bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒02‒06
twenty-nine papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.
  2. Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
  3. Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
  4. The role of mitophagy during oocyte aging in human, mouse, and Drosophila: implications for oocyte quality and mitochondrial disease.
  5. The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice.
  6. Cerebellar Bottom of Fissure Hyperintensities in MT-ATP6-associated Ataxia.
  7. Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
  8. Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
  9. Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH.
  10. Mitochondrion-Toxic Compounds Need to be avoided in Leigh Syndrome.
  11. Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration.
  12. Oocyte mitochondria - Key regulators of oocyte function and potential therapeutic targets for improving fertility.
  13. A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia.
  14. Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases.
  15. Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.
  16. Toward ethical regulation of mitochondrial donation.
  17. Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
  18. Alzheimer's disease is causally associated with mitochondrial dysfunction.
  19. Real-Time Analysis of Mitochondrial Electron Transport Chain Function in Toxoplasma gondii Parasites Using a Seahorse XFe96 Extracellular Flux Analyzer.
  20. Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence.
  21. Editorial: Current and Future Developments in the Therapeutic Management of Neuromuscular Diseases.
  22. iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.
  23. Juvenile PLA2G6-Parkinsonism Due to Indian 'Asian' p.R741Q Mutation, and Response to STN DBS.
  24. Mutyh deficiency downregulates mitochondrial fusion proteins and causes cardiac dysfunction via α-ketoglutaric acid reduction with oxidative stress.
  25. Albumin binds to uncoupler CCCP to diminish depolarization of mitochondria.
  26. ApoE4 confers mitochondrial substrate oxidation defects that can be bioenergetically compensated by a ketogenic substrate beta-hydroxy butyrate (BHB).
  27. UCP1 Knockin Induces Lipid Dynamics and Transcriptional Programs in the Skeletal Muscles of Pigs.
  28. Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.
  29. Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence.
  1. Nat Commun. 2022 Feb 03. 13(1): 653
    TAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A.
    Jun-Ha Hwang, Kyung Min Kim, Ho Taek Oh, Gi Don Yoo, Mi Gyeong Jeong, Hyun Lee, Joori Park, Kwon Jeong, Yoon Ki Kim, Young-Gyu Ko, Eun Sook Hwang, Jeong-Ho Hong.
      Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.
    DOI:  https://doi.org/10.1038/s41467-022-28247-2
  2. Nat Commun. 2022 Feb 03. 13(1): 651
    Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
    Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.
      Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
    DOI:  https://doi.org/10.1038/s41467-022-28272-1
  3. Ann Neurol. 2022 Jan 30.
    Leigh syndrome: a study of 209 patients at the Beijing Children's Hospital.
    Sarah L Stenton, Ying Zou, Hua Cheng, Zhimei Liu, Junling Wang, Danmin Shen, Hong Jin, Changhong Ding, Xiaolu Tang, Suzhen Sun, Hong Han, Yanli Ma, Weihua Zhang, Ruifeng Jin, Hua Wang, Dan Sun, Jun Lan Lv, Holger Prokisch, Fang Fang.
      OBJECTIVE: Leigh syndrome (LS) is a heterogeneous neurodegenerative disease and the most frequent pediatric manifestation of mitochondrial disease. In the largest patient collection to date, this study aimed to provide new insights into the clinical and genetic spectrum of LS, defect-specific associations, and predictors of disease course and survival.METHODS: Clinical, metabolic, neuroimaging, onset, and survival data were collected from the medical records of 209 patients referred to the Beijing Children's Hospital with symmetrical basal ganglia and/or brainstem neuroimaging changes indicative of LS by 30 centers from the Chinese network of mitochondrial disease (mitoC-NET) between January 2013 and July 2021 for exploratory analysis.
    RESULTS: Pathogenic variants were identified in 52 genes, most frequently MT-ATP6, SURF1, and PDHA1. Maternally inherited variants accounted for 42% (heteroplasmy level ≥ 90% in 64%). Phenotypes spanned 92 Human Phenotype Ontology terms. Elevated serum lactate (144/195), global developmental delay (142/209), and developmental regression (103/209) were most frequent. Discriminating neuroimaging and/or clinical features were identified for MT-ATP6 (m.9176 T > C), MT-ND5, PDHA1, SUCLG1, and SURF1. Poorest survival was associated with MT-ND5, MT-ATP6 (m.8993 T > C and m.9176 T > C), SURF1, and ALDH5A1 (≤50% 3 year survival), in contrast to milder defects with specific treatment (ECHS1 and SLC19A3, 100% 3 year survival).
    INTERPRETATION: Our data define phenotype, onset, and survival of LS in a defect-specific manner, identifying features discriminating between genetic defects and predictive of disease outcome. These findings are essential to early diagnosis, in optimizing family counselling, and to the design and monitoring of future clinical trials, the next frontier of LS research. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ana.26313
  4. Reprod Fertil. 2021 Dec;2(4): R113-R129
    The role of mitophagy during oocyte aging in human, mouse, and Drosophila: implications for oocyte quality and mitochondrial disease.
    Rachel T Cox, Joanna Poulton, Suzannah A Williams.
      There is a worldwide trend for women to have their first pregnancy later in life. However, as oocyte quality declines with maternal aging, this trend leads to an increase in subfertility. The cellular mechanisms underlying this decline in oocyte competence are poorly understood. Oocyte mitochondria are the subcellular organelles that supply the energy that drives early embryogenesis, and thus their quality is critical for successful conception. Mitochondria contain their own DNA (mtDNA) and mutations in mtDNA cause mitochondrial diseases with severe symptoms, such as neurodegeneration and heart disease. Since mitochondrial function declines in tissues as humans age accompanied by an accumulation of mtDNA mutations, mtDNA is implicated as a cause of declining oocyte quality in older mothers. While this mutation load could be caused by declining accuracy of the mitochondrial replisome, age-related decline in mitochondrial quality control likely contributes, however knowledge is lacking. Mitophagy, a cellular process which specifically targets and recycles damaged mitochondria may be involved, but studies are scarce. And although assisted reproductive technologies can help older mothers, how these techniques affect the mechanisms that regulate mitochondrial and oocyte quality have not been studied. With the long-term goal of understanding the molecular mechanisms that control mitochondrial quality in the oocyte, model systems including Drosophila and mouse as well as human oocytes have been used. In this review, we explore the contribution of mitophagy to oocyte quality and the need for further systematic investigation in oocytes during maternal aging using different systems.Lay summary: Mitochondria are small parts of cells called organelles that generate the chemical energy needed for life. Hundreds of thousands of mitochondria in the developing eggs of the mother support the initial growth and development of the fertilized egg. However, due to increasingly diminished function over time, mitochondria generate less energy as we age, posing real problems for older women considering pregnancy. It is possible that this declining energy could be responsible for declining fertility as women age. Energy may decline because mitochondria fail and the cell's way of keeping them healthy become less efficient as we age. This review summarizes what is known about mitochondrial quality control in developing eggs as they age. In the future, understanding how the best mitochondria are selected and maintained in the egg, and hence the future baby, may enable older women with or without mitochondrial problems, to have healthy children.
    Keywords:  ARTs; Drosophila; human; mitochondria; mitophagy; mouse; mtDNA; oocyte; ovary
    DOI:  https://doi.org/10.1530/RAF-21-0060
  5. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2120476119. [Epub ahead of print]119(6):
    The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice.
    Catherine A Makarewich, Amir Z Munir, Svetlana Bezprozvannaya, Aaron M Gibson, Soo Young Kim, Misty S Martin-Sandoval, Thomas P Mathews, Luke I Szweda, Rhonda Bassel-Duby, Eric N Olson.
      Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small size. To search for cardiac-expressed microproteins, we used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contributed to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function.
    Keywords:  cardiac; microprotein; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2120476119
  6. Ann Neurol. 2022 Jan 29.
    Cerebellar Bottom of Fissure Hyperintensities in MT-ATP6-associated Ataxia.
    Benjamin Roeben, Eva Bültmann, Claudia Stendel, Matthis Synofzik.
      
    Keywords:  Cerebellar Bottom of Fissure Hyperintensities; MRI; MT-ATP6; MT-ATP6-associated disease; ataxia; mitochondrial ataxia; mitochondrial disease
    DOI:  https://doi.org/10.1002/ana.26311
  7. Biol Chem. 2022 Jan 31.
    Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
    Nupur Sharma, Christof Osman.
      The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.
    Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome
    DOI:  https://doi.org/10.1515/hsz-2021-0398
  8. Ageing Res Rev. 2022 Jan 31. pii: S1568-1637(22)00020-4. [Epub ahead of print] 101578
    Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
    Arianna Manini, Elena Abati, Giacomo Pietro Comi, Stefania Corti, Dario Ronchi.
      Maintenance of mitochondrial DNA (mtDNA) homeostasis includes a variety of processes, such as mtDNA replication, repair, and nucleotides synthesis, aimed at preserving the structural and functional integrity of mtDNA molecules. Mutations in several nuclear genes (i.e., POLG, POLG2, TWNK, OPA1, DGUOK, MPV17, TYMP) impair mtDNA maintenance, leading to clinical syndromes characterized by mtDNA depletion and/or deletions in affected tissues. In the past decades, studies have demonstrated a progressive accumulation of multiple mtDNA deletions in dopaminergic neurons of the substantia nigra in elderly population and, to a greater extent, in Parkinson's disease patients. Moreover, parkinsonism has been frequently described as a prominent clinical feature in mtDNA instability syndromes. Among Parkinson's disease-related genes with a significant role in mitochondrial biology, PARK2 and LRRK2 specifically take part in mtDNA maintenance. Moreover, a variety of murine models (i.e., "Mutator", "MitoPark", "PD-mitoPstI", "Deletor", "Twinkle-dup" and "TwinkPark") provided in vivo evidence that mtDNA stability is required to preserve nigrostriatal integrity. Here, we review and discuss the clinical, genetic, and pathological background underlining the link between impaired mtDNA homeostasis and dopaminergic degeneration.
    Keywords:  POLG1, Twinkle; Parkinsonism; Parkinson’s disease; mitochondrion; mtDNA homeostasis
    DOI:  https://doi.org/10.1016/j.arr.2022.101578
  9. Acta Pharmacol Sin. 2022 Feb 01.
    Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH.
    Yu-Feng Li, Zhi-Fu Xie, Qian Song, Jing-Ya Li.
      Mitochondrial biology and behavior are central to the physiology of liver. Multiple mitochondrial quality control mechanisms remodel mitochondrial homeostasis under physiological and pathological conditions. Mitochondrial dysfunction and damage induced by overnutrition lead to oxidative stress, inflammation, liver cell death, and collagen production, which advance hepatic steatosis to nonalcoholic steatohepatitis (NASH). Accumulating evidence suggests that specific interventions that target mitochondrial homeostasis, including energy metabolism, antioxidant effects, and mitochondrial quality control, have emerged as promising strategies for NASH treatment. However, clinical translation of these findings is challenging due to the complex and unclear mechanisms of mitochondrial homeostasis in the pathophysiology of NASH.
    Keywords:  NASH; liver; metabolism; mitochondria; mitochondrial homeostasis
    DOI:  https://doi.org/10.1038/s41401-022-00864-z
  10. J Coll Physicians Surg Pak. 2022 Feb;32(2): 270-271
    Mitochondrion-Toxic Compounds Need to be avoided in Leigh Syndrome.
    Josef Finsterer.
      Null.
    DOI:  https://doi.org/10.29271/jcpsp.2022.02.270
  11. Front Integr Neurosci. 2021 ;15 747901
    Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration.
    Nguyen Thanh Nhu, Shu-Yun Xiao, Yijie Liu, V Bharath Kumar, Zhen-Yang Cui, Shin-Da Lee.
      Neural mitochondrial dysfunction, neural oxidative stress, chronic neuroinflammation, toxic protein accumulation, and neural apoptosis are common causes of neurodegeneration. Elamipretide, a small mitochondrially-targeted tetrapeptide, exhibits therapeutic effects and safety in several mitochondria-related diseases. In neurodegeneration, extensive studies have shown that elamipretide enhanced mitochondrial respiration, activated neural mitochondrial biogenesis via mitochondrial biogenesis regulators (PCG-1α and TFAM) and the translocate factors (TOM-20), enhanced mitochondrial fusion (MNF-1, MNF-2, and OPA1), inhibited mitochondrial fission (Fis-1 and Drp-1), as well as increased mitophagy (autophagy of mitochondria). In addition, elamipretide has been shown to attenuate neural oxidative stress (hydrogen peroxide, lipid peroxidation, and ROS), neuroinflammation (TNF, IL-6, COX-2, iNOS, NLRP3, cleaved caspase-1, IL-1β, and IL-18), and toxic protein accumulation (Aβ). Consequently, elamipretide could prevent neural apoptosis (cytochrome c, Bax, caspase 9, and caspase 3) and enhance neural pro-survival (Bcl2, BDNF, and TrkB) in neurodegeneration. These findings suggest that elamipretide may prevent the progressive development of neurodegenerative diseases via enhancing mitochondrial respiration, mitochondrial biogenesis, mitochondrial fusion, and neural pro-survival pathway, as well as inhibiting mitochondrial fission, oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis. Elamipretide or mitochondrially-targeted peptide might be a targeted agent to attenuate neurodegenerative progression.
    Keywords:  Bendavia; MTP-31; SS-31; brain; mitochondrial; neurodegeneration
    DOI:  https://doi.org/10.3389/fnint.2021.747901
  12. Biol Reprod. 2022 Jan 31. pii: ioac024. [Epub ahead of print]
    Oocyte mitochondria - Key regulators of oocyte function and potential therapeutic targets for improving fertility.
    Deepak Adhikari, In-Won Lee, Wai Shan Yuen, John Carroll.
      The development of oocytes and early embryos is dependent on mitochondrial ATP production. This reliance on mitochondrial activity, together with the exclusively maternal inheritance of mitochondria in development, places mitochondria as central regulators of both fertility and transgenerational inheritance mechanisms. Mitochondrial mass and mtDNA content massively increase during oocyte growth. They are highly dynamic organelles and oocyte maturation is accompanied by mitochondrial trafficking around subcellular compartments. Due to their key roles in generation of ATP and reactive oxygen species, oocyte mitochondrial defects have largely been linked with energy deficiency and oxidative stress. Pharmacological treatments and mitochondrial supplementation have been proposed to improve oocyte quality and fertility by enhancing ATP generation and reducing reactive oxygen species levels. More recently, the role of mitochondria-derived metabolites in controlling epigenetic modifiers has provided a mechanistic basis for mitochondria-nuclear crosstalk, allowing adaptation of gene expression to specific metabolic states. Here, we discuss the multi-faceted mechanisms by which mitochondrial function influence oocyte quality, as well as longer-term developmental events within and across generations.
    Keywords:  Mitochondria; Oocyte; Therapeutic targets
    DOI:  https://doi.org/10.1093/biolre/ioac024
  13. Front Genet. 2021 ;12 812640
    A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia.
    Christina Votsi, Antonis Ververis, Paschalis Nicolaou, Yiolanda-Panayiota Christou, Kyproula Christodoulou, Eleni Zamba-Papanicolaou.
      The SPG7 gene encodes the paraplegin protein, an inner mitochondrial membrane-localized protease. It was initially linked to pure and complicated hereditary spastic paraplegia with cerebellar atrophy, and now represents a frequent cause of undiagnosed cerebellar ataxia and spastic ataxia. We hereby report the molecular characterization and the clinical features of a large Cypriot family with five affected individuals presenting with spastic ataxia in an autosomal recessive transmission mode, due to a novel SPG7 homozygous missense variant. Detailed clinical histories of the patients were obtained, followed by neurological and neurophysiological examinations. Whole exome sequencing (WES) of the proband, in silico gene panel analysis, variant filtering and family segregation analysis of the candidate variants with Sanger sequencing were performed. RNA and protein expression as well as in vitro protein localization studies and mitochondria morphology evaluation were carried out towards functional characterization of the identified variant. The patients presented with typical spastic ataxia features while some intrafamilial phenotypic variation was noted. WES analysis revealed a novel homozygous missense variant in the SPG7 gene (c.1763C > T, p. Thr588Met), characterized as pathogenic by more than 20 in silico prediction tools. Functional studies showed that the variant does not affect neither the RNA or protein expression, nor the protein localization. However, aberrant mitochondrial morphology has been observed thus indicating mitochondrial dysfunction and further demonstrating the pathogenicity of the identified variant. Our study is the first report of an SPG7 pathogenic variant in the Cypriot population and broadens the spectrum of SPG7 pathogenic variants.
    Keywords:  Cypriot family; SPG7 gene; novel missense variant; paraplegin; spastic ataxia
    DOI:  https://doi.org/10.3389/fgene.2021.812640
  14. Front Cardiovasc Med. 2021 ;8 788505
    Regulation of Mitochondrial Dynamics by Aerobic Exercise in Cardiovascular Diseases.
    Changping Gu, Jie Yan, Liang Zhao, Guanghan Wu, Yue-Lan Wang.
      Mitochondrial dynamics, including continuous biogenesis, fusion, fission, and autophagy, are crucial to maintain mitochondrial integrity, distribution, size, and function, and play an important role in cardiovascular homeostasis. Cardiovascular health improves with aerobic exercise, a well-recognized non-pharmaceutical intervention for both healthy and ill individuals that reduces overall cardiovascular disease (CVD) mortality. Increasing evidence shows that aerobic exercise can effectively regulate the coordinated circulation of mitochondrial dynamics, thus inhibiting CVD development. This review aims to illustrate the benefits of aerobic exercise in prevention and treatment of cardiovascular disease by modulating mitochondrial function.
    Keywords:  aerobic exercise; cardiovascular disease; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; myocardial mitochondria
    DOI:  https://doi.org/10.3389/fcvm.2021.788505
  15. Alzheimers Dement. 2021 Dec;17 Suppl 3 e056456
    Allopregnanolone potentiates bioenergetic capacity and mitochondrial biogenesis in astrocytes.
    Tian Wang, Shuhua Chen, Zisu Mao, Yuan Shang, Roberta Diaz Brinton.
      BACKGROUND: We reported previously that the neurosteroid allopregnanolone (Allo) promotes neural stem cell regeneration and differentiation, reverses neurogenic, metabolic and cognitive deficits and reduces Alzheimer's disease (AD) pathology in a mouse model of AD. To further investigate the cell-type specific mechanisms of Allo in regulating brain energy metabolism, we assessed the effect of Allo on mitochondrial bioenergetic profile and biogenesis in rat hippocampal astrocytes.METHOD: E18 rat hippocampal astrocyte were cultured for 10 days in DMEM:F12(1:1) with 10% FBS and then starved in 10% Charcoal stripped-FBS / DMEM:F12 for 24 hours before treatment with 100nM Allo or 0.001% Vehicle overnight. Upon completion of treatment, cells were subject to morphological, biochemical, metabolic and transcriptomic characterization of their mitochondrial phenotypes.
    RESULT: In primary hippocampal astrocytes, Allo significantly attenuates serum deprivation-induced bioenergetic deficits and oxidative stress by enhancing mitochondrial biogenesis and rebalancing mitochondrial dynamics. Allo treatment significantly enhances astrocytic mitochondrial biogenesis via Nrf1/Tfam signaling and reverses mitochondrial hyperfusion by elevating the ratio of mitochondrial fission protein Drp1 to the fusion protein Opa1. Functionally, Allo-induced improvement in bioenergetic function is coupled with reduced inflammasome activation in astrocytes.
    CONCLUSION: Outcomes of our findings further support the promising therapeutic effects of Allo against bioenergetic deficits that emerge in early phases of AD, with mitochondria being a major effector.
    DOI:  https://doi.org/10.1002/alz.056456
  16. Med J Aust. 2022 Feb 03.
    Toward ethical regulation of mitochondrial donation.
    Julian Koplin, Esther Lestrell.
      
    Keywords:  Reproductive techniques; assisted
    DOI:  https://doi.org/10.5694/mja2.51396
  17. J Cell Sci. 2022 Jan 31. pii: jcs.258956. [Epub ahead of print]
    Drp1 regulates transcription of ribosomal protein genes in embryonic hearts.
    Qiancong Zhao, Shun Yan, Jin Lu, Danitra J Parker, Huiying Wu, Qianchuang Sun, David K Crossman, Shanrun Liu, Qin Wang, Hiromi Sesaki, Kasturi Mitra, Kexiang Liu, Kai Jiao.
      Mitochondrial dysfunction causes severe congenital cardiac abnormalities and prenatal/neonatal lethality. The lack of sufficient knowledge regarding how mitochondrial abnormalities affect cardiogenesis poses a major barrier for the development of clinical applications that target mitochondrial deficiency induced inborn cardiomyopathies. Mitochondrial morphology, which is regulated by fission and fusion, plays a key role in determining mitochondrial activity. Dnm1l encodes a dynamin-related GTPase, Drp1, which is required for mitochondrial fission. To investigate the role of Drp1 on cardiogenesis during the embryonic metabolic shift period, we specifically inactivated Dnm1l in second heart field-derived structures. Mutant cardiomyocytes in the right ventricle (RV) displayed severe defects in mitochondrial morphology, ultrastructure, and activity. These defects caused increased cell death, decreased cell survival, disorganized cardiomyocytes, and embryonic lethality. Through characterizing this model, we reveal a novel AMPK-SIRT7-GABPB axis that relays the reduced cellular energy level to decreased transcription of ribosomal protein genes in cardiomyocytes. We therefore provide the first mouse genetic evidence to suggest that Drp1 is essential for RV development. Our research provides further mechanistic insight regarding how mitochondrial dysfunction causes pathological molecular and cellular alterations during cardiogenesis.
    Keywords:  Drp1; Heart development; RP gene transcription
    DOI:  https://doi.org/10.1242/jcs.258956
  18. Alzheimers Dement. 2021 Dec;17 Suppl 3 e057480
    Alzheimer's disease is causally associated with mitochondrial dysfunction.
    Shea J Andrews.
      BACKGROUND: Mitochondria regulate energy and metabolic homeostasis, with increasing evidence implicating mitochondrial dysfunction in Alzheimer's disease (AD) pathogenesis. Each mitochondrion contains multiple copies of the mitochondrial genome (mtDNA), with mtDNA copy number (mtDNAcn) been used as a surrogate measure of mitochondrial function. Here we evaluate the association of mtDNAcn with neuropathological diagnosis of AD and evaluate shared genetic etiology between AD and mtDNAcn.METHODS: We evaluated the association of mtDNAcn with a neuropathological diagnosis of AD in 1194 non-Hispanic white subjects (cases = 706, controls = 468) from three cohorts (ROSMAP, MSBB, Mayo) from the Accelerating Medicines Partnership Alzheimer's disease (AMP-AD). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA using whole genome sequencing data from DNA isolated from brain tissue. Neuropathological AD was determined based on neuropathological burden of amyloid plaques and tangles. Logistic regression adjusting for mitochondrial haplogroup, age of death, sex, APOE, post-mortem interval and source tissue was used to evaluate the association of mtDNAcn with AD in each cohort separately and jointly in an inverse weighted fixed-effects meta-analysis (IVW FE). Additionally, we estimated the genetic correlation between mtDNAcn and AD, evaluated the association of a mtDNAcn polygenic risk score (PRS) with clinical AD (cases = 13312, controls = 13119), and conducted bidirectional two-sample Mendelian randomization to estimate the causal relationship between mtDNAcn and AD.
    RESULTS: Higher mtDNAcn was associated with a reduced risk of neuropathological AD (IVW FE: OR[95%CI] = 0.70 [0.58, 0.84]. mtDNAcn was not genetically correlated with AD (rg = 0.13 (0.16), p = 0.4) and a mtDNAcn PRS was not associated with clinical AD (OR[95%CI] = 1 [0.97, 1.03], p = 0.884). Mendelian randomization did not support a causal relationship between mtDNAcn and AD (OR[95%CI] = 0.93 [0.74, 1.14], p = 0.46).
    CONCLUSION: Elevated mtDNAcn estimated from brain tissue was associated with a reduced risk of neuropathological AD, suggesting that mitochondrial dysfunction is associated with AD pathogenesis. However, genetically predicted mtDNAcn estimated from peripheral blood was not associated with AD using genetically informed approaches. As such, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis.
    DOI:  https://doi.org/10.1002/alz.057480
  19. Bio Protoc. 2022 Jan 05. 12(1): e4288
    Real-Time Analysis of Mitochondrial Electron Transport Chain Function in Toxoplasma gondii Parasites Using a Seahorse XFe96 Extracellular Flux Analyzer.
    Jenni A Hayward, Esther Rajendran, F Victor Makota, Brad J Bassett, Michael Devoy, Teresa Neeman, Giel G van Dooren.
      The mitochondrial electron transport chain (ETC) performs several critical biological functions, including maintaining mitochondrial membrane potential, serving as an electron sink for important metabolic pathways, and contributing to the generation of ATP via oxidative phosphorylation. The ETC is important for the survival of many eukaryotic organisms, including intracellular parasites such as the apicomplexan Toxoplasma gondii. The ETC of T. gondii and related parasites differs in several ways from the ETC of the mammalian host cells they infect, and can be targeted by anti-parasitic drugs, including the clinically used compound atovaquone. To characterize the function of novel ETC proteins found in the parasite and to identify new ETC inhibitors, a scalable assay that assesses both ETC function and non-mitochondrial parasite metabolism (e.g., glycolysis) is desirable. Here, we describe methods to measure the oxygen consumption rate (OCR) of intact T. gondii parasites and thereby assess ETC function, while simultaneously measuring the extracellular acidification rate (ECAR) as a measure of general parasite metabolism, using a Seahorse XFe96 extracellular flux analyzer. We also describe a method to pinpoint the location of ETC defects and/or the targets of inhibitors, using permeabilized T. gondii parasites. We have successfully used these methods to investigate the function of T. gondii proteins, including the apicomplexan parasite-specific protein subunit TgQCR11 of the coenzyme Q:cytochrome c oxidoreductase complex (ETC Complex III). We note that these methods are also amenable to screening compound libraries to identify candidate ETC inhibitors.
    Keywords:  Electron transport chain; Metabolism; Mitochondrion; Seahorse XFe96; Toxoplasma gondii
    DOI:  https://doi.org/10.21769/BioProtoc.4288
  20. Aging (Albany NY). 2022 Jan 30. 14(undefined):
    Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence.
    Yun Haeng Lee, Doyoung Choi, Geonhee Jang, Ji Yun Park, Eun Seon Song, Haneur Lee, Myeong Uk Kuk, Junghyun Joo, Soon Kil Ahn, Youngjoo Byun, Joon Tae Park.
      Senescence is a distinct set of changes in the senescence-associated secretory phenotype (SASP) and leads to aging and age-related diseases. Here, we screened compounds that could ameliorate senescence and identified an oxazoloquinoline analog (KB1541) designed to inhibit IL-33 signaling pathway. To elucidate the mechanism of action of KB1541, the proteins binding to KB1541 were investigated, and an interaction between KB1541 and 14-3-3ζ protein was found. Specifically, KB1541 interacted with 14-3-3ζ protein and phosphorylated of 14-3-3ζ protein at serine 58 residue. This phosphorylation increased ATP synthase 5 alpha/beta dimerization, which in turn promoted ATP production through increased oxidative phosphorylation (OXPHOS) efficiency. Then, the increased OXPHOS efficiency induced the recovery of mitochondrial function, coupled with senescence alleviation. Taken together, our results demonstrate a mechanism by which senescence is regulated by ATP synthase 5 alpha/beta dimerization upon fine-tuning of KB1541-mediated 14-3-3ζ protein activity.
    Keywords:  14–3–3ζ; ATPase synthase 5; KB1541; OXPHOS; senescence amelioration
    DOI:  https://doi.org/10.18632/aging.203858
  21. Front Neurol. 2021 ;12 835839
    Editorial: Current and Future Developments in the Therapeutic Management of Neuromuscular Diseases.
    George K Papadimas, Roser Pons, Johanna Palmio.
      
    Keywords:  myasthenia; myopathy; neuromuscular diseases; neuropathy; treatment
    DOI:  https://doi.org/10.3389/fneur.2021.835839
  22. Cell Stem Cell. 2022 Feb 03. pii: S1934-5909(22)00007-8. [Epub ahead of print]29(2): 189-208
    iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders.
    Hideyuki Okano, Satoru Morimoto.
      It has been 15 years since the birth of human induced pluripotent stem cell (iPSC) technology in 2007, and the scope of its application has been expanding. In addition to the development of cell therapies using iPSC-derived cells, pathological analyses using disease-specific iPSCs and clinical trials to confirm the safety and efficacy of drugs developed using iPSCs are progressing. With the innovation of related technologies, iPSC applications are about to enter a new stage. This review outlines advances in iPSC modeling and therapeutic development for cardinal neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease.
    Keywords:  AD; ALS; Alzheimer’s disease; PD; Parkinson’s disease; amyotrophic lateral sclerosis; disease modeling; drug repositioning; iPSCs; induced pluripotent stem cells; stratification
    DOI:  https://doi.org/10.1016/j.stem.2022.01.007
  23. Mov Disord. 2022 Feb 03.
    Juvenile PLA2G6-Parkinsonism Due to Indian 'Asian' p.R741Q Mutation, and Response to STN DBS.
    Parthvi Ravat, Swati Shinde, Shilpa R Shinde, Santosh Bangar, Naren Nayak, Pankaj A Agarwal.
      
    Keywords:  DBS; Indian; PLA2G6; parkinsonism; young-onset parkinsonism
    DOI:  https://doi.org/10.1002/mds.28950
  24. Free Radic Res. 2022 Jan 30. 1-16
    Mutyh deficiency downregulates mitochondrial fusion proteins and causes cardiac dysfunction via α-ketoglutaric acid reduction with oxidative stress.
    Jingwen Chen, Xin Wu, Yanyi Wang, Yunfeng Pan, Yan Ren, Yusaku Nakabeppu, Yimei Fan, Yaping Wang.
      MutY homolog (MUTYH), an important protein in base excision repair (BER) system, excises adenine in the nascent strand opposite 8-oxoguanine in template DNA and restores G:C base-pair to maintain the fidelity of DNA replication. The loss of MUTYH causes oxidative stress and influences cardiac function, but the mechanism remains to be addressed. Here we demonstrate that Mutyh deficiency alters mitochondrial structure and impairs mitochondrial function through downregulation of mitochondrial fusion protein Mfn2 and alteration of the ratio of L-Opa1/S-Opa1 accompanied by reduction of α-ketoglutaric acid (α-KG) under oxidative stress condition. Further analysis reveals that the Mutyh deficiency may cause downregulation of histone demethylases and DNA demethylases and inhibition of the Mfn2 transcription. Oxidative stress associated with tert-butyl hydroperoxide (t-BHP) exposure results in the degradation of L-Opa1 and impairs the balance of L-Opa1/S-Opa1. Interestingly, α-KG supplementation alleviates the damage associated with Mutyh deficiency, restores the expression of Mfn2 and prevents degradation of L-Opa1. The current study demonstrates the relationship among Mutyh deficiency-coupled oxidative stress, the altered expressions of Mfn2 and Opa1, and the mitochondrial dysfunction, in which an intermediate in the tricarboxylic acid (TCA) cycle, α-KG has a key regulatory role.
    Keywords:  MUTYH; cardiac dysfunction; mitochondrial fusion; oxidative stress; α-KG
    DOI:  https://doi.org/10.1080/10715762.2022.2036336
  25. Toxicol In Vitro. 2022 Feb 01. pii: S0887-2333(22)00022-4. [Epub ahead of print] 105325
    Albumin binds to uncoupler CCCP to diminish depolarization of mitochondria.
    Ganjoo Mahalaxmi, Sivasailam Ashok, Gangadharan Arun, Gopala Srinivas.
      Mitochondria are at the core of cellular energy metabolism and are also involved in the oxidative stress response and programmed cell death pathways. Mitochondrial dysfunction is found to be associated with many disease conditions like metabolic syndrome, neurodegenerative disorders, coronary artery diseases, cancer, etc. This has generated considerable interest in the scientific community over the assessment of mitochondrial function and mitochondrial damage. One of the most common methodologies in these studies is by analysing the mitochondrial activity in the presence of mitochondrial substrates, inhibitors and uncouplers. Apart from the specific effects of these molecules on mitochondria, their interactions with the components of the experimental system could interfere with the results derived. Therefore, the role some specific experimental conditions would have on the outcome should be carefully elucidated. Fetal Bovine Serum or Bovine Serum Albumin (BSA); routinely used in in vitro experiments for their growth promoting and surfactant properties; can have profound impact on the pharmacokinetics of chemical compounds as albumin residue can bind to and affect their bioavailability. In the present study, we demonstrate that Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) induced mitochondrial depolarization is hindered in the presence of albumin due to the molecular interaction between CCCP and albumin.
    Keywords:  Albumin; BSA; CCCP; Mitochondrial depolarization; Serum
    DOI:  https://doi.org/10.1016/j.tiv.2022.105325
  26. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054355
    ApoE4 confers mitochondrial substrate oxidation defects that can be bioenergetically compensated by a ketogenic substrate beta-hydroxy butyrate (BHB).
    Chase Garcia, Alexey Tomilov, Jose Sandoval, Gino A Cortopassi.
      BACKGROUND: Mitochondria are at the center of neural biogenergetics, and ApoE4 is the single most impactful risk factor for AD. We investigated the impact of ApoE on insulin sensitivity, on mitochondrial substrate utilization and bioenergetics. Persons with ApoE4 have reduced brain carbohydrate metabolism. To test for ApoE4 conferred neural mitochondrial metabolic differences, we constructed a novel stable-ApoE 2,3 and 4 N2a cell model, and tested ApoE's effects on Insulin sensitivity, and mitochondrial glucose, lipid and ketone oxidation.METHOD: Binding of ApoE isoforms E2, E3 and E4 to Insulin Receptor (IR) was measured by BLI and Co-IP, the impact of ApoE isoforms on mitochondrial glucose and lipid oxidation was measured by Seahorse.
    RESULT: ApoE3 was found to sensitize to insulin about 2-fold more potently than ApoE4. ApoE isoforms directly bind Insulin Receptor; the binding constants was in the range 200-300nM. Consistent with the previous insulin-sensitivity finding, ApoE3 caused a significant increase of the glycolytic rate and glucose oxidation relative to ApoE4. As there was no difference in oxidation of TCA cycle intermediates substrates in permeabilized cells, we infer ApoE3's glucose advantage is the result of increased insulin sensitivity. ApoE4 contributed a significant palmitate oxidation defect relative to ApoE2 and ApoE3. As this palmitate oxidation defect was observed in both mitochondria and cells it is likely to occur at or within mitochondria. We observed that the relative defect in ApoE4-dependent glucose and palmitate oxidation can be overcome by 5mM BHB. Thus, at the neural cell level, the metabolic defects contributed by ApoE 4 appear to be rescued by a ketogenic molecule, BHB, that requires neither insulin nor apolipoprotein particle to reach neural mitochondria and provide alternative metabolic support.
    CONCLUSION: ApoE4 confers 'double trouble' in mitochondrial glucose and lipid oxidation. ApoE4 confers a defect in mitochondrial lipid oxidation relative to all other isoforms. Simultaneously, ApoE4 lacks the benefit in glucose oxidation conferred by ApoE3, which appears to be driven by the reduced insulin sensitization potency of ApoE4. We also find that BHB can be an alternative source of neural bioenergy that enters mitochondria directly and thus is not affected by ApoE4 'double trouble'.
    DOI:  https://doi.org/10.1002/alz.054355
  27. Front Cell Dev Biol. 2021 ;9 808095
    UCP1 Knockin Induces Lipid Dynamics and Transcriptional Programs in the Skeletal Muscles of Pigs.
    Ziye Xu, Wentao Chen, Liyi Wang, Wenjing You, Yanfang Wang, Yizhen Wang, Jianguo Zhao, Tizhong Shan.
      Uncoupling protein 1 (UCP1), the hallmark protein responsible for nonshivering thermogenesis in adipose tissue (especially brown adipose tissue) has regained researchers' attention in the context of metabolic disorders following the realization that UCP1 can be activated in adult humans and reconstituted in pigs. Both skeletal muscle and adipose tissue are highly dynamic tissues that interact at the metabolic and hormonal level in response to internal and external stress, and they coordinate in maintaining whole-body metabolic homeostasis. Here, we utilized lipidomics and transcriptomics to identify the altered lipid profiles and regulatory pathways in skeletal muscles from adipocyte-specific UCP1 knock-in (KI) pigs. UCP1 KI changed the contents of glycerophospholipids and acyl carnitines of skeletal muscles. Several metabolic regulatory pathways were more enriched in the UCP1 KI skeletal muscle. Comparison of the transcriptomes of adipose and skeletal muscle suggested that nervous system or chemokine signaling might account for the crosstalk between these two tissues in UCP1 KI pigs. Comparison of the lipid biomarkers from UCP1 KI pigs and other mammals suggested associations between UCP1 KI-induced metabolic alternations and metabolic and muscle dysfunction. Our study reveals the lipid dynamics and transcriptional programs in the skeletal muscle of UCP1 KI pigs and suggests that a network regulates metabolic homeostasis between skeletal muscle and adipose tissue.
    Keywords:  UCP1-KI; adipose tissue; crosstalk; lipidomics; obesity; pig; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.3389/fcell.2021.808095
  28. Dis Model Mech. 2022 Feb 02. pii: dmm.049161. [Epub ahead of print]
    Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.
    Carmen Martínez-Fernández, Milana Bergamino, Alfonso Schiavi, David Brena, Natascia Ventura, Sebastian Honnen, Alberto Villanueva, Ernest Nadal, Julián Cerón.
      Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we use C. elegans to explore cisplatin effects on mitochondrial functions and investigate cisplatin-induced neurotoxicity through a high-resolution system for evaluating locomotion. Firstly, we report that a high-glucose diet sensitizes C. elegans to cisplatin at the physiological level and that mitochondrial CED-13 protects the cell from cisplatin-induced oxidative stress. Additionally, by assessing mitochondrial function with a Seahorse Analyzer, we observed a detrimental effect of cisplatin and glucose in mitochondrial respiration. Secondly, since catechol-O-methyltransferases (involved in dopamine degradation) are upregulated upon cisplatin exposure, we studied the protective role of dopamine against cisplatin-induced neurotoxicity. To implement the use of the Tierpsy Tracker system for measuring neurotoxicity, we showed that abnormal displacements and body postures in cat-2 mutants, which have the dopamine synthesis disrupted, can be rescued by adding dopamine. Then, we demonstrated that dopamine treatment protects from the dose-dependent neurotoxicity caused by cisplatin.
    Keywords:  C. elegans; CRISPR-Cas9; Cisplatin; Glucose; Mitochondria; Neurotoxicity
    DOI:  https://doi.org/10.1242/dmm.049161
  29. Front Neurol. 2021 ;12 814174
    Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence.
    Arianna Manini, Elena Abati, Andi Nuredini, Stefania Corti, Giacomo Pietro Comi.
      Duchenne muscular dystrophy (DMD) is an X-linked recessive, infancy-onset neuromuscular disorder characterized by progressive muscle weakness and atrophy, leading to delay of motor milestones, loss of autonomous ambulation, respiratory failure, cardiomyopathy, and premature death. DMD originates from mutations in the DMD gene that result in a complete absence of dystrophin. Dystrophin is a cytoskeletal protein which belongs to the dystrophin-associated protein complex, involved in cellular signaling and myofiber membrane stabilization. To date, the few available therapeutic options are aimed at lessening disease progression, but persistent loss of muscle tissue and function and premature death are unavoidable. In this scenario, one of the most promising therapeutic strategies for DMD is represented by adeno-associated virus (AAV)-mediated gene therapy. DMD gene therapy relies on the administration of exogenous micro-dystrophin, a miniature version of the dystrophin gene lacking unnecessary domains and encoding a truncated, but functional, dystrophin protein. Limited transgene persistence represents one of the most significant issues that jeopardize the translatability of DMD gene replacement strategies from the bench to the bedside. Here, we critically review preclinical and clinical studies of AAV-mediated gene therapy in DMD, focusing on long-term transgene persistence in transduced tissues, which can deeply affect effectiveness and sustainability of gene replacement in DMD. We also discuss the role played by the overactivation of the immune host system in limiting long-term expression of genetic material. In this perspective, further studies aimed at better elucidating the need for immune suppression in AAV-treated subjects are warranted in order to allow for life-long therapy in DMD patients.
    Keywords:  Duchenne muscular dystrophy; adeno-associated virus; dystrophin; gene therapy; microdystrophin; persistence
    DOI:  https://doi.org/10.3389/fneur.2021.814174
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