bims-mitmed 2023-12-31 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–12–31
nineteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

The genetic puzzle of a SOD1-patient with ocular ptosis and a motor neuron disease: a case report.
Weaning difficulty after severe pneumonia in adult-onset mitochondrial myopathy with A3243G mutation in the mitochondrial tRNA gene: A case report.
Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene.
Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.
Dual barrier system against xenomitochondrial contamination in mouse embryos.
Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period.
A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
Protein N-myristoylation plays a critical role in the mitochondrial localization of human mitochondrial complex I accessory subunit NDUFB7.
Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.
Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).
The role of lysine acetylation in the function of mitochondrial ribosomal protein L12.
Prenatal air pollution exposure in relation to the telomere-mitochondrial axis of aging at birth: A systematic review.
Considerations for liver transplantation in deoxyguanosine kinase deficiency: A case series and review of the literature.
Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts.
Structural basis for DNA proofreading.
Dystonia, spastic tetraplegia, and ataxia due to a novel mutation in the dynamin domain of OPA1.
Toxicity mechanism of engineered nanomaterials: Focus on mitochondria.
The mitochondriogenic but not the immunosuppressant effects of mTOR inhibitors prompt neuroprotection and delay disease evolution in a mouse model of progressive multiple sclerosis.
New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Front Genet. 2023 ;14 1322067

The genetic puzzle of a SOD1-patient with ocular ptosis and a motor neuron disease: a case report.

Veria Vacchiano, Flavia Palombo, Danara Ormanbekova, Claudio Fiorini, Alessia Fiorentino, Leonardo Caporali, Andrea Mastrangelo, Maria Lucia Valentino, Sabina Capellari, Rocco Liguori, Valerio Carelli.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex genetic architecture, showing monogenic, oligogenic, and polygenic inheritance. In this study, we describe the case of a 71 years-old man diagnosed with ALS with atypical clinical features consisting in progressive ocular ptosis and sensorineural deafness. Genetic analyses revealed two heterozygous variants, in the SOD1 (OMIM*147450) and the TBK1 (OMIM*604834) genes respectively, and furthermore mitochondrial DNA (mtDNA) sequencing identified the homoplasmic m.14484T>C variant usually associated with Leber's Hereditary Optic Neuropathy (LHON). We discuss how all these variants may synergically impinge on mitochondrial function, possibly contributing to the pathogenic mechanisms which might ultimately lead to the neurodegenerative process, shaping the clinical ALS phenotype enriched by adjunctive clinical features.

Keywords:  SOD1; TBK1; amyotrophic lateral sclerosis; mitochondrial DNA; oligogenic inheritance

DOI:  https://doi.org/10.3389/fgene.2023.1322067
Heliyon. 2023 Dec;9(12): e23300

Weaning difficulty after severe pneumonia in adult-onset mitochondrial myopathy with A3243G mutation in the mitochondrial tRNA gene: A case report.

Xiong Peng, Li-Xiu Ma, Ce Xiao, Zhi-Zhe Zhang, Min Zhu, Dao-Jun Hong, Yi-An Zhan.

   Background: Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia.
Case presentation: We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged.
Conclusion: This case presented an uncommon cause of difficult weaning and extubation-acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.

Keywords:  A3243G mutation; Acute respiratory failure; Difficulty in weaning; Mitochondrial myopathy; Severe pneumonia

DOI:  https://doi.org/10.1016/j.heliyon.2023.e23300
Stem Cell Res. 2023 Dec 16. pii: S1873-5061(23)00275-1. [Epub ahead of print]74 103289

Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene.

Istaq Ahmad, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq.

Friedreich's ataxia (FRDA) is a rare neurodegenerativedisorder caused by over expansion of GAA repeats in thefirstintron ofFXN gene. Here, we generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron ofFXNgene.IGIBi014-A and IGIBi015-Aboth iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY),the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression. These cell lines will be utilized to comprehend the pathophysiology of the illness and the FRDA's predictive phenotypes.

DOI: https://doi.org/10.1016/j.scr.2023.103289
Metabolism. 2023 Dec 26. pii: S0026-0495(23)00372-4. [Epub ahead of print] 155768

Impact of fasting on the AMPK and PGC-1α axis in rodent and human skeletal muscle: A systematic review.

K L Storoschuk, D Lesiuk, J Nuttall, M LeBouedec, A Khansari, H Islam, B J Gurd.

  Based primarily on evidence from rodent models fasting is currently believed to improve metabolic health in via activation of the AMPK-PGC-1α axis in skeletal muscle. However, it is unclear whether the skeletal muscle AMPK-PGC-1α axis is activated by fasting in humans. The current systematic review examined the fasting response in skeletal muscle from 34 selected studies (7 human, 21 mouse, and 6 rat). From these studies, we gathered 38 unique data points related to AMPK and 47 related to PGC-1α. In human studies, fasting mediated activation of the AMPK-PGC-1α axis is largely absent. Although evidence does support fasting-induced activation of the AMPK-PGC-1α axis in rodent skeletal muscle, the evidence is less robust than anticipated. Our findings question the ability of fasting to activate the AMPK-PGC-1α axis in human skeletal muscle and suggest that the metabolic benefits of fasting in humans are associated with caloric restriction rather than the induction of mitochondrial biogenesis. Registration: https://doi.org/10.17605/OSF.IO/KWNQY.

Keywords:  AMPK; Fasting; Mitochondrial biogenesis; PGC-1α

DOI:  https://doi.org/10.1016/j.metabol.2023.155768
Sci Rep. 2023 Dec 27. 13(1): 23058

Dual barrier system against xenomitochondrial contamination in mouse embryos.

Masaya Komatsu, Hikaru Takuma, Shun Imai, Maiko Yamane, Masashi Takahashi, Takuto Ikegawa, Hanako Bai, Hidehiko Ogawa, Manabu Kawahara.

Heteroplasmic mammalian embryos between genetically distant species fail to develop to term, preventing transmission of xenomitochondrial DNA to progeny. However, there is no direct evidence indicating the mechanisms by which species specificity of the mitochondrial genome is ensured during mammalian development. Here, we have uncovered a two-step strategy underlying the prevention of xenomitochondrial DNA transmission in mouse embryos harboring bovine mitochondria (mtB-M embryos). First, mtB-M embryos showed metabolic disorder by transient increase of reactive oxygen species at the 4-cell stage, resulting in repressed development. Second, trophoblasts of mtB-M embryos led to implantation failure. Therefore, we tested cell aggregation with tetraploid embryos to compensate for the placentation of mtB-M embryos. The 14 mtB-M embryos harboring bovine mtDNAs developed to term at embryonic day 19.5. Taken together, our results show that contamination of bovine mtDNA is prohibited by embryonic lethality due to metabolic disruption and failure of placentation, suggesting these represent xenomitochondrial elimination mechanisms in mammalian embryos.

DOI: https://doi.org/10.1038/s41598-023-50444-2
Elife. 2023 Dec 27. pii: RP88008. [Epub ahead of print]12

Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period.

David Bolumar, Javier Moncayo-Arlandi, Javier Gonzalez-Fernandez, Ana Ochando, Inmaculada Moreno, Ana Monteagudo-Sanchez, Carlos Marin, Antonio Diez, Paula Fabra, Miguel Angel Checa, Juan Jose Espinos, David K Gardner, Carlos Simon, Felipe Vilella.

  The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of mitochondrial (mt)DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived nuclear-encoded (n)DNA/mtDNA by trophoblast cells of murine embryos, which associates with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that nDNA/mtDNA become packaged into secreted EVs that the embryo uptakes, and that the transfer of DNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.

Keywords:  developmental biology; endometrium; exosomes; extracellular vesicles; human; maternal-embryonic crosstalk; medicine; metabolism; mitochondrial DNA; mouse

DOI:  https://doi.org/10.7554/eLife.88008
Mol Cell. 2023 Dec 21. pii: S1097-2765(23)01014-6. [Epub ahead of print]

A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang.

  Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

Keywords:  Cullin; FBXL4; PPTC7; metabolism; mitochondrial mass; mitophagy receptors BNIP3 and NIX; ubiquitin

DOI:  https://doi.org/10.1016/j.molcel.2023.11.038
Sci Rep. 2023 12 27. 13(1): 22991

Protein N-myristoylation plays a critical role in the mitochondrial localization of human mitochondrial complex I accessory subunit NDUFB7.

Haruna Harada, Koko Moriya, Hirotsugu Kobuchi, Naotada Ishihara, Toshihiko Utsumi.

The present study examined human N-myristoylated proteins that specifically localize to mitochondria among the 1,705 human genes listed in MitoProteome, a mitochondrial protein database. We herein employed a strategy utilizing cellular metabolic labeling with a bioorthogonal myristic acid analog in transfected COS-1 cells established in our previous studies. Four proteins, DMAC1, HCCS, NDUFB7, and PLGRKT, were identified as N-myristoylated proteins that specifically localize to mitochondria. Among these proteins, DMAC1 and NDUFB7 play critical roles in the assembly of complex I of the mitochondrial respiratory chain. DMAC1 functions as an assembly factor, and NDUFB7 is an accessory subunit of complex I. An analysis of the intracellular localization of non-myristoylatable G2A mutants revealed that protein N-myristoylation occurring on NDUFB7 was important for the mitochondrial localization of this protein. Furthermore, an analysis of the role of the CHCH domain in NDUFB7 using Cys to Ser mutants revealed that it was essential for the mitochondrial localization of NDUFB7. Therefore, the present results showed that NDUFB7, a vital component of human mitochondrial complex I, was N-myristoylated, and protein N-myrisotylation and the CHCH domain were both indispensable for the specific targeting and localization of NDUFB7 to mitochondria.

DOI: https://doi.org/10.1038/s41598-023-50390-z
Mol Metab. 2023 Dec 23. pii: S2212-8778(23)00193-X. [Epub ahead of print] 101859

Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.

Anna Janz, Katharina Walz, Alexandra Cirnu, Jessica Surjanto, Daniela Urlaub, Miriam Leskien, Michael Kohlhaas, Alexander Nickel, Theresa Brand, Naoko Nose, Philipp Wörsdörfer, Nicole Wagner, Takahiro Higuchi, Christoph Maack, Jan Dudek, Kristina Lorenz, Eva Klopocki, Süleyman Ergün, Henry J Duff, Brenda Gerull.

   BACKGROUND: Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy.
METHODS: We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca2+ kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tvHeLa).
RESULTS: Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca2+ concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation.
CONCLUSIONS: Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and mitochondrial function, which suggests that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca2+ kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.

Keywords:  Contractility; Dilated cardiomyopathy with ataxia; Genetics; Metabolism; Mitochondria; OXPHOS; ROS

DOI:  https://doi.org/10.1016/j.molmet.2023.101859
J Gerontol A Biol Sci Med Sci. 2023 Dec 27. pii: glad283. [Epub ahead of print]

Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA).

Philip A Kramer, Paul M Coen, Peggy M Cawthon, Giovanna Distefano, Steven R Cummings, Bret H Goodpaster, Russell T Hepple, Stephen B Kritchevsky, Eric G Shankland, David J Marcinek, Frederico G S Toledo, Kate A Duchowny, Sofhia V Ramos, Stephanie Harrison, Anne B Newman, Anthony J A Molina.

  The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery score ≤ 8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (e.g. Maximal Complex I&II OXPHOS: Women=55.06 +/- 15.95; Men=65.80 +/- 19.74; p<0.001) and in individuals with mobility impairment compared to those without (e.g., Maximal Complex I&II OXPHOS in women: SPPB≥9=56.59 +/- 16.22; SPPB≤8=47.37 +/- 11.85; p<0.001). Muscle energetics were negatively associated with age only in men (e.g., Maximal ETS capacity: R=-0.15, p=0.02; age/sex interaction, p=0.04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, ORage-adjusted=1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, ORage-adjusted=1.05, 95% CI=0.52, 2.15, p=0.89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.

Keywords:  Mitochondria; bioenergetics; disability; gender; lower-extremity

DOI:  https://doi.org/10.1093/gerona/glad283
Proteins. 2023 Dec 25.

The role of lysine acetylation in the function of mitochondrial ribosomal protein L12.

Katelynn V Paluch, Karlie R Platz, Emma J Rudisel, Ryan R Erdmann, Taylor R Laurin, Kristin E Dittenhafer-Reed.

  Mitochondria play a central role in energy production and cellular metabolism. Mitochondria contain their own small genome (mitochondrial DNA, mtDNA) that carries the genetic instructions for proteins required for ATP synthesis. The mitochondrial proteome, including the mitochondrial transcriptional machinery, is subject to post-translational modifications (PTMs), including acetylation and phosphorylation. We set out to determine whether PTMs of proteins associated with mtDNA may provide a potential mechanism for the regulation of mitochondrial gene expression. Here, we focus on mitochondrial ribosomal protein L12 (MRPL12), which is thought to stabilize mitochondrial RNA polymerase (POLRMT) and promote transcription. Numerous acetylation sites of MRPL12 were identified by mass spectrometry. We employed amino acid mimics of the acetylated (lysine to glutamine mutants) and deacetylated (lysine to arginine mutants) versions of MRPL12 to interrogate the role of lysine acetylation in transcription initiation in vitro and mitochondrial gene expression in HeLa cells. MRPL12 acetyl and deacetyl protein mimics were purified and assessed for their ability to impact mtDNA promoter binding of POLRMT. We analyzed mtDNA content and mitochondrial transcript levels in HeLa cells upon overexpression of acetyl and deacetyl mimics of MRPL12. Our results suggest that MRPL12 single-site acetyl mimics do not change the mtDNA promoter binding ability of POLRMT or mtDNA content in HeLa cells. Individual acetyl mimics may have modest effects on mitochondrial transcript levels. We found that the mitochondrial deacetylase, Sirtuin 3, is capable of deacetylating MRPL12 in vitro, suggesting a potential role for dynamic acetylation controlling MRPL12 function in a role outside of the regulation of gene expression.

Keywords:  acetylation; mitochondrial DNA; mitochondrial genome; mitochondrial proteins; post-translational protein modification; transcription

DOI:  https://doi.org/10.1002/prot.26654
Environ Res. 2023 Dec 21. pii: S0013-9351(23)02794-9. [Epub ahead of print] 117990

Prenatal air pollution exposure in relation to the telomere-mitochondrial axis of aging at birth: A systematic review.

Shradha Mishra, Charlotte Van Der Stukken, Stacy Drury, Tim S Nawrot, Dries S Martens.

   BACKGROUND: Telomere length (TL) and mitochondrial DNA (mtDNA) are central markers of vital biological mechanisms, including cellular aging. Prenatal air pollution exposure may impact molecular markers of aging leading to adverse health effects.
OBJECTIVE: To perform a systematic review on human population-based studies investigating the association between prenatal air pollution exposure and TL or mtDNA content at birth.
METHODOLOGY: Searches were undertaken on PubMed and Web of Science until July 2023. The framework of the review was based on the PRISMA-P guidelines.
RESULTS: Nineteen studies studied prenatal air pollution and TL or mtDNA content at birth. Studies investigating TL or mtDNA content measured at any other time or did not evaluate prenatal air pollution were excluded. Twelve studies (including 4381 participants with study sample range: 97 to 743 participants) investigated newborn TL and eight studies (including 3081 participants with study sample range: 120 to 743 participants) investigated mtDNA content at birth. Seven studies focused on particulate matter (PM2.5) exposure and newborn TL of which all, except two, showed an inverse association in at least one of the gestational trimesters. Of the eight studies on mtDNA content, four focused on PM2.5 air pollution with two of them reporting an inverse association. For PM2.5 exposure, observations on trimester-specific effects were inconsistent. Current literature showing associations with other prenatal air pollutants (including nitrogen oxides, sulfur dioxide, carbon monoxide and ozone) is inconsistent.
CONCLUSION: This review provides initial evidence that prenatal PM2.5 exposure impacts the telomere-mitochondrial axis of aging at birth. The current evidence did not reveal harmonious observations for trimester-specific associations nor showed consistent effects of other air pollutants. Future studies should elucidate the specific contribution of prenatal exposure to pollutants other than PM in relation to TL and mtDNA content at birth, and the potential later life health consequences.

Keywords:  Air pollution; Early life; Mitochondrial DNA; Newborns; Prenatal exposure; Telomere length

DOI:  https://doi.org/10.1016/j.envres.2023.117990
Pediatr Transplant. 2023 Dec 27. e14670

Considerations for liver transplantation in deoxyguanosine kinase deficiency: A case series and review of the literature.

Jennifer T Duong, M Cristina Pacheco, Evelyn Hsu, Niviann Blondet.

   BACKGROUND: Deoxyguanosine kinase (DGUOK) deficiency is a rare mitochondrial disorder characterized by early onset liver failure and varying degrees of neurologic dysfunction. Patients typically present during infancy with progressive hepatic dysfunction leading to liver failure, which can precede neurologic deterioration. Outcomes posttransplantation are historically worse than average and the role of liver transplantation remains controversial. These factors, in combination with the increasing number of patients being diagnosed via molecular genetic testing, may impede waitlist access.
METHODS: We report our single-center experience with three patients with DGUOK deficiency, all of whom were considered for transplant. We review the current literature regarding management and discuss the role of liver transplantation in DGUOK deficiency-associated liver failure.
RESULTS: Two patients presented with hypoglycemia, conjugated hyperbilirubinemia, and lactic acidosis within the first week of life, were diagnosed with DGUOK deficiency prior to 2 months of age and had severe neurologic involvement. The third patient presented in later infancy was diagnosed with DGUOK deficiency at 18 months of age and had minimal neurologic involvement. All three patients were considered for transplant, though only two patients were listed. All three died from complications of end-stage liver failure prior to liver transplantation between the ages of 5-20 months.
CONCLUSION: Selection for liver transplantation in DGUOK deficiency is complex, requiring a multidisciplinary team approach. Recent data suggest that liver transplantation can be successful in select patients with absent or mild neurologic manifestations. National databases reporting long-term outcomes posttransplantation are needed.

Keywords:   DGUOK ; deoxyguanosine kinase deficiency; liver failure; liver transplantation

DOI:  https://doi.org/10.1111/petr.14670
Front Cell Dev Biol. 2023 ;11 1274807

Generation of somatic de novo structural variation as a hallmark of cellular senescence in human lung fibroblasts.

Valentina Woronzow, Jonas Möhner, Daniel Remane, Hans Zischler.

  Cellular senescence is characterized by replication arrest in response to stress stimuli. Senescent cells accumulate in aging tissues and can trigger organ-specific and possibly systemic dysfunction. Although senescent cell populations are heterogeneous, a key feature is that they exhibit epigenetic changes. Epigenetic changes such as loss of repressive constitutive heterochromatin could lead to subsequent LINE-1 derepression, a phenomenon often described in the context of senescence or somatic evolution. LINE-1 elements decode the retroposition machinery and reverse transcription generates cDNA from autonomous and non-autonomous TEs that can potentially reintegrate into genomes and cause structural variants. Another feature of cellular senescence is mitochondrial dysfunction caused by mitochondrial damage. In combination with impaired mitophagy, which is characteristic of senescent cells, this could lead to cytosolic mtDNA accumulation and, as a genomic consequence, integrations of mtDNA into nuclear DNA (nDNA), resulting in mitochondrial pseudogenes called numts. Thus, both phenomena could cause structural variants in aging genomes that go beyond epigenetic changes. We therefore compared proliferating and senescent IMR-90 cells in terms of somatic de novo numts and integrations of a non-autonomous composite retrotransposons - the so-called SVA elements-that hijack the retropositional machinery of LINE-1. We applied a subtractive and kinetic enrichment technique using proliferating cell DNA as a driver and senescent genomes as a tester for the detection of nuclear flanks of de novo SVA integrations. Coupled with deep sequencing we obtained a genomic readout for SVA retrotransposition possibly linked to cellular senescence in the IMR-90 model. Furthermore, we compared the genomes of proliferative and senescent IMR-90 cells by deep sequencing or after enrichment of nuclear DNA using AluScan technology. A total of 1,695 de novo SVA integrations were detected in senescent IMR-90 cells, of which 333 were unique. Moreover, we identified a total of 81 de novo numts with perfect identity to both mtDNA and nuclear hg38 flanks. In summary, we present evidence for possible age-dependent structural genomic changes by paralogization that go beyond epigenetic modifications. We hypothesize, that the structural variants we observe potentially impact processes associated with replicative aging of IMR-90 cells.

Keywords:  RDA; SVA; cellular senescence; mtDNA; numts; retrotransposition; somatic mosaicism

DOI:  https://doi.org/10.3389/fcell.2023.1274807
Nat Commun. 2023 Dec 27. 14(1): 8501

Structural basis for DNA proofreading.

Gina Buchel, Ashok R Nayak, Karl Herbine, Azadeh Sarfallah, Viktoriia O Sokolova, Angelica Zamudio-Ochoa, Dmitry Temiakov.

DNA polymerase (DNAP) can correct errors in DNA during replication by proofreading, a process critical for cell viability. However, the mechanism by which an erroneously incorporated base translocates from the polymerase to the exonuclease site and the corrected DNA terminus returns has remained elusive. Here, we present an ensemble of nine high-resolution structures representing human mitochondrial DNA polymerase Gamma, Polγ, captured during consecutive proofreading steps. The structures reveal key events, including mismatched base recognition, its dissociation from the polymerase site, forward translocation of DNAP, alterations in DNA trajectory, repositioning and refolding of elements for primer separation, DNAP backtracking, and displacement of the mismatched base into the exonuclease site. Altogether, our findings suggest a conserved 'bolt-action' mechanism of proofreading based on iterative cycles of DNAP translocation without dissociation from the DNA, facilitating primer transfer between catalytic sites. Functional assays and mutagenesis corroborate this mechanism, connecting pathogenic mutations to crucial structural elements in proofreading steps.

DOI: https://doi.org/10.1038/s41467-023-44198-8
Ann Clin Transl Neurol. 2023 Dec 26.

Dystonia, spastic tetraplegia, and ataxia due to a novel mutation in the dynamin domain of OPA1.

YuZhi Shi, Kang Zhang, GeHong Dong, Hua Pan, Bin Chen, An Wang, SongTao Niu, XinGao Wang, ZaiQiang Zhang.

Movement disorders manifest in various hereditary neurodegenerative diseases. We reported a young man who presented with progressive upper limb dystonia, spastic tetraplegia, and ataxia. Whole-exome sequencing (WES) revealed a novel variant, c.2357A > G, in the dynamin domain of OPA1. No mtDNA deletion was detected in muscle by long-range PCR. Atrophy and decreased glucose metabolism of the basal ganglia were discovered. Decreased mtDNA copy number, fragmented mitochondria, slightly impaired oxidative phosphorylation, and increased autophagy were detected in mutant fibroblasts. Evident oxidative phosphorylation impairment and mtDNA deletions were not involved in the pathogenicity of this mutation unlike mutations in the GTPase domain of OPA1.

DOI: https://doi.org/10.1002/acn3.51981
Environ Pollut. 2023 Dec 26. pii: S0269-7491(23)02233-9. [Epub ahead of print] 123231

Toxicity mechanism of engineered nanomaterials: Focus on mitochondria.

Yongshuai Yao, Ting Zhang, Meng Tang.

  With the rapid development of nanotechnology, engineered nanomaterials (ENMs) are widely used in various fields. This has exacerbated the environmental pollution and human exposure of ENMs. The study of toxicity of ENMs and its mechanism has become a hot research topic in recent years. Mitochondrial damage plays an important role in the toxicity of ENMs. This paper reviews the structural damage, dysfunction, and molecular level perturbations caused by different ENMs to mitochondria, including ZnO NPs, Ag NPs, TiO2 NPs, iron oxide NPs, cadmium-based quantum dots, CuO NPs, silica NPs, carbon-based nanomaterials. Among them, mitochondrial quality control plays an important role in mitochondrial damage. We further summarize the cellular level outcomes caused by mitochondrial damage, mainly including, apoptosis, ferroptosis, pyroptosis and inflammation response. In addition, we concluded that reducing mitochondrial damage at source as well as accelerating recovery from mitochondrial damage through ENMs modification and pharmacological intervention are two feasible strategies. This review further provides new insights into the mitochondrial toxicity mechanisms of ENMs and provides a new foothold for predicting human health and environmental risks of ENMs.

Keywords:  ENMs design strategies; Engineered nanomaterials (ENMs); Ferroptosis; Inflammation; Mitochondrial quality control; Mitochondrial toxicity

DOI:  https://doi.org/10.1016/j.envpol.2023.123231
Neurobiol Dis. 2023 Dec 22. pii: S0969-9961(23)00403-5. [Epub ahead of print] 106387

The mitochondriogenic but not the immunosuppressant effects of mTOR inhibitors prompt neuroprotection and delay disease evolution in a mouse model of progressive multiple sclerosis.

Daniela Buonvicino, Sara Pratesi, Giuseppe Ranieri, Alessandra Pistolesi, Daniele Guasti, Alberto Chiarugi.

   INTRODUCTION: Purportedly, the progression of multiple sclerosis (MS) occurs when neurodegenerative processes due to derangement of axonal bioenergetics take over the autoimmune response. However, a clear picture of the causative interrelationship between autoimmunity and axonal mitochondrial dysfunction in progressive MS (PMS) pathogenesis waits to be provided.
METHODS: In the present study, by adopting the NOD mouse model of PMS, we compared the pharmacological effects of the immunosuppressants dexamethasone and fingolimod with those of mTOR inhibitors rapamycin and everolimus that, in addition to immunosuppression, also regulate mitochondrial functioning. Female Non-Obese Diabetic (NOD) mice were immunized with MOG35-55 and treated with drugs to evaluate functional, immune and mitochondrial parameters during disease evolution.
RESULTS: We found that dexamethasone and fingolimod did not affect the pattern of progression as well as survival. Conversely, mTOR inhibitors rapamycin and everolimus delayed disease progression and robustly extended survival of immunized mice. The same effects were obtained when treatment was delayed by 30 days after immunization. Remarkably, dexamethasone and fingolimod prompted the same degree of immunosuppression of rapamycin within both spleen and spinal cord of mice. However, only rapamycin prompted mitochondriogenesis by increasing mitochondrial content, and expression of several mitochondrial respiratory complex subunits, thereby preventing mtDNA reduction in the spinal cords of immunized mice. These pharmacodynamic effects were not reproduced in healthy NOD mice, suggesting a disease context-dependent pharmacodynamic effect.
DISCUSSION: Data corroborate the key role of mitochondriogenesis to treatment of MS progression, and for the first time disclose the translational potential of mTOR inhibitors in PMS therapy.

Keywords:  Dexamethasone; Fingolimod; Mitochondria; Progressive EAE; Rapamycin

DOI:  https://doi.org/10.1016/j.nbd.2023.106387
Brain. 2023 Dec 26. pii: awad432. [Epub ahead of print]

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer's disease.

Sourav Samanta, Firoz Akhter, Anuradha Roy, Doris Chen, Benjamin Turner, Yongfu Wang, Nicolina Clemente, Chunyu Wang, Russell Howard Swerdlow, Kevin P Battaile, Scott Lovell, Shi Fang Yan, Shirley ShiDu Yan.

  Mitochondrial dysfunction is an early pathological feature of Alzheimer disease (AD) and plays a crucial role in the development and progression of AD. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore (mPTP), leading to mitochondrial dysfunction and cell death. Blocking mPTP opening by inhibiting CypD activity is a promising therapeutic approach for AD. However, there is currently no effective CypD inhibitor for AD, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility, and low selectivity. Here, we report a new class of nontoxic and biocompatible CypD inhibitor, Ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-Ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on AD mitochondrial and glycolytic bioenergetics in AD-derived mitochondrial cybrid cells, an ex-vivo human sporadic AD mitochondrial model, and on synaptic function, inflammatory response, and learning and memory in AD mouse models. Inhibition of CypD by Ebselen protects against sporadic AD- and amyloid beta (Aβ)-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of AD mouse models, which is linked to CypD-related mPTP formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including AD, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Keywords:  Alzheimer disease; CypD inhibitor; amyloid beta; high-throughput screening; mitochondrial respiratory and glycolytic function

DOI:  https://doi.org/10.1093/brain/awad432