on published findings and datasets that study AD. We have focused on published findings and datasets that study AD. We analyzed published data and provide examples for mitochondrial-related pathways. These pathways are strikingly dysregulated in AD neurons and glia in sex-, cell- and disease stage-specific manners. Analysis of mitochondrial omics data highlights the involvement of mitochondria in AD, providing a rationale for further disease modeling and drug targeting.

Keywords:  ATAC-seq; Mitochondria; Neurodegeneration; Omics; RNA-seq

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119326
Nat Metab. 2022 Jul 11.

Mitochondrial heterogeneity and homeostasis through the lens of a neuron.

Gulcin Pekkurnaz, Xinnan Wang.

Mitochondria are vital organelles with distinct morphological features and functional properties. The dynamic network of mitochondria undergoes structural and functional adaptations in response to cell-type-specific metabolic demands. Even within the same cell, mitochondria can display wide diversity and separate into functionally distinct subpopulations. Mitochondrial heterogeneity supports unique subcellular functions and is crucial to polarized cells, such as neurons. The spatiotemporal metabolic burden within the complex shape of a neuron requires precisely localized mitochondria. By travelling great lengths throughout neurons and experiencing bouts of immobility, mitochondria meet distant local fuel demands. Understanding mitochondrial heterogeneity and homeostasis mechanisms in neurons provides a framework to probe their significance to many other cell types. Here, we put forth an outline of the multifaceted role of mitochondria in regulating neuronal physiology and cellular functions more broadly.

DOI: https://doi.org/10.1038/s42255-022-00594-w
FASEB J. 2022 Aug;36(8): e22443

Tafazzin deficiency in mouse mesenchymal stem cells promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.

Hana M Zegallai, Ejlal Abu-El-Rub, Folayemi Olayinka-Adefemi, Laura K Cole, Genevieve C Sparagna, Aaron J Marshall, Grant M Hatch.

  Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutation in the TAFAZZIN gene. Tafazzin (Taz) deficiency in BTHS patients results in an increased risk of infections. Mesenchymal stem cells (MSCs) are well known for their immune-inhibitory function. We examined how Taz-deficiency in murine MSCs impact their ability to modulate the function of lipopolysaccharide (LPS)-activated wild type (WT) B lymphocytes. MSCs from tafazzin knockdown (TazKD) mice exhibited a reduction in mitochondrial cardiolipin compared to wild type (WT) MSCs. However, mitochondrial bioenergetics and membrane potential were unaltered. In contrast, TazKD MSCs exhibited increased reactive oxygen species generation and increased glycolysis. The increased glycolysis was associated with an elevated proliferation, phosphatidylinositol-3-kinase expression and expression of the immunosuppressive markers indoleamine-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4, interleukin-10, and cluster of differentiation 59 compared to controls. Inhibition of glycolysis with 2-deoxyglucose attenuated the TazKD-mediated increased expression of cytotoxic T-lymphocyte-associated protein 4 and interleukin-10. When co-cultured with LPS-activated WT B cells, TazKD MSCs inhibited B cell proliferation and growth rate and reduced B cell secretion of immunoglobulin M compared to controls. In addition, co-culture of LPS-activated WT B cells with TazKD MSCs promoted B cell differentiation toward interleukin-10 secreting plasma cells and B regulatory cells compared to controls. The results indicate that Taz deficiency in MSCs promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.

Keywords:  Barth syndrome; activated B lymphocytes; cardiolipin; immune function; lipopolysaccharide; mesenchymal stem cells; mitochondria; tafazzin

DOI:  https://doi.org/10.1096/fj.202200145R
J Dev Orig Health Dis. 2022 Jul 13. 1-11

Developmental programming of mitochondrial substrate metabolism in skeletal muscle of adult sheep by cortisol exposure before birth.

Katie L Davies, Emily J Camm, Danielle J Smith, Jack Miles, Alison J Forhead, Andrew J Murray, Abigail L Fowden.

  Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes. In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations. There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally. In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase. Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programmes mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.

Keywords:  Mitochondria; cortisol; development programming

DOI:  https://doi.org/10.1017/S204017442200040X
JIMD Rep. 2022 Jul;63(4): 265-270

Management of pregnancy in a patient with long-chain 3-hydroxyacyl CoA dehydrogenase deficiency.

Loai A Shakerdi, Jenny McNulty, Barbara Gillman, Claire M McCarthy, Jessica Ivory, Alison Sheerin, James J O'Byrne, Jennifer C Donnelly, Eileen P Treacy.

  Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare mitochondrial defect of β-oxidation of long-chain fatty acids. Patients may present with muscle pain, hypotonia, peripheral neuropathy, cardiomyopathy, recurrent rhabdomyolysis and sudden death. Dietary management of LCHADD aims at preventing prolonged fasting and decreasing energy production from long-chain fatty acids compensated by an increase in medium-chain triglyceride fat. Herein, we present medical and dietetic management of a successful pregnancy in a LCHADD female patient and the delivery of a healthy baby boy.

Keywords:  acylcarnitine; long‐chain 3‐hydroxyacyl CoA dehydrogenase deficiency; pregnancy; rhabdomyolysis

DOI:  https://doi.org/10.1002/jmd2.12284
Cell Biol Int. 2022 Jul 12.

Tamoxifen modulates mitochondrial dynamics through AMPK and MAPK during nutrition deprivation.

Gangipangi Vijayakumar, Uppalapati S Swetha, Selvaraju Sudhagar.

  The interaction of cancer cells with their tumor microenvironment determines key events in the progression of the disease, therapeutic efficacy, and the development of drug resistance. Here, we presented evidence that tamoxifen support breast cancer growth during nutrition deprivation by modulating mitochondrial dynamics through AMPK and MAPK signaling. Tamoxifen enhances mitochondrial fusion under nutrition-deprived conditions by suppressing Drp1 ser616 phosphorylation and upregulating Mfn1 levels. Tamoxifen-induced mitochondrial fusion is mediated by the activation of AMPK as evident by the pharmacological inhibition of AMPK reverse mitochondrial fusion. Interestingly, JNK activation by tamoxifen controls the mitochondrial fusion morphology by downregulating Mfn2. Collectively, tamoxifen support cell growth by enhancing mitochondrial fusion by regulating stress kinase signaling under nutrition deprivation condition.

Keywords:  AMPK; MAPK; Tamoxifen; mitochondrial dynamics; nutrition deprivation

DOI:  https://doi.org/10.1002/cbin.11853
Neurol Res Pract. 2022 Jul 11. 4(1): 34

Heterozygous POLG variant Ser1181Asn is associated with autosomal dominant neuro-myopathy in one family with no further specific manifestations of mitochondrial syndrome.

Maike F Dohrn, Danique Beijer, Lejla Mulahasanovic.

DOI: https://doi.org/10.1186/s42466-022-00197-6
Front Aging. 2022 ;3 851039

Somatic Mutations Detected in Parkinson Disease Could Affect Genes With a Role in Synaptic and Neuronal Processes.

Irene Lobon, Manuel Solís-Moruno, David Juan, Ashraf Muhaisen, Federico Abascal, Paula Esteller-Cucala, Raquel García-Pérez, Maria Josep Martí, Eduardo Tolosa, Jesús Ávila, Raheleh Rahbari, Tomas Marques-Bonet, Ferran Casals, Eduardo Soriano.

  The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. However, to date, no study has shown their relation to Parkinson disease's phenotype. To explore the relevance of embryonic somatic mutations in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and a careful filtering strategy (COSMOS). We validated 27 of them with amplicon-based ultra-deep sequencing, with a 70% validation rate for the highest-confidence variants. The identified sSNVs are in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. Most of the sSNVs were only called in blood but were also found in the brain tissues with ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs.

Keywords:  Parkinson disease; brain mosaicism; neurodegenaration; somatic genome alteration; somatic mutations

DOI:  https://doi.org/10.3389/fragi.2022.851039
Am J Med Genet C Semin Med Genet. 2022 Jul 15.

Newborn screening for neurodevelopmental diseases: Are we there yet?

Wendy K Chung, Jonathan S Berg, Jeffrey R Botkin, Steven E Brenner, Jeffrey P Brosco, Kyle B Brothers, Robert J Currier, Amy Gaviglio, Walter E Kowtoniuk, Colleen Olson, Michele Lloyd-Puryear, Annamarie Saarinen, Mustafa Sahin, Yufeng Shen, Elliott H Sherr, Michael S Watson, Zhanzhi Hu.

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

DOI: https://doi.org/10.1002/ajmg.c.31988
Acta Neuropathol Commun. 2022 Jul 14. 10(1): 103

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures.

Rebecca R Valentino, Chloe Ramnarine, Michael G Heckman, Patrick W Johnson, Alexandra I Soto-Beasley, Ronald L Walton, Shunsuke Koga, Koji Kasanuki, Melissa E Murray, Ryan J Uitti, Julie A Fields, Hugo Botha, Vijay K Ramanan, Kejal Kantarci, Val J Lowe, Clifford R Jack, Nilufer Ertekin-Taner, Rodolfo Savica, Jonathan Graff-Radford, Ronald C Petersen, Joseph E Parisi, R Ross Reichard, Neill R Graff-Radford, Tanis J Ferman, Bradley F Boeve, Zbigniew K Wszolek, Dennis W Dickson, Owen A Ross.

  Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Keywords:  Dementia with Lewy-bodies; Lewy body disease; Mitochondrial DNA; Mitochondrial haplogroups; Neuropathology

DOI:  https://doi.org/10.1186/s40478-022-01399-4
Biochem J. 2022 Jul 15. 479(13): 1455-1466

The mitochondrial translocator protein (TSPO): a key multifunctional molecule in the nervous system.

Léa El Chemali, Yvette Akwa, Liliane Massaad-Massade.

  Translocator protein (TSPO, 18 kDa), formerly known as peripheral benzodiazepine receptor, is an evolutionary well-conserved protein located on the outer mitochondrial membrane. TSPO is involved in a variety of fundamental physiological functions and cellular processes. Its expression levels are regulated under many pathological conditions, therefore, TSPO has been proposed as a tool for diagnostic imaging and an attractive therapeutic drug target in the nervous system. Several synthetic TSPO ligands have thus been explored as agonists and antagonists for innovative treatments as neuroprotective and regenerative agents. In this review, we provide state-of-the-art knowledge of TSPO functions in the brain and peripheral nervous system. Particular emphasis is placed on its contribution to important physiological functions such as mitochondrial homeostasis, energy metabolism and steroidogenesis. We also report how it is involved in neuroinflammation, brain injury and diseases of the nervous system.

Keywords:  biomarker; neuroinflammation; neuropathology; neuroprotection; steroidogenesis; translocator protein (TSPO)

DOI:  https://doi.org/10.1042/BCJ20220050