bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒12‒11
twenty-six papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
  2. A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.
  3. Mitochondrial cristae architecture protects against mtDNA release and inflammation.
  4. Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
  5. Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice.
  6. Mitochondrial biology and dysfunction in secondary mitochondrial disease.
  7. Mitolysosome exocytosis: a novel mitochondrial quality control pathway linked with parkinsonism-like symptoms.
  8. Novel biallelic mutations in TMEM126B cause splicing defects and lead to Leigh-like syndrome with severe complex I deficiency.
  9. Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2.
  10. Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.
  11. Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
  12. Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
  13. Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
  14. DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
  15. The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila.
  16. FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
  17. Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants.
  18. Human embryos donated for human embryonic stem cell derivation.
  19. The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
  20. The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
  21. Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
  22. NAD precursors cycle between host tissues and the gut microbiome.
  23. Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control.
  24. Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility.
  25. Analysis of compound heterozygous and homozygous mutations found in peripheral subunits of human respiratory Complex I, NDUFS1, NDUFS2, NDUFS8 and NDUFV1, by modeling in the E. coli enzyme.
  26. The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
  1. Nat Biomed Eng. 2022 Dec 05.
    A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.
    Pedro Silva-Pinheiro, Christian D Mutti, Lindsey Van Haute, Christopher A Powell, Pavel A Nash, Keira Turner, Michal Minczuk.
      The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.
    DOI:  https://doi.org/10.1038/s41551-022-00968-1
  2. Sci Data. 2022 Dec 03. 9(1): 751
    A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.
    Gabriel Sturm, Anna S Monzel, Kalpita R Karan, Jeremy Michelson, Sarah A Ware, Andres Cardenas, Jue Lin, Céline Bris, Balaji Santhanam, Michael P Murphy, Morgan E Levine, Steve Horvath, Daniel W Belsky, Shuang Wang, Vincent Procaccio, Brett A Kaufman, Michio Hirano, Martin Picard.
      Aging is a process of progressive change. To develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omics longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n = 6) and individuals with lifespan-shortening mitochondrial disease (n = 3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the "hallmarks of aging", with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/.
    DOI:  https://doi.org/10.1038/s41597-022-01852-y
  3. Cell Rep. 2022 Dec 06. pii: S2211-1247(22)01657-6. [Epub ahead of print]41(10): 111774
    Mitochondrial cristae architecture protects against mtDNA release and inflammation.
    Baiyu He, Huatong Yu, Shanshan Liu, Huayun Wan, Song Fu, Siqi Liu, Jun Yang, Zihan Zhang, Huanwei Huang, Qi Li, Fengchao Wang, Zhaodi Jiang, Qinghua Liu, Hui Jiang.
      Mitochondrial damage causes mitochondrial DNA (mtDNA) release to activate the type I interferon (IFN-I) response via the cGAS-STING pathway. mtDNA-induced inflammation promotes autoimmune- and aging-related degenerative disorders. However, the global picture of inflammation-inducing mitochondrial damages remains obscure. Here, we have performed a mitochondria-targeted CRISPR knockout screen for regulators of the IFN-I response. Strikingly, our screen reveals dozens of hits enriched with key regulators of cristae architecture, including phospholipid cardiolipin and protein complexes such as OPA1, mitochondrial contact site and cristae organization (MICOS), sorting and assembly machinery (SAM), mitochondrial intermembrane space bridging (MIB), prohibitin (PHB), and the F1Fo-ATP synthase. Disrupting these cristae organizers consistently induces mtDNA release and the STING-dependent IFN-I response. Furthermore, knocking out MTX2, a subunit of the SAM complex whose null mutations cause progeria in humans, induces a robust STING-dependent IFN-I response in mouse liver. Taken together, beyond revealing the central role of cristae architecture to prevent mtDNA release and inflammation, our results mechanistically link mitochondrial cristae disorganization and inflammation, two emerging hallmarks of aging and aging-related degenerative diseases.
    Keywords:  CP: Cell biology; CP: Molecular biology; MICOS; Metaxin2; OPA1; SAM; cGAS-STING; cristae architecture; inflammation; mtDNA release; type I interferon response
    DOI:  https://doi.org/10.1016/j.celrep.2022.111774
  4. Biochim Biophys Acta Bioenerg. 2022 Dec 05. pii: S0005-2728(22)00417-0. [Epub ahead of print] 148947
    Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease.
    Carlo Viscomi, Anthony L Moore, Massimo Zeviani, Marten Szibor.
      The mitochondrial respiratory chain or electron transport chain (ETC) facilitates redox reactions which ultimately lead to the reduction of oxygen to water (respiration). Energy released by this process is used to establish a proton electrochemical gradient which drives ATP formation (oxidative phosphorylation, OXPHOS). It also plays an important role in vital processes beyond ATP formation and cellular metabolism, such as heat production, redox and ion homeostasis. Dysfunction of the ETC can thus impair cellular and organismal viability and is thought to be the underlying cause of a heterogeneous group of so-called mitochondrial diseases. Plants, yeasts, and many lower organisms, but not insects and vertebrates, possess an enzymatic mechanism that confers resistance to respiratory stress conditions, i.e. the alternative oxidase (AOX). Even in cells that naturally lack AOX, it is autonomously imported into the mitochondrial compartment upon xenotopic expression, where it refolds and becomes catalytically engaged when the cytochrome segment of the ETC is blocked. AOX was therefore proposed as a tool to study disease etiologies. To this end, AOX has been xenotopically expressed in mammalian cells and disease models of the fruit fly and mouse. Surprisingly, AOX showed remarkable rescue effects in some cases, whilst in others it had no effect or even exacerbated a condition. Here we summarize what has been learnt from the use of AOX in various disease models and discuss issues which still need to be addressed in order to understand the role of the ETC in health and disease.
    Keywords:  Alternative oxidase; Disease models; Mitochondria; Mitochondrial disease; Mouse; Xenogene
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148947
  5. Cell Prolif. 2022 Dec 08. e13372
    Supplementation of mitochondria from endometrial mesenchymal stem cells improves oocyte quality in aged mice.
    Qi Zhang, Jian-Xiu Hao, Bo-Wen Liu, Ying-Chun Ouyang, Jia-Ni Guo, Ming-Zhe Dong, Zhen-Bo Wang, Fei Gao, Yuan-Qing Yao.
      Maternal ageing is one of the major causes of reduced ovarian reserve and low oocyte quality in elderly women. Decreased oocyte quality is the main cause of age-related infertility. Mitochondria are multifunctional energy stations that determine the oocyte quality. The mitochondria in aged oocytes display functional impairments with mtDNA damage, which leads to reduced competence and developmental potential of oocytes. To improve oocyte quality, mitochondrial supplementation is carried out as a potential therapeutic approach. However, the selection of suitable cells as the source of mitochondria remains controversial. We cultivated endometrial mesenchymal stem cells (EnMSCs) from aged mice and extracted mitochondria from EnMSCs. To improve the quality of oocytes, GV oocytes were supplemented with mitochondria via microinjection. And MII oocytes from aged mice were fertilized by intracytoplasmic sperm injection (ICSI), combining EnMSCs' mitochondrial microinjection. In this study, we found that the mitochondria derived from EnMSCs could significantly improve the quality of aged oocytes. Supplementation with EnMSC mitochondria significantly increased the blastocyst ratio of MII oocytes from aged mice after ICSI. We also found that the birth rate of mitochondria-injected ageing oocytes was significantly increased after embryo transplantation. Our study demonstrates that supplementation with EnMSC-derived mitochondria can improve the quality of oocytes and promote embryo development in ageing mice, which might provide a prospective strategy for clinical treatment.
    DOI:  https://doi.org/10.1111/cpr.13372
  6. Open Biol. 2022 Dec;12(12): 220274
    Mitochondrial biology and dysfunction in secondary mitochondrial disease.
    Megan J Baker, Jordan J Crameri, David R Thorburn, Ann E Frazier, Diana Stojanovski.
      Mitochondrial diseases are a broad, genetically heterogeneous class of metabolic disorders characterized by deficits in oxidative phosphorylation (OXPHOS). Primary mitochondrial disease (PMD) defines pathologies resulting from mutation of mitochondrial DNA (mtDNA) or nuclear genes affecting either mtDNA expression or the biogenesis and function of the respiratory chain. Secondary mitochondrial disease (SMD) arises due to mutation of nuclear-encoded genes independent of, or indirectly influencing OXPHOS assembly and operation. Despite instances of novel SMD increasing year-on-year, PMD is much more widely discussed in the literature. Indeed, since the implementation of next generation sequencing (NGS) techniques in 2010, many novel mitochondrial disease genes have been identified, approximately half of which are linked to SMD. This review will consolidate existing knowledge of SMDs and outline discrete categories within which to better understand the diversity of SMD phenotypes. By providing context to the biochemical and molecular pathways perturbed in SMD, we hope to further demonstrate the intricacies of SMD pathologies outside of their indirect contribution to mitochondrial energy generation.
    Keywords:  mitochondria; mitochondrial protein import; mitochondrial quality control; secondary mitochondrial disease
    DOI:  https://doi.org/10.1098/rsob.220274
  7. Biochem Soc Trans. 2022 Dec 09. pii: BST20220726. [Epub ahead of print]
    Mitolysosome exocytosis: a novel mitochondrial quality control pathway linked with parkinsonism-like symptoms.
    Feixiang Bao, Lingyan Zhou, Jiahui Xiao, Xingguo Liu.
      Quality control of mitochondria is essential for their homeostasis and function. Light chain 3 (LC3) associated autophagosomes-mediated mitophagy represents a canonical mitochondrial quality control pathway. Alternative quality control processes, such as mitochondrial-derived vesicles (MDVs), have been discovered, but the intact mitochondrial quality control remains unknown. We recently discovered a novel mitolysosome exocytosis mechanism for mitochondrial quality control in flunarizine (FNZ)-induced mitochondria clearance, where autophagosomes are not required, but rather mitochondria are engulfed directly by lysosomes, mediating mitochondrial secretion. As FNZ results in parkinsonism, we propose that excessive mitolysosome exocytosis is the cause.
    Keywords:  extracellular vesicles; lysosome; mitochondria-free; mitochondrial quality control; parkinsonism
    DOI:  https://doi.org/10.1042/BST20220726
  8. J Hum Genet. 2022 Dec 08.
    Novel biallelic mutations in TMEM126B cause splicing defects and lead to Leigh-like syndrome with severe complex I deficiency.
    Xiyue Zhou, Xiaoting Lou, Yuwei Zhou, Yaojun Xie, Xinyu Han, Qiyu Dong, Xiaojie Ying, Mahlatsi Refiloe Laurentinah, Luyi Zhang, Zhehui Chen, Dongxiao Li, Hezhi Fang, Jianxin Lyu, Yanling Yang, Ya Wang.
      Leigh syndrome (LS)/Leigh-like syndrome (LLS) is one of the most common mitochondrial disease subtypes, caused by mutations in either the nuclear or mitochondrial genomes. Here, we identified a novel intronic mutation (c.82-2 A > G) and a novel exonic insertion mutation (c.290dupT) in TMEM126B from a Chinese patient with clinical manifestations of LLS. In silico predictions, minigene splicing assays and patients' RNA analyses determined that the c.82-2 A > G mutation resulted in complete exon 2 skipping, and the c.290dupT mutation provoked partial and complete exon 3 skipping, leading to translational frameshifts and premature termination. Functional analysis revealed the impaired mitochondrial function in patient-derived lymphocytes due to severe complex I content and assembly defect. Altogether, this is the first report of LLS in a patient carrying mutations in TMEM126B. Our data uncovers the functional effect and the molecular mechanism of the pathogenic variants c.82-2 A > G and c.290dupT, which expands the gene mutation spectrum of LLS and clinical spectrum caused by TMEM126B mutations, and thus help to clinical diagnosis of TMEM126B mutation-related mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s10038-022-01102-4
  9. Free Radic Res. 2022 Dec 08. 1-15
    Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2.
    Maria Tolomeo, Guglielmina Chimienti, Martina Lanza, Roberto Barbaro, Alessia Nisco, Tiziana Latronico, Piero Leone, Giuseppe Petrosillo, Grazia Maria Liuzzi, Bryony Ryder, Michal Inbar-Feigenberg, Matilde Colella, Angela M S Lezza, Rikke K J Olsen, Maria Barile.
      Flavin adenine dinucleotide (FAD) synthase (EC 2.7.7.2), encoded by human flavin adenine dinucleotide synthetase 1 (FLAD1), catalyzes the last step of the pathway converting riboflavin (Rf) into FAD. FLAD1 variations were identified as a cause of LSMFLAD (lipid storage myopathy due to FAD synthase deficiency, OMIM #255100), resembling Multiple Acyl-CoA Dehydrogenase Deficiency, sometimes treatable with high doses of Rf; no alternative therapeutic strategies are available. We describe here cell morphological and mitochondrial alterations in dermal fibroblasts derived from a LSMFLAD patient carrying a homozygous truncating FLAD1 variant (c.745C > T) in exon 2. Despite a severe decrease in FAD synthesis rate, the patient had decreased cellular levels of Rf and flavin mononucleotide and responded to Rf treatment.We hypothesized that disturbed flavin homeostasis and Rf-responsiveness could be due to a secondary impairment in the expression of the Rf transporter 2 (RFVT2), encoded by SLC52A2, in the frame of an adaptive retrograde signaling to mitochondrial dysfunction. Interestingly, an antioxidant response element (ARE) is found in the region upstream of the transcriptional start site of SLC52A2. Accordingly, we found that abnormal mitochondrial morphology and impairments in bioenergetics were accompanied by increased cellular reactive oxygen species content and mtDNA oxidative damage. Concomitantly, an active response to mitochondrial stress is suggested by increased levels of PPARγ-co-activator-1α and Peroxiredoxin III. In this scenario, the treatment with high doses of Rf might compensate for the secondary RFVT2 molecular defect, providing a molecular rationale for the Rf responsiveness in patients with loss of function variants in FLAD1 exon 2.HIGHLIGHTSFAD synthase deficiency alters mitochondrial morphology and bioenergetics;FAD synthase deficiency triggers a mitochondrial retrograde response;FAD synthase deficiency evokes nuclear signals that adapt the expression of RFVT2.
    Keywords:  FLAD1; LSMFLAD; MADD; RFVT2; mitochondrial myopathy
    DOI:  https://doi.org/10.1080/10715762.2022.2146501
  10. Biochim Biophys Acta Bioenerg. 2022 Dec 06. pii: S0005-2728(22)00419-4. [Epub ahead of print] 148949
    Inner mitochondrial membrane structure and fusion dynamics are altered in senescent human iPSC-derived and primary rat cardiomyocytes.
    Silke Morris, Isidora Molina-Riquelme, Gonzalo Barrientos, Francisco Bravo, Geraldine Aedo, Wileidy Gómez, Daniel Lagos, Hugo Verdejo, Stefan Peischard, Guiscard Seebohm, Olympia Ekaterini Psathaki, Verónica Eisner, Karin B Busch.
      Dysfunction of the aging heart is a major cause of death in the human population. Amongst other tasks, mitochondria are pivotal to supply the working heart with ATP. The mitochondrial inner membrane (IMM) ultrastructure is tailored to meet these demands and to provide nano-compartments for specific tasks. Thus, function and morphology are closely coupled. Senescent cardiomyocytes from the mouse heart display alterations of the inner mitochondrial membrane. To study the relation between inner mitochondrial membrane architecture, dynamics and function is hardly possible in living organisms. Here, we present two cardiomyocyte senescence cell models that allow in cellular studies of mitochondrial performance. We show that doxorubicin treatment transforms human iPSC-derived cardiomyocytes and rat neonatal cardiomyocytes in an aged phenotype. The treated cardiomyocytes display double-strand breaks in the nDNA, have β-galactosidase activity, possess enlarged nuclei, and show p21 upregulation. Most importantly, they also display a compromised inner mitochondrial structure. This prompted us to test whether the dynamics of the inner membrane was also altered. We found that the exchange of IMM components after organelle fusion was faster in doxorubicin-treated cells than in control cells, with no change in mitochondrial fusion dynamics at the meso-scale. Such altered IMM morphology and dynamics may have important implications for local OXPHOS protein organization, exchange of damaged components, and eventually the mitochondrial bioenergetics function of the aged cardiomyocyte.
    Keywords:  Cardiomyocytes; Cristae structure; Doxorubicin; Inner mitochondrial membrane dynamics; Mitochondrial fusion and fission dynamics; Senescence
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148949
  11. Front Cell Dev Biol. 2022 ;10 1030390
    Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy.
    Hong-Mei Luo, Jia Xu, Dan-Xia Huang, Yun-Qiang Chen, Yi-Zhou Liu, Ya-Jie Li, Hong Chen.
      Neurodegenerative diseases (NDDs) are disorders in which neurons are lost owing to various factors, resulting in a series of dysfunctions. Their rising prevalence and irreversibility have brought physical pain to patients and economic pressure to both individuals and society. However, the pathogenesis of NDDs has not yet been fully elucidated, hampering the use of precise medication. Induced pluripotent stem cell (IPSC) modeling provides a new method for drug discovery, and exploring the early pathological mechanisms including mitochondrial dysfunction, which is not only an early but a prominent pathological feature of NDDs. In this review, we summarize the iPSC modeling approach of Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, as well as outline typical mitochondrial dysfunction and recapitulate corresponding therapeutic strategies.
    Keywords:  IPSCs (induced pluripotent stem cells); mitochondrial dynamic; mitochondrial dysfunction; mitochondrial energy metabolism; mitochondrial transport; neurodegenerative diseases; therapeutic strategy
    DOI:  https://doi.org/10.3389/fcell.2022.1030390
  12. Exp Mol Med. 2022 Dec 06.
    Mitochondrial PARP1 regulates NAD+-dependent poly ADP-ribosylation of mitochondrial nucleoids.
    Jong-Hyuk Lee, Mansoor Hussain, Edward W Kim, Shang-Jung Cheng, Anthony K L Leung, Nima Borhan Fakouri, Deborah L Croteau, Vilhelm A Bohr.
      PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD+ depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD+ to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD+ stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD+-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.
    DOI:  https://doi.org/10.1038/s12276-022-00894-x
  13. Nat Commun. 2022 Dec 09. 13(1): 7598
    Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes.
    Koen Kole, Bas J B Voesenek, Maria E Brinia, Naomi Petersen, Maarten H P Kole.
      Parvalbumin-expressing (PV+) basket cells are fast-spiking inhibitory interneurons that exert critical control over local circuit activity and oscillations. PV+ axons are often myelinated, but the electrical and metabolic roles of interneuron myelination remain poorly understood. Here, we developed viral constructs allowing cell type-specific investigation of mitochondria with genetically encoded fluorescent probes. Single-cell reconstructions revealed that mitochondria selectively cluster to myelinated segments of PV+ basket cells, confirmed by analyses of a high-resolution electron microscopy dataset. In contrast to the increased mitochondrial densities in excitatory axons cuprizone-induced demyelination abolished mitochondrial clustering in PV+ axons. Furthermore, with genetic deletion of myelin basic protein the mitochondrial clustering was still observed at internodes wrapped by noncompacted myelin, indicating that compaction is dispensable. Finally, two-photon imaging of action potential-evoked calcium (Ca2+) responses showed that interneuron myelination attenuates both the cytosolic and mitochondrial Ca2+ transients. These findings suggest that oligodendrocyte ensheathment of PV+ axons assembles mitochondria to branch selectively fine-tune metabolic demands.
    DOI:  https://doi.org/10.1038/s41467-022-35350-x
  14. Neurobiol Dis. 2022 Dec 05. pii: S0969-9961(22)00333-3. [Epub ahead of print]176 105941
    DJ-1 promotes energy balance by regulating both mitochondrial and autophagic homeostasis.
    Federica De Lazzari, Francesco Agostini, Nicoletta Plotegher, Michele Sandre, Elisa Greggio, Aram Megighian, Luigi Bubacco, Federica Sandrelli, Alexander J Whitworth, Marco Bisaglia.
      The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1β as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1β null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1β leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1β null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.
    Keywords:  Autophagy; DJ-1; Energy balance; Mitochondria; Redox homeostasis
    DOI:  https://doi.org/10.1016/j.nbd.2022.105941
  15. Elife. 2022 Dec 07. pii: e80245. [Epub ahead of print]11
    The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila.
    Arnau Llobet Rosell, Maria Paglione, Jonathan Gilley, Magdalena Kocia, Giulia Perillo, Massimiliano Gasparrini, Lucia Cialabrini, Nadia Raffaelli, Carlo Angeletti, Giuseppe Orsomando, Pei-Hsuan Wu, Michael P Coleman, Andrea Loreto, Lukas Jakob Neukomm.
      Axon degeneration contributes to the disruption of neuronal circuit function in diseased and injured nervous systems. Severed axons degenerate following the activation of an evolutionarily conserved signaling pathway, which culminates in the activation of SARM1 in mammals to execute the pathological depletion of the metabolite NAD+. SARM1 NADase activity is activated by the NAD+ precursor nicotinamide mononucleotide (NMN). In mammals, keeping NMN levels low potently preserves axons after injury. However, it remains unclear whether NMN is also a key mediator of axon degeneration and dSarm activation in flies. Here, we demonstrate that lowering NMN levels in Drosophila through the expression of a newly generated prokaryotic NMN-Deamidase (NMN-D) preserves severed axons for months and keeps them circuit-integrated for weeks. NMN-D alters the NAD+ metabolic flux by lowering NMN, while NAD+ remains unchanged in vivo. Increased NMN synthesis, by the expression of mouse nicotinamide phosphoribosyltransferase (mNAMPT), leads to faster axon degeneration after injury. We also show that NMN-induced activation of dSarm mediates axon degeneration in vivo. Finally, NMN-D delays neurodegeneration caused by loss of the sole NMN-consuming and NAD+-synthesizing enzyme dNmnat. Our results reveal a critical role for NMN in neurodegeneration in the fly, which extends beyond axonal injury. The potent neuroprotection by reducing NMN levels is similar to the interference with other essential mediators of axon degeneration in Drosophila.
    Keywords:  D. melanogaster; cell biology; neuroscience
    DOI:  https://doi.org/10.7554/eLife.80245
  16. Cell Death Dis. 2022 Dec 05. 13(12): 1020
    FUNDC1 protects against doxorubicin-induced cardiomyocyte PANoptosis through stabilizing mtDNA via interaction with TUFM.
    Yaguang Bi, Haixia Xu, Xiang Wang, Hong Zhu, Junbo Ge, Jun Ren, Yingmei Zhang.
      Doxorubicin (DOX) is an effective anthracycline chemotherapeutic anticancer drug with its life-threatening cardiotoxicity severely limiting its clinical application. Mitochondrial damage-induced cardiomyocyte death is considered an essential cue for DOX cardiotoxicity. FUN14 domain containing 1 (FUNDC1) is a mitochondrial membrane protein participating in the regulation of mitochondrial integrity in multiple diseases although its role in DOX cardiomyopathy remains elusive. Here, we examined whether PANoptosis, a novel type of programmed cell death closely associated with mitochondrial damage, was involved in DOX-induced heart injury, and FUNDC1-mediated regulation of cardiomyocyte PANoptosis, if any. FUNDC1 was downregulated in heart tissues in patients with dilated cardiomyopathy (DCM) and DOX-challenged mice. FUNDC1 deficiency aggravated DOX-induced cardiac dysfunction, mitochondrial injury, and cardiomyocyte PANoptosis. Further examination revealed that FUNDC1 countered cytoplasmic release of mitochondrial DNA (mtDNA) and activation of PANoptosome through interaction with mitochondrial Tu translation elongation factor (TUFM), a key factor in the translational expression and repair of mitochondrial DNA, via its 96-133 amino acid domain. TUFM intervention reversed FUNDC1-elicited protection against DOX-induced mtDNA cytosolic release and cardiomyocyte PANoptosis. Our findings shed light toward a beneficial role of FUNDC1 in DOX cardiotoxicity and cardiomyocyte PANoptosis, thus offering therapeutic promises in DOX-induced cardiotoxicity.
    DOI:  https://doi.org/10.1038/s41419-022-05460-x
  17. Am J Med Genet A. 2022 Dec 10.
    Progressive brain atrophy and severe neurodevelopmental phenotype in siblings with biallelic COASY variants.
    Justin Rosati, Jessica Johnson, Zinandre Stander, Amy White, Silvia Tortorelli, Diana Bailey, Chin-To Fong, Bo Hoon Lee.
      Biallelic pathogenic variants in the COASY gene have been associated with two distinct disease phenotypes, that is, COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12). We present two siblings that independently presented with significant hypotonia and respiratory insufficiency at birth. Comprehensive genetic testing revealed homozygous variants within COASY, however, the progressive clinical and neuroradiologic findings described here are unique and have not been described previously. Magnetic resonance imaging showed progressive diffuse parenchymal loss throughout the bilateral cerebral hemispheres and atrophy of the basal ganglia and brainstem. As such, this article brings forth two additional cases of COASY-related disorder with abnormal newborn screening acylcarnitine profiles resembling carnitine palmitoyl transferase 1a (CPT1a) deficiency in two siblings who presented at birth with contractures, marked hypotonia and absent respiratory drive.
    Keywords:  COASY; CPT1; PCH; pontocerebellar hypoplasia
    DOI:  https://doi.org/10.1002/ajmg.a.63076
  18. Fertil Steril. 2022 Dec 06. pii: S0015-0282(22)01973-2. [Epub ahead of print]
    Human embryos donated for human embryonic stem cell derivation.
    Salomeh Salari, Eli Y Adashi, Laura Keller, Timothy R B Johnson, Gary D Smith.
      Human embryonic stem cells (hESCs), produced from human embryos, are demonstrating: utility and promise in disease modeling; enhanced and unique understanding of early events in basic genetic or molecular or cellular or epigenetic development; novel human approaches to pharmaceutical screening; pathways toward the discoveries of disease treatments and cures; and foundational importance for regenerative medicine. The regulatory landscape is rigorous, and rightly so. Here, we discuss the current US federal and state regulatory environment. A unique approach of presenting anonymized embryo donor statements is provided to personalize the decision-making process of human embryo donation for hESC derivation. From the uses of preimplantation genetic-tested and affected human embryos to derived disease-specific hESCs, one can glean the much needed information on early human genetics and developmental biology, which are presented here. Finally, we discuss the future uses of hESCs, and other pluripotent stem cells, in general and reproductive medicine.
    Keywords:  Human embryos; human embryonic stem cells; preimplantation genetic testing
    DOI:  https://doi.org/10.1016/j.fertnstert.2022.10.023
  19. Front Immunol. 2022 ;13 1028953
    The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.
    Jessica Astorga, Naschla Gasaly, Karen Dubois-Camacho, Marjorie De la Fuente, Glauben Landskron, Klaas Nico Faber, Félix A Urra, Marcela A Hermoso.
      Inflammatory Bowel Disease (IBD) is characterized by a loss of intestinal barrier function caused by an aberrant interaction between the immune response and the gut microbiota. In IBD, imbalance in cholesterol homeostasis and mitochondrial bioenergetics have been identified as essential events for activating the inflammasome-mediated response. Mitochondrial alterations, such as reduced respiratory complex activities and reduced production of tricarboxylic acid (TCA) cycle intermediates (e.g., citric acid, fumarate, isocitric acid, malate, pyruvate, and succinate) have been described in in vitro and clinical studies. Under inflammatory conditions, mitochondrial architecture in intestinal epithelial cells is dysmorphic, with cristae destruction and high dynamin-related protein 1 (DRP1)-dependent fission. Likewise, these alterations in mitochondrial morphology and bioenergetics promote metabolic shifts towards glycolysis and down-regulation of antioxidant Nuclear erythroid 2-related factor 2 (Nrf2)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) signaling. Although the mechanisms underlying the mitochondrial dysfunction during mucosal inflammation are not fully understood at present, metabolic intermediates and cholesterol may act as signals activating the NLRP3 inflammasome in IBD. Notably, dietary phytochemicals exhibit protective effects against cholesterol imbalance and mitochondrial function alterations to maintain gastrointestinal mucosal renewal in vitro and in vivo conditions. Here, we discuss the role of cholesterol and mitochondrial metabolism in IBD, highlighting the therapeutic potential of dietary phytochemicals, restoring intestinal metabolism and function.
    Keywords:  IBD - inflammatory bowel disease; NLRP3 inflammasome; diet phytochemicals; inflammasome; intracellular cholesterol accumulation; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fimmu.2022.1028953
  20. Nat Commun. 2022 Dec 08. 13(1): 7576
    The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction.
    Guanlan Hu, Catriona Ling, Lijun Chi, Mehakpreet K Thind, Samuel Furse, Albert Koulman, Jonathan R Swann, Dorothy Lee, Marjolein M Calon, Celine Bourdon, Christian J Versloot, Barbara M Bakker, Gerard Bryan Gonzales, Peter K Kim, Robert H J Bandsma.
      Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.
    DOI:  https://doi.org/10.1038/s41467-022-35317-y
  21. Brain. 2022 Dec 07. pii: awac464. [Epub ahead of print]
    Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson's disease.
    Joanne Trinh, Andrew A Hicks, Inke R König, Sylvie Delcambre, Theresa Lüth, Susen Schaake, Kobi Wasner, Jenny Ghelfi, Max Borsche, Carles Vilariño-Güell, Faycel Hentati, Elisabeth L Germer, Peter Bauer, Masashi Takanashi, Vladimir Kostić, Anthony E Lang, Norbert Brüggemann, Peter P Pramstaller, Irene Pichler, Alex Rajput, Nobutaka Hattori, Matthew J Farrer, Katja Lohmann, Hansi Weissensteiner, Patrick May, Christine Klein, Anne Grünewald.
      Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner.
    Keywords:  PINK1; PRKN; modifiers; mtDNA heteroplasmy; penetrance
    DOI:  https://doi.org/10.1093/brain/awac464
  22. Cell Metab. 2022 Dec 06. pii: S1550-4131(22)00495-8. [Epub ahead of print]34(12): 1947-1959.e5
    NAD precursors cycle between host tissues and the gut microbiome.
    Karthikeyani Chellappa, Melanie R McReynolds, Wenyun Lu, Xianfeng Zeng, Mikhail Makarov, Faisal Hayat, Sarmistha Mukherjee, Yashaswini R Bhat, Siddharth R Lingala, Rafaella T Shima, Hélène C Descamps, Timothy Cox, Lixin Ji, Connor Jankowski, Qingwei Chu, Shawn M Davidson, Christoph A Thaiss, Marie E Migaud, Joshua D Rabinowitz, Joseph A Baur.
      Nicotinamide adenine dinucleotide (NAD) is an essential redox cofactor in mammals and microbes. Here we use isotope tracing to investigate the precursors supporting NAD synthesis in the gut microbiome of mice. We find that dietary NAD precursors are absorbed in the proximal part of the gastrointestinal tract and not available to microbes in the distal gut. Instead, circulating host nicotinamide enters the gut lumen and supports microbial NAD synthesis. The microbiome converts host-derived nicotinamide into nicotinic acid, which is used for NAD synthesis in host tissues and maintains circulating nicotinic acid levels even in the absence of dietary consumption. Moreover, the main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, we establish the capacity for circulating host micronutrients to feed the gut microbiome, and in turn be transformed in a manner that enhances host metabolic flexibility.
    Keywords:  NAD; flux; gastrointestinal; microbe; microbiome; mononucleotide; niacin; nicotinamide; nicotinic acid; riboside
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.004
  23. iScience. 2022 Dec 22. 25(12): 105654
    Enzymatically dissociated muscle fibers display rapid dedifferentiation and impaired mitochondrial calcium control.
    Charlotte Gineste, Sonia Youhanna, Sabine U Vorrink, Sara Henriksson, Andrés Hernández, Arthur J Cheng, Thomas Chaillou, Andreas Buttgereit, Dominik Schneidereit, Oliver Friedrich, Kjell Hultenby, Joseph D Bruton, Niklas Ivarsson, Linda Sandblad, Volker M Lauschke, Håkan Westerblad.
      Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. By comparing adult mouse skeletal muscle fibers, isolated either by mechanical dissection or by collagenase-induced ECM digestion, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling. RNA-sequencing showed striking differences in gene expression patterns between the two isolation methods with enzymatically dissociated fibers resembling myopathic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria following enzymatic dissociation. Repeated contractions resulted in a prolonged mitochondrial Ca2+ accumulation in enzymatically dissociated fibers, which was partially prevented by cyclophilin inhibitors. Of importance, muscle fibers of mice with severe mitochondrial myopathy show pathognomonic mitochondrial Ca2+ accumulation during repeated contractions and this accumulation was concealed with enzymatic dissociation, making this an ambiguous method in studies of native intracellular Ca2+ fluxes.
    Keywords:  Cell biology; Cellular physiology; Developmental biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105654
  24. iScience. 2022 Dec 22. 25(12): 105573
    Mitochondrial succinate dehydrogenase function is essential for sperm motility and male fertility.
    Rachel M Woodhouse, Natalya Frolows, Guoqiang Wang, Azelle Hawdon, Edmund Heng Kin Wong, Linda C Dansereau, Yingying Su, Liam D Adair, Elizabeth J New, Ashleigh M Philp, Wei Kang Tan, Andrew Philp, Alyson Ashe.
      Mitochondrial health is crucial to sperm quality and male fertility, but the precise role of mitochondria in sperm function remains unclear. SDHA is a component of the succinate dehydrogenase (SDH) complex and plays a critical role in mitochondria. In humans, SDH activity is positively correlated with sperm quality, and mutations in SDHA are associated with Leigh Syndrome. Here we report that the C. elegans SDHA orthologue SDHA-2 is essential for male fertility: sdha-2 mutants produce dramatically fewer offspring due to defective sperm activation and motility, have hyperfused sperm mitochondria, and disrupted redox balance. Similar sperm motility defects in sdha-1 and icl-1 mutant animals suggest an imbalance in metabolites may underlie the fertility defect. Our results demonstrate a role for SDHA-2 in sperm motility and male reproductive health and establish an animal model of SDH deficiency-associated infertility.
    Keywords:  Biological sciences; biochemistry; cell biology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105573
  25. Mitochondrion. 2022 Nov 30. pii: S1567-7249(22)00104-0. [Epub ahead of print]68 87-104
    Analysis of compound heterozygous and homozygous mutations found in peripheral subunits of human respiratory Complex I, NDUFS1, NDUFS2, NDUFS8 and NDUFV1, by modeling in the E. coli enzyme.
    Hind A Alkhaldi, Steven B Vik.
      Respiratory Complex I (NADH:ubiquinone oxidoreductase) is composed of 45 subunits, seven mitochondrially-encoded and 38 imported. Mutations in the nuclearly-encoded subunits have been regularly discovered in humans in recent years, and many lead to cardiomyopathy, Leigh Syndrome, and early death. From the literature, we have identified mutations at 17 different sites and constructed 31 mutants in a bacterial model system. Many of these mutations, found in NDUFS1, NDUFS2, NDUFS8, and NDUFV1, map to subunit interfaces, and we hypothesized that they would disrupt assembly of Complex I. The mutations were constructed in the homologous E. coli genes, nuoG, nuoCD, nuoI and nuoF, respectively, and expressed from a plasmid containing all Complex I genes. Membrane vesicles were prepared and rates of deamino-NADH oxidase activity measured, which indicated a range of reduced activity. Some mutants were also analyzed using recently developed assays of assembly, time-delayed expression, and co-immunoprecipitation, which showed that assembly was disrupted. With compound heterozygotes, we determined which mutation was more deleterious. Construction of alanine mutations allowed us to distinguish between phenotypes that were caused by loss of the original amino acid or introduction of the mutant residue.
    Keywords:  Bioenergetics; Cardiomyopathy; Complex I; Mitochondria; Mutations; NADH dehydrogenase
    DOI:  https://doi.org/10.1016/j.mito.2022.11.007
  26. Hear Res. 2022 Nov 24. pii: S0378-5955(22)00227-1. [Epub ahead of print]427 108659
    The roles of NADPH and isocitrate dehydrogenase in cochlear mitochondrial antioxidant defense and aging.
    Karessa White, Shinichi Someya.
      Hearing loss is the third most prevalent chronic health condition affecting older adults. Age-related hearing loss affects one in three adults over 65 years of age and is caused by both extrinsic and intrinsic factors, including genetics, aging, and exposure to noise and toxins. All cells possess antioxidant defense systems that play an important role in protecting cells against these factors. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) serves as a co-factor for antioxidant enzymes such as glutathione reductase and thioredoxin reductase and is produced by glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, isocitrate dehydrogenase 1 (IDH1) or malic enzyme 1 in the cytosol, while in the mitochondria, NADPH is generated from mitochondrial transhydrogenase, glutamate dehydrogenase, malic enzyme 3 or IDH2. There are three isoforms of IDH: cytosolic IDH1, and mitochondrial IDH2 and IDH3. Of these, IDH2 is thought to be the major supplier of NADPH to the mitochondrial antioxidant defense system. The NADP+/NADPH and NAD+/NADH couples are essential for maintaining a large array of biological processes, including cellular redox state, and energy metabolism, mitochondrial function. A growing body of evidence indicates that mitochondrial dysfunction contributes to age-related structural or functional changes of cochlear sensory hair cells and neurons, leading to hearing impairments. In this review, we describe the current understanding of the roles of NADPH and IDHs in cochlear mitochondrial antioxidant defense and aging.
    Keywords:  antioxidant defense; cochlea; inner ear; isocitrate dehydrogenase; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.heares.2022.108659
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