bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒05‒09
twenty papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Distinct fission signatures predict mitochondrial degradation or biogenesis.
  2. Revolutionary view of two ways to split a mitochondrion.
  3. Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever.
  4. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.
  5. C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.
  6. Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake.
  7. OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21.
  8. Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress.
  9. Monitoring mammalian mitochondrial translation with MitoRiboSeq.
  10. Fluorescent probe for early mitochondrial voltage dynamics.
  11. FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans.
  12. Mitochondrial Network State Scales mtDNA Genetic Dynamics.
  13. Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy and the mitochondrial UPR.
  14. Mitochondria ensure immune surveillance by retro-communication with the nucleus.
  15. A PERKy way to make mitochondrial cristae.
  16. Adaptation of mitochondrial network dynamics and velocity of mitochondrial movement to chronic stress present in fibroblasts derived from patients with sporadic form of Alzheimer's disease.
  17. Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice.
  18. Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease.
  19. Too much of a good thing: Excess exercise can harm mitochondria.
  20. Gendering the seed: Mitochondrial replacement techniques and the erasure of the maternal.
  1. Nature. 2021 May 05.
    Distinct fission signatures predict mitochondrial degradation or biogenesis.
    Tatjana Kleele, Timo Rey, Julius Winter, Sofia Zaganelli, Dora Mahecic, Hélène Perreten Lambert, Francesco Paolo Ruberto, Mohamed Nemir, Timothy Wai, Thierry Pedrazzini, Suliana Manley.
      Mitochondrial fission is a highly regulated process that, when disrupted, can alter metabolism, proliferation and apoptosis1-3. Dysregulation has been linked to neurodegeneration3,4, cardiovascular disease3 and cancer5. Key components of the fission machinery include the endoplasmic reticulum6 and actin7, which initiate constriction before dynamin-related protein 1 (DRP1)8 binds to the outer mitochondrial membrane via adaptor proteins9-11, to drive scission12. In the mitochondrial life cycle, fission enables both biogenesis of new mitochondria and clearance of dysfunctional mitochondria through mitophagy1,13. Current models of fission regulation cannot explain how those dual fates are decided. However, uncovering fate determinants is challenging, as fission is unpredictable, and mitochondrial morphology is heterogeneous, with ultrastructural features that are below the diffraction limit. Here, we used live-cell structured illumination microscopy to capture mitochondrial dynamics. By analysing hundreds of fissions in African green monkey Cos-7 cells and mouse cardiomyocytes, we discovered two functionally and mechanistically distinct types of fission. Division at the periphery enables damaged material to be shed into smaller mitochondria destined for mitophagy, whereas division at the midzone leads to the proliferation of mitochondria. Both types are mediated by DRP1, but endoplasmic reticulum- and actin-mediated pre-constriction and the adaptor MFF govern only midzone fission. Peripheral fission is preceded by lysosomal contact and is regulated by the mitochondrial outer membrane protein FIS1. These distinct molecular mechanisms explain how cells independently regulate fission, leading to distinct mitochondrial fates.
    DOI:  https://doi.org/10.1038/s41586-021-03510-6
  2. Nature. 2021 May 05.
    Revolutionary view of two ways to split a mitochondrion.
    Rajarshi Chakrabarti, Henry N Higgs.
      
    Keywords:  Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-021-01173-x
  3. Elife. 2021 May 04. pii: e66865. [Epub ahead of print]10
    Metabolic flexibility via mitochondrial BCAA carrier SLC25A44 is required for optimal fever.
    Takeshi Yoneshiro, Naoya Kataoka, Jacquelyn M Walejko, Kenji Ikeda, Zachary Brown, Momoko Yoneshiro, Scott B Crown, Tsuyoshi Osawa, Juro Sakai, Robert W McGarrah, Phillip J White, Kazuhiro Nakamura, Shingo Kajimura.
      Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAA) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood. The present study reports the role of SLC25A44, a recently identified mitochondrial BCAA carrier (MBC), in the regulation of mitochondrial BCAA catabolism and adaptive response to fever in rodents. We found that mitochondrial BCAA oxidation in brown adipose tissue (BAT) is significantly enhanced during fever in response to the pyrogenic mediator prostaglandin E2 (PGE2) and psychological stress in mice and rats. Genetic deletion of MBC in a BAT-specific manner blunts mitochondrial BCAA oxidation and non-shivering thermogenesis following intracerebroventricular PGE2 administration. At a cellular level, MBC is required for mitochondrial BCAA deamination as well as the synthesis of mitochondrial amino acids and TCA intermediates. Together, these results illuminate the role of MBC as a determinant of metabolic flexibility to mitochondrial BCAA catabolism and optimal febrile responses. This study also offers an opportunity to control fever by rewiring the subcellular BCAA fate.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.66865
  4. Cell Rep. 2021 May 04. pii: S2211-1247(21)00407-1. [Epub ahead of print]35(5): 109076
    Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response.
    Silvia Vaena, Paramita Chakraborty, Han Gyul Lee, Alhaji H Janneh, Mohamed Faisal Kassir, Gyda Beeson, Zachariah Hedley, Ahmet Yalcinkaya, M Hanief Sofi, Hong Li, Monica L Husby, Robert V Stahelin, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.
    Keywords:  CerS6; PKA; SS SphK2; T cell; aging; immunotherapy; lipid signaling; melanoma; mitophagy; sphingolipids and ceramide
    DOI:  https://doi.org/10.1016/j.celrep.2021.109076
  5. J Clin Invest. 2021 May 04. pii: 143078. [Epub ahead of print]
    C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.
    Eva Lausberg, Sebastian Gießelmann, Joseph P Dewulf, Elsa Wiame, Anja Holz, Ramona Salvarinova, Clara D van Karnebeek, Patricia Klemm, Kim Ohl, Michael Mull, Till Braunschweig, Joachim Weis, Clemens J Sommer, Stephanie Demuth, Claudia Haase, Claudia Stollbrink-Peschgens, François-Guillaume Debray, Cecile Libioulle, Daniela Choukair, Prasad T Oommen, Arndt Borkhardt, Harald Surowy, Dagmar Wieczorek, Norbert Wagner, Robert Meyer, Thomas Eggermann, Matthias Begemann, Emile Van Schaftingen, Martin Häusler, Klaus Tenbrock, Lambert van den Heuvel, Miriam Elbracht, Ingo Kurth, Florian Kraft.
      BACKGROUND: Deciphering the function of the many genes previously classified as uncharacterized "open reading frame" (orf) completes our understanding of cell function and its pathophysiology.METHODS: Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.
    RESULTS: We identified loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients showed signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicated an additional impact of C2orf69 on glycogen metabolism.
    CONCLUSIONS: Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.
    Keywords:  Genetic diseases; Genetics; Mitochondria; Neurological disorders
    DOI:  https://doi.org/10.1172/JCI143078
  6. Cell Rep. 2021 May 04. pii: S2211-1247(21)00420-4. [Epub ahead of print]35(5): 109087
    Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake.
    Gaia Butera, Denis Vecellio Reane, Marta Canato, Laura Pietrangelo, Simona Boncompagni, Feliciano Protasi, Rosario Rizzuto, Carlo Reggiani, Anna Raffaello.
      Parvalbumin (PV) is a cytosolic Ca2+-binding protein highly expressed in fast skeletal muscle, contributing to an increased relaxation rate. Moreover, PV is an "atrogene" downregulated in most muscle atrophy conditions. Here, we exploit mice lacking PV to explore the link between the two PV functions. Surprisingly, PV ablation partially counteracts muscle loss after denervation. Furthermore, acute PV downregulation is accompanied by hypertrophy and upregulation by atrophy. PV ablation has a minor impact on sarcoplasmic reticulum but is associated with increased mitochondrial Ca2+ uptake, mitochondrial size and number, and contacts with Ca2+ release sites. Mitochondrial calcium uniporter (MCU) silencing abolishes the hypertrophic effect of PV ablation, suggesting that mitochondrial Ca2+ uptake is required for hypertrophy. In turn, an increase of mitochondrial Ca2+ is required to enhance expression of the pro-hypertrophy gene PGC-1α4, whose silencing blocks hypertrophy due to PV ablation. These results reveal how PV links cytosolic Ca2+ control to mitochondrial adaptations, leading to muscle mass regulation.
    Keywords:  calcium buffer; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2021.109087
  7. Elife. 2021 May 04. pii: e66519. [Epub ahead of print]10
    OPA1 deletion in brown adipose tissue Improves thermoregulation and systemic metabolism via FGF21.
    Renata O Pereira, Alex Marti, Angela Crystal Olvera, Satya Murthy Tadinada, Sarah Hartwick Bjorkman, Eric Thomas Weatherford, Donald A Morgan, Michael Westphal, Pooja H Patel, Ana Karina Kirby, Rana Hewezi, William Bùi Trần, Luis Miguel García-Peña, Rhonda A Souvenir, Monika Mittal, Christopher M Adams, Kamal Rahmouni, Matthew J Potthoff, E Dale Abel.
      Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.
    Keywords:  biochemistry; chemical biology; mouse
    DOI:  https://doi.org/10.7554/eLife.66519
  8. EMBO Rep. 2021 May 05. e52122
    Fatty acid oxidation is required for embryonic stem cell survival during metabolic stress.
    Hualong Yan, Navdeep Malik, Young-Im Kim, Yunlong He, Mangmang Li, Wendy Dubois, Huaitian Liu, Tyler J Peat, Joe T Nguyen, Yu-Chou Tseng, Gamze Ayaz, Waseem Alzamzami, King Chan, Thorkell Andresson, Lino Tessarollo, Beverly A Mock, Maxwell P Lee, Jing Huang.
      Metabolic regulation is critical for the maintenance of pluripotency and the survival of embryonic stem cells (ESCs). The transcription factor Tfcp2l1 has emerged as a key factor for the naïve pluripotency of ESCs. Here, we report an unexpected role of Tfcp2l1 in metabolic regulation in ESCs-promoting the survival of ESCs through regulating fatty acid oxidation (FAO) under metabolic stress. Tfcp2l1 directly activates many metabolic genes in ESCs. Deletion of Tfcp2l1 leads to an FAO defect associated with upregulation of glucose uptake, the TCA cycle, and glutamine catabolism. Mechanistically, Tfcp2l1 activates FAO by inducing Cpt1a, a rate-limiting enzyme transporting free fatty acids into the mitochondria. ESCs with defective FAO are sensitive to cell death induced by glycolysis inhibition and glutamine deprivation. Moreover, the Tfcp2l1-Cpt1a-FAO axis promotes the survival of quiescent ESCs and diapause-like blastocysts induced by mTOR inhibition. Thus, our results reveal how ESCs orchestrate pluripotent and metabolic programs to ensure their survival in response to metabolic stress.
    Keywords:  Tfcp2l1; diapause; embryonic stem cell; fatty acid oxidation; metabolism
    DOI:  https://doi.org/10.15252/embr.202052122
  9. Nat Protoc. 2021 May 05.
    Monitoring mammalian mitochondrial translation with MitoRiboSeq.
    Sophia Hsin-Jung Li, Michel Nofal, Lance R Parsons, Joshua D Rabinowitz, Zemer Gitai.
      Several essential components of the electron transport chain, the major producer of ATP in mammalian cells, are encoded in the mitochondrial genome. These 13 proteins are translated within mitochondria by 'mitoribosomes'. Defective mitochondrial translation underlies multiple inborn errors of metabolism and has been implicated in pathologies such as aging, metabolic syndrome and cancer. Here, we provide a detailed ribosome profiling protocol optimized to interrogate mitochondrial translation in mammalian cells (MitoRiboSeq), wherein mitoribosome footprints are generated with micrococcal nuclease and mitoribosomes are separated from cytosolic ribosomes and other RNAs by ultracentrifugation in a single straightforward step. We highlight critical steps during library preparation and provide a step-by-step guide to data analysis accompanied by open-source bioinformatic code. Our method outputs mitoribosome footprints at single-codon resolution. Codons with high footprint densities are sites of mitoribosome stalling. We recently applied this approach to demonstrate that defects in mitochondrial serine catabolism or in mitochondrial tRNA methylation cause stalling of mitoribosomes at specific codons. Our method can be applied to study basic mitochondrial biology or to characterize abnormalities in mitochondrial translation in patients with mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41596-021-00517-1
  10. Chem Commun (Camb). 2021 May 06.
    Fluorescent probe for early mitochondrial voltage dynamics.
    Cinthia Hernández-Juárez, Ricardo Flores-Cruz, Arturo Jiménez-Sánchez.
      Mitochondrial voltage dynamics plays a crucial role in cell healthy and disease. Here, a new fluorescent probe to monitor mitochondrial early voltage variations is described. The slowly permeant probe is retained in mitochondria during measurements to avoid interferences from natural membrane potential by incorporating an hydrolizable ester function. Voltage, local polarity, pH parameters and transmembrane dynamics were found to be deeply correlated opening a approach in mitochondrial sensing.
    DOI:  https://doi.org/10.1039/d1cc01944a
  11. Genetics. 2020 Feb 01. 214(2): 409-418
    FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans.
    Sungjin Kim, Derek Sieburth.
      The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.
    Keywords:  FSHR-1; UPRmt; paraquat; sphingosine kinase
    DOI:  https://doi.org/10.1534/genetics.119.302947
  12. Genetics. 2019 Aug 01. 212(4): 1429-1443
    Mitochondrial Network State Scales mtDNA Genetic Dynamics.
    Juvid Aryaman, Charlotte Bowles, Nick S Jones, Iain G Johnston.
      Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. mtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion:fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate, and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.
    Keywords:  cellular noise; heteroplasmy variance; mitochondrial DNA; mitochondrial networks
    DOI:  https://doi.org/10.1534/genetics.119.302423
  13. Aging Cell. 2021 May 03. e13359
    Prohibitin depletion extends lifespan of a TORC2/SGK-1 mutant through autophagy and the mitochondrial UPR.
    Patricia de la Cruz-Ruiz, Blanca Hernando-Rodríguez, Mercedes M Pérez-Jiménez, María Jesús Rodríguez-Palero, Manuel D Martínez-Bueno, Antoni Pla, Roxani Gatsi, Marta Artal-Sanz.
      Mitochondrial prohibitins (PHB) are highly conserved proteins with a peculiar effect on lifespan. While PHB depletion shortens lifespan of wild-type animals, it enhances longevity of a plethora of metabolically compromised mutants, including target of rapamycin complex 2 (TORC2) mutants sgk-1 and rict-1. Here, we show that sgk-1 mutants have impaired mitochondrial homeostasis, lipogenesis and yolk formation, plausibly due to alterations in membrane lipid and sterol homeostasis. Remarkably, all these features are suppressed by PHB depletion. Our analysis shows the requirement of SRBP1/SBP-1 for the lifespan extension of sgk-1 mutants and the further extension conferred by PHB depletion. Moreover, although the mitochondrial unfolded protein response (UPRmt ) and autophagy are induced in sgk-1 mutants and upon PHB depletion, they are dispensable for lifespan. However, the enhanced longevity caused by PHB depletion in sgk-1 mutants requires both, the UPRmt and autophagy, but not mitophagy. We hypothesize that UPRmt induction upon PHB depletion extends lifespan of sgk-1 mutants through autophagy and probably modulation of lipid metabolism.
    Keywords:  SGK-1; UPRmt; autophagy; lipogenesis; mitochondria; prohibitin
    DOI:  https://doi.org/10.1111/acel.13359
  14. Cell Metab. 2021 May 04. pii: S1550-4131(21)00179-0. [Epub ahead of print]33(5): 853-855
    Mitochondria ensure immune surveillance by retro-communication with the nucleus.
    Manuel Rigon, Amelia R Townley, Michelangelo Campanella.
      Mitochondria cover several functions within the cell, including an influence on the transcription of nuclear genes. Recent work by Tigano et al. (2021) in Nature has identified a pathway of mitochondrial retrograde communication in which the nucleus senses aberrations in the mtDNA to drive the innate immune response.
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.013
  15. Trends Endocrinol Metab. 2021 May 03. pii: S1043-2760(21)00075-8. [Epub ahead of print]
    A PERKy way to make mitochondrial cristae.
    Barbara Cannon, Jan Nedergaard.
      PERK protein, that is canonically associated with the response to endoplasmic reticulum stress, may be acquiring a new role as a regulator of the growth of mitochondrial cristae. This role is pertinent not only to the recruitment of brown adipose tissue thermogenic capacity but probably also to directing cristae formation in highly metabolically active organs such as the heart.
    Keywords:  MICOS; brown adipose tissue; cristae; endoplasmic reticulum stress; mitochondria; norepinephrine
    DOI:  https://doi.org/10.1016/j.tem.2021.04.003
  16. FASEB J. 2021 Jun;35(6): e21586
    Adaptation of mitochondrial network dynamics and velocity of mitochondrial movement to chronic stress present in fibroblasts derived from patients with sporadic form of Alzheimer's disease.
    Karolina Drabik, Karolina Piecyk, Artur Wolny, Lidia Szulc-Dąbrowska, Grażyna Dębska-Vielhaber, Stefan Vielhaber, Jerzy Duszyński, Dominika Malińska, Joanna Szczepanowska.
      Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Only 10% of all cases are familial form, the remaining 90% are sporadic form with unknown genetic background. The etiology of sporadic AD is still not fully understood. Pathogenesis and pathobiology of this disease are limited due to the limited number of experimental models. We used primary culture of fibroblasts derived from patients diagnosed with sporadic form of AD for investigation of dynamic properties of mitochondria, including fission-fusion process and localization of mitochondria within the cell. We observed differences in mitochondrial network organization with decreased mitochondrial transport velocity, and a drop in the frequency of fusion-fission events. These studies show how mitochondrial dynamics adapt to the conditions of long-term mitochondrial stress that prevails in cells of sporadic form of AD.
    Keywords:  Alzheimer’s disease; fibroblasts; mitochondrial dynamics
    DOI:  https://doi.org/10.1096/fj.202001978RR
  17. Sci Rep. 2021 May 06. 11(1): 9660
    Mitochondrial calcium uniporter is essential for hearing and hair cell preservation in congenic FVB/NJ mice.
    Mayakannan Manikandan, Steven Walker, Aditi R Deshmukh, Elizabeth Perea, Danqi Wang, Kumar N Alagramam, Ruben Stepanyan.
      Mitochondrial Ca2+ regulates a wide range of cell processes, including morphogenesis, metabolism, excitotoxicity, and survival. In cochlear hair cells, the activation of mechano-electrical transduction and voltage-gated Ca2+ channels result in a large influx of Ca2+. The intracellular rise in Ca2+ is partly balanced by the mitochondria which rapidly uptakes Ca2+ via a highly selective channel comprised of the main pore-forming subunit, the mitochondrial Ca2+ uniporter (MCU), and associated regulatory proteins. MCU thus contributes to Ca2+ buffering, ensuring cytosolic homeostasis, and is posited to have a critical role in hair cell function and hearing. To test this hypothesis, Ca2+ homeostasis in hair cells and cochlear function were investigated in FVB/NJ mice carrying the knockout allele of Mcu (Mcu+/- or Mcu-/-). The Mcu knockout allele, which originated in C57BL/6 strain cosegregated along with Cdh23ahl allele to the FVB/NJ strain, due to the close proximity of these genes. Neither Mcu+/- nor Mcu-/- genotypes affected cochlear development, morphology, or Ca2+ homeostasis of auditory hair cells in the first two postnatal weeks. However, Mcu-/- mice displayed high-frequency hearing impairment as early as 3 weeks postnatal, which then progressed to profound hearing loss at all frequencies in about 6 months. In Mcu+/- mice, significantly elevated ABR thresholds were observed at 6 months and 9 months of age only at 32 kHz frequency. In three-month-old Mcu-/- mice, up to 18% of the outer hair cells and occasionally some inner hair cells were missing in the mid-cochlear region. In conclusion, mitochondrial Ca2+ uniporter is not required for the development of cochlea in mice, but is essential for hearing and hair cell preservation in congenic FVB/NJ mice.
    DOI:  https://doi.org/10.1038/s41598-021-88841-0
  18. Autophagy. 2021 May 04. 1-3
    Upregulation of brain cholesterol levels inhibits mitophagy in Alzheimer disease.
    Vicente Roca-Agujetas, Cristina de Dios, Xenia Abadin, Anna Colell.
      Mitochondrial dysfunction is behind several neurodegenerative diseases, including Alzheimer disease (AD). Accumulation of damaged mitochondria is already observed at the early stages of AD and has been linked to impaired mitophagy, but the mechanisms underlying this alteration are still not fully known. In our recent study, we show that intracellular cholesterol enrichment can downregulate amyloid beta (Aβ)-induced mitophagy. Mitochondrial glutathione depletion resulting from high cholesterol levels promotes PINK1 (PTEN induced kinase 1)-mediated mitophagosome formation; however, mitophagy flux is ultimately disrupted, most likely due to fusion deficiency of endosomes-lysosomes caused by cholesterol. Meanwhile, in APP-PSEN1-SREBF2 mice, an AD mouse model that overexpresses the cholesterol-related transcription factor SREBF2, cholesterol accumulation prompts an oxidative- and age-dependent cytosolic aggregation of the mitophagy adaptor OPTN (optineurin), which prevents mitophagosome formation despite enhanced PINK1-PRKN/parkin signaling. Hippocampal neurons from postmortem brain of AD individuals reproduce the progressive accumulation of OPTN in aggresome-like structures accompanied by high levels of mitochondrial cholesterol in advanced stages of the disease. Overall, these data provide new insights into the impairment of the PINK1-PRKN mitophagy pathway in AD and suggest the combination of mitophagy inducers with strategies focused on restoring the cholesterol homeostasis and mitochondrial redox balance as a potential disease-modifying therapy for AD.
    Keywords:  Alzheimer disease; Mitophagy; PINK1; aggresomes; autophagy; cholesterol; optineurin; parkin
    DOI:  https://doi.org/10.1080/15548627.2021.1920814
  19. Cell Metab. 2021 May 04. pii: S1550-4131(21)00174-1. [Epub ahead of print]33(5): 847-848
    Too much of a good thing: Excess exercise can harm mitochondria.
    Mark W Pataky, K Sreekumaran Nair.
      Health benefits of aerobic exercise are indisputable and are closely related to the maintenance of mitochondrial energy homeostasis and insulin sensitivity. Flockhart et al. (2021) demonstrate, however, that a high volume of high-intensity aerobic exercise adversely affects mitochondrial function and may cause impaired glucose tolerance.
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.008
  20. Bioethics. 2021 May 04.
    Gendering the seed: Mitochondrial replacement techniques and the erasure of the maternal.
    Robert Sparrow, Catherine Mills, John Carroll.
      In order to avoid the implication that 'mitochondrial replacement techniques' (MRT) would produce 'three parent babies', discourses around these techniques typically dismiss the contribution of the mitochondria to genetic parenthood and personal identity. According to many participants in debates about MRT, 'real parenthood' is a matter of contributing nuclear DNA, which in turn implies that men and women make the same contribution to the embryo. Even when the importance of the mitochondria is acknowledged, an emphasis on mitochondrial DNA still has the effect of valorizing the role of DNA (and thus the paternal contribution to conception) at the expense of the role played by the cytoplasm of the oocyte in the development of the embryo and placenta, and that of the mother's body in gestation. In this way, discourses around MRT falsely imply that what men and women contribute to reproduction and parenthood is the same-nuclear DNA-and thus erase the distinctive contribution that women make to conception. The potential of MRT to reconfigure relationships between the sexes in the service of patriarchal norms is perhaps one of the most significant things about it and should, we argue, be counted in the discussion of the ethical and policy implications of legitimating these procedures.
    Keywords:  ethics; gender; genetic parenthood; mitochondrial replacement techniques; reproduction
    DOI:  https://doi.org/10.1111/bioe.12868
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