bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–06–25
twenty-one papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Metabolic inflexibility and unusual catabolism in Leigh-like syndrome due to m.10191T>C.
  2. Invasive and noninvasive markers of human skeletal muscle mitochondrial function.
  3. Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.
  4. A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.
  5. Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
  6. The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy.
  7. The evolution of the mitochondrial disease diagnostic odyssey.
  8. Analysis of MT-ATP8 gene variants reported in patients by modeling in silico and in yeast model organism.
  9. Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
  10. Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.
  11. PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
  12. Structural basis for the binding of DNP and purine nucleotides onto UCP1.
  13. Abnormal energy metabolism in ALS: a key player?
  14. Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.
  15. NAD+ Precursors in Human Health and Disease: Current Status and Future Prospects.
  16. Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells.
  17. FDA grants accelerated approval to first gene therapy for Duchenne muscular dystrophy, despite internal objections.
  18. Structural basis of mitochondrial protein import by the TIM23 complex.
  19. Generation of Human Blastoids from Naive Pluripotent Stem Cells.
  20. Human stem cells turned into detailed lab replicas of embryos.
  21. Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.
  1. Clin Nutr ESPEN. 2023 08;pii: S2405-4577(23)00131-6. [Epub ahead of print]56 149-151
    Metabolic inflexibility and unusual catabolism in Leigh-like syndrome due to m.10191T>C.
    Shaundra M Newstead, Josef Finsterer.
       BACKGROUND AND AIMS: Hypercatabolism is a well-known feature of mitochondrial diseases but some patients may present with hypometabolism, as the following case.
    METHODS: Case report using standard investigation methods.
    RESULTS: The patient is a 32 years-old female with a Leigh-like syndrome due to the mtDNA variant m.10191 T > C in MT-ND3. Leigh-like syndrome is characterized by symmetric basal ganglia or brainstem lesions plus involvement of organs other than the brain. The patient presented with hypometabolism, which did not respond to ketogenic diet but responded to fasting. The patient showed a Warburg-like effect, which resulted in reliance on glucose due to the exclusion of oxidative phosphorylation with an extremely low VO2max. The patient only entered substantial ketosis when all gluconeogenic substrates were removed. Prolonged survival in the index patient may have possibly resulted from this previously unreported protective mechanism to reduce oxidative stress. The unusual Warburg-like phenomenon was interpreted as a possible mechanism of patients with a mitochondrial disease to survive into adulthood.
    CONCLUSIONS: This case shows that mitochondrial disease can manifest with hypometabolism and that an unusual Warburg-like effect may be responsible in some patients with mitochondrial disease to survive into adulthood.
    Keywords:  Ketogenic diet; Leigh-like syndrome; Mitochondrial disease; Respiratory chain; Warburg effect
    DOI:  https://doi.org/10.1016/j.clnesp.2023.05.007
  2. Physiol Rep. 2023 06;11(12): e15734
    Invasive and noninvasive markers of human skeletal muscle mitochondrial function.
    Rodrigo Mancilla, Diego Pava-Mejia, Nynke van Polanen, Vera de Wit, Maaike Bergman, Lotte Grevendonk, Johanna Jorgensen, Esther Kornips, Joris Hoeks, Matthijs K C Hesselink, Vera B Schrauwen-Hinderling.
      Mitochondria are organelles that fuel cellular energy requirements by ATP formation via aerobic metabolism. Given the wide variety of methods to assess skeletal muscle mitochondrial capacity, we tested how well different invasive and noninvasive markers of skeletal muscle mitochondrial capacity reflect mitochondrial respiration in permeabilized muscle fibers. Nineteen young men (mean age: 24 ± 4 years) were recruited, and a muscle biopsy was collected to determine mitochondrial respiration from permeabilized muscle fibers and to quantify markers of mitochondrial capacity, content such as citrate synthase (CS) activity, mitochondrial DNA copy number, TOMM20, VDAC, and protein content for complex I-V of the oxidative phosphorylation (OXPHOS) system. Additionally, all participants underwent noninvasive assessments of mitochondrial capacity: PCr recovery postexercise (by 31 P-MRS), maximal aerobic capacity, and gross exercise efficiency by cycling exercise. From the invasive markers, Complex V protein content and CS activity showed the strongest concordance (Rc = 0.50 to 0.72) with ADP-stimulated coupled mitochondrial respiration, fueled by various substrates. Complex V protein content showed the strongest concordance (Rc = 0.72) with maximally uncoupled mitochondrial respiration. From the noninvasive markers, gross exercise efficiency, VO2max , and PCr recovery exhibited concordance values between 0.50 and 0.77 with ADP-stimulated coupled mitochondrial respiration. Gross exercise efficiency showed the strongest concordance with maximally uncoupled mitochondrial respiration (Rc = 0.67). From the invasive markers, Complex V protein content and CS activity are surrogates that best reflect skeletal muscle mitochondrial respiratory capacity. From the noninvasive markers, exercise efficiency and PCr recovery postexercise most closely reflect skeletal muscle mitochondrial respiratory capacity.
    Keywords:  human skeletal muscle; mitochondrial function; skeletal muscle mitochondrial respiration
    DOI:  https://doi.org/10.14814/phy2.15734
  3. Nat Commun. 2023 Jun 22. 14(1): 3716
    Mitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response.
    Eunah Kim, Andrea Annibal, Yujin Lee, Hae-Eun H Park, Seokjin Ham, Dae-Eun Jeong, Younghun Kim, Sangsoon Park, Sujeong Kwon, Yoonji Jung, JiSoo Park, Sieun S Kim, Adam Antebi, Seung-Jae V Lee.
      Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.
    DOI:  https://doi.org/10.1038/s41467-023-39393-6
  4. Diabetes. 2023 Jun 21. pii: db220728. [Epub ahead of print]
    A DEFECT IN MITOCHONDRIAL COMPLEX III BUT NOT IN COMPLEXES I OR IV CAUSES EARLY BETA CELL DYSFUNCTION AND HYPERGLYCEMIA IN MICE.
    Anna L Lang, Nadee Nissanka, Ruy A Louzada, Alejandro Tamayo, Elizabeth Pereira, Carlos T Moraes, Alejandro Caicedo.
      Mitochondrial metabolism and oxidative respiration are crucial for pancreatic beta cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to beta cell function is unknown. We generated beta cell specific, inducible OxPhos complex KO mouse models to investigate the effects of disrupting Complex I, Complex III, or Complex IV on beta cell function. Although all KO models had similar mitochondrial respiratory defects, Complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted depending on the complex targeted, supporting the unique roles of each complex in beta cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from Complex III KO, but not from Complex I or IV KO mice, indicating that severe diabetic phenotype in the Complex III deficient mice is causing alterations in cellular redox status. The current study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes.
    DOI:  https://doi.org/10.2337/db22-0728
  5. Cell Mol Life Sci. 2023 Jun 20. 80(7): 183
    Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.
    Lijun Chi, Dorothy Lee, Sharon Leung, Guanlan Hu, Bijun Wen, Paul Delgado-Olguin, Miluska Vissa, Ren Li, John H Brumell, Peter K Kim, Robert H J Bandsma.
      Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.
    Keywords:  Fenofibrate; Malnutrition; Metabolism; Mitophagy; Nuclear hormone receptor; mTOR
    DOI:  https://doi.org/10.1007/s00018-023-04827-3
  6. J Periodontal Res. 2023 Jun 18.
    The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy.
    Wentao Jiang, Yujing Wang, Zelin Cao, Yifan Chen, Chenli Si, Xiaoyu Sun, Shengbin Huang.
      Periodontitis is an inflammatory and destructive disease of tooth-supporting tissue and has become the leading cause of adult tooth loss. The most central pathological features of periodontitis are tissue damage and inflammatory reaction. As the energy metabolism center of eukaryotic cells, mitochondrion plays a notable role in various processes, such as cell function and inflammatory response. When the intracellular homeostasis of mitochondrion is disrupted, it can lead to mitochondrial dysfunction and inability to generate adequate energy to maintain basic cellular biochemical reactions. Recent studies have revealed that mitochondrial dysfunction is closely related to the initiation and development of periodontitis. The excessive production of mitochondrial reactive oxygen species, imbalance of mitochondrial biogenesis and dynamics, mitophagy and mitochondrial DNA damage can all affect the development and progression of periodontitis. Thus, targeted mitochondrial therapy is potentially promising in periodontitis treatment. In this review, we summarize the above mitochondrial mechanism in the pathogenesis of periodontitis and discuss some potential approaches that can exert therapeutic effects on periodontitis by modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in periodontitis might provide new research directions for pathological intervention or treatment of periodontitis.
    Keywords:  mitochondrial DNA; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial oxidative stress; mitophagy; periodontitis; therapy
    DOI:  https://doi.org/10.1111/jre.13152
  7. Orphanet J Rare Dis. 2023 Jun 22. 18(1): 157
    The evolution of the mitochondrial disease diagnostic odyssey.
    John L P Thompson, Amel Karaa, Hung Pham, Philip Yeske, Jeffrey Krischer, Yi Xiao, Yuelin Long, Amanda Kramer, David Dimmock, Amy Holbert, Cliff Gorski, Kristin M Engelstad, Richard Buchsbaum, Xiomara Q Rosales, Michio Hirano.
       BACKGROUND: Mitochondrial diseases often require multiple years and clinicians to diagnose. We lack knowledge of the stages of this diagnostic odyssey, and factors that affect it. Our goals are to report the results of the 2018 Odyssey2 (OD2) survey of patients with a medical diagnosis of mitochondrial disease; and to propose steps to reduce the odyssey going forward, and procedures to evaluate them.
    METHODS: Data are from the NIH-funded NAMDC-RDCRN-UMDF OD2 survey (N = 215). The main outcomes are Time from symptom Onset to mitochondrial disease Diagnosis (TOD) and Number of Doctors Seen during this diagnostic process (NDOCS).
    RESULTS: Expert recoding increased analyzable responses by 34% for final mitochondrial diagnosis and 39% for prior non-mitochondrial diagnosis. Only one of 122 patients who initially saw a primary care physician (PCP) received a mitochondrial diagnosis, compared to 26 of 86 (30%) who initially saw a specialist (p < 0.001). Mean TOD overall was 9.9 ± 13.0 years, and mean NDOCS 6.7 ± 5.2. Mitochondrial diagnosis brings extensive benefits through treatment changes and increased membership in and support of advocacy groups.
    CONCLUSIONS: Because TOD is long and NDOCS high, there is great potential for shortening the mitochondrial odyssey. Although prompt patient contact with primary mitochondrial disease specialists, or early implementation of appropriate tests, may shorten the diagnostic odyssey, specific proposals for improvement require testing and confirmation with adequately complete, unbiased data across all its stages, and appropriate methods. Electronic Health Record (EHRs) may help by accessing diagnostic codes early, but their reliability and diagnostic utility have not been established for this group of diseases.
    DOI:  https://doi.org/10.1186/s13023-023-02754-x
  8. Sci Rep. 2023 Jun 20. 13(1): 9972
    Analysis of MT-ATP8 gene variants reported in patients by modeling in silico and in yeast model organism.
    Chiranjit Panja, Katarzyna Niedzwiecka, Emilia Baranowska, Jaroslaw Poznanski, Roza Kucharczyk.
      Defects in ATP synthase functioning due to the substitutions in its two mitochondrially encoded subunits a and 8 lead to untreatable mitochondrial diseases. Defining the character of variants in genes encoding these subunits is challenging due to their low frequency, heteroplasmy of mitochondrial DNA in patients' cells and polymorphisms of mitochondrial genome. We successfully used yeast S. cerevisiae as a model to study the effects of variants in MT-ATP6 gene and our research led to understand how eight amino acid residues substitutions impact the proton translocation through the channel formed by subunit a and c-ring of ATP synthase at the molecular level. Here we applied this approach to study the effects of the m.8403T>C variant in MT-ATP8 gene. The biochemical data from yeast mitochondria indicate that equivalent mutation is not detrimental for the yeast enzyme functioning. The structural analysis of substitutions in subunit 8 introduced by m.8403T>C and five other variants in MT-ATP8 provides indications about the role of subunit 8 in the membrane domain of ATP synthase and potential structural consequences of substitutions in this subunit.
    DOI:  https://doi.org/10.1038/s41598-023-36637-9
  9. Science. 2023 Jun 23. 380(6651): eadh9351
    Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.
    Déborah Naón, María Isabel Hernández-Alvarez, Satoko Shinjo, Milosz Wieczor, Saska Ivanova, Olga Martins de Brito, Albert Quintana, Juan Hidalgo, Manuel Palacín, Pilar Aparicio, Juan Castellanos, Luis Lores, David Sebastián, Sonia Fernández-Veledo, Joan Vendrell, Jorge Joven, Modesto Orozco, Antonio Zorzano, Luca Scorrano.
      In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities.
    DOI:  https://doi.org/10.1126/science.adh9351
  10. Nat Commun. 2023 Jun 23. 14(1): 3746
    Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice.
    Anna Park, Kwang-Eun Kim, Isaac Park, Sang Heon Lee, Kun-Young Park, Minkyo Jung, Xiaoxu Li, Maroun Bou Sleiman, Su Jeong Lee, Dae-Soo Kim, Jaehoon Kim, Dae-Sik Lim, Eui-Jeon Woo, Eun Woo Lee, Baek Soo Han, Kyoung-Jin Oh, Sang Chul Lee, Johan Auwerx, Ji Young Mun, Hyun-Woo Rhee, Won Kon Kim, Kwang-Hee Bae, Jae Myoung Suh.
      Brown adipose tissue (BAT) has abundant mitochondria with the unique capability of generating heat via uncoupled respiration. Mitochondrial uncoupling protein 1 (UCP1) is activated in BAT during cold stress and dissipates mitochondrial proton motive force generated by the electron transport chain to generate heat. However, other mitochondrial factors required for brown adipocyte respiration and thermogenesis under cold stress are largely unknown. Here, we show LETM1 domain-containing protein 1 (LETMD1) is a BAT-enriched and cold-induced protein required for cold-stimulated respiration and thermogenesis of BAT. Proximity labeling studies reveal that LETMD1 is a mitochondrial matrix protein. Letmd1 knockout male mice display aberrant BAT mitochondria and fail to carry out adaptive thermogenesis under cold stress. Letmd1 knockout BAT is deficient in oxidative phosphorylation (OXPHOS) complex proteins and has impaired mitochondrial respiration. In addition, BAT-specific Letmd1 deficient mice exhibit phenotypes identical to those observed in Letmd1 knockout mice. Collectively, we demonstrate that the BAT-enriched mitochondrial matrix protein LETMD1 plays a tissue-autonomous role that is essential for BAT mitochondrial function and thermogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-39106-z
  11. EMBO Rep. 2023 Jun 19. e56399
    PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems.
    Felix Kraus, Ellen A Goodall, Ian R Smith, Yizhi Jiang, Julia C Paoli, Frank Adolf, Jiuchun Zhang, Joao A Paulo, Brenda A Schulman, J Wade Harper.
      The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving ubiquitin (Ub) phosphorylation (pUb), Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins to support the recruitment of mitophagy receptors. The ubiquitin ligase substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed a role for FBXO7 in promoting Parkin-dependent mitophagy. Here, we systematically examine the involvement of FBXO7 in depolarization and mt UPR-dependent mitophagy in the well-established HeLa and induced-neurons cell systems. We find that FBXO7-/- cells have no demonstrable defect in: (i) kinetics of pUb accumulation, (ii) pUb puncta on mitochondria by super-resolution imaging, (iii) recruitment of Parkin and autophagy machinery to damaged mitochondria, (iv) mitophagic flux, and (v) mitochondrial clearance as quantified by global proteomics. Moreover, global proteomics of neurogenesis in the absence of FBXO7 reveals no obvious alterations in mitochondria or other organelles. These results argue against a general role for FBXO7 in Parkin-dependent mitophagy and point to the need for additional studies to define how FBXO7 mutations promote parkinsonian-pyramidal syndrome.
    Keywords:  FBXO7; iNeurons; mitophagy; proteomics; ubiquitin ligase
    DOI:  https://doi.org/10.15252/embr.202256399
  12. Nature. 2023 Jun 19.
    Structural basis for the binding of DNP and purine nucleotides onto UCP1.
    Yunlu Kang, Lei Chen.
      Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat1,2. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP3-5. However, the mechanism by which UCP1 binds these ligands remains elusive. Here, we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state, and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with TM2 and TM6. ATP also binds inside the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5, and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.
    DOI:  https://doi.org/10.1038/s41586-023-06332-w
  13. Curr Opin Neurol. 2023 Jun 20.
    Abnormal energy metabolism in ALS: a key player?
    Thibaut Burg, Ludo Van Den Bosch.
       PURPOSE OF THE REVIEW: Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease of the motor system due to the selective and progressive degeneration of both upper and lower motor neurons. Disturbances in energy homeostasis were repeatedly associated with the ALS pathogenesis and appear early during the disease process. In this review, we highlight recent work demonstrating the crucial role of energy metabolism in ALS and discuss its potential clinical relevance.
    RECENT FINDINGS: The alteration of various metabolic pathways contributes to the heterogeneity of the clinical phenotype of ALS. Recent work showed that different ALS mutations selectively impact these pathways and translate to the disease phenotypes in patients and disease models. Strikingly, a growing number of studies point towards an early, even presymptomatic, contribution of abnormal energy homeostasis to the ALS pathogenesis. Advances in metabolomics generated valuable tools to study altered metabolic pathways, to test their therapeutic potential, and to develop personalized medicine. Importantly, recent preclinical studies and clinical trials demonstrated that targeting energy metabolism is a promising therapeutic approach.
    SUMMARY: Abnormal energy metabolism is a key player in ALS pathogenesis, emerging as a source of potential disease biomarkers and therapeutic targets.
    DOI:  https://doi.org/10.1097/WCO.0000000000001164
  14. Cell. 2023 Jun 19. pii: S0092-8674(23)00591-3. [Epub ahead of print]
    Cooperative sensing of mitochondrial DNA by ZBP1 and cGAS promotes cardiotoxicity.
    Yuanjiu Lei, Jordyn J VanPortfliet, Yi-Fan Chen, Joshua D Bryant, Ying Li, Danielle Fails, Sylvia Torres-Odio, Katherine B Ragan, Jingti Deng, Armaan Mohan, Bing Wang, Olivia N Brahms, Shawn D Yates, Michael Spencer, Carl W Tong, Marcus W Bosenberg, Laura Ciaccia West, Gerald S Shadel, Timothy E Shutt, Jason W Upton, Pingwei Li, A Phillip West.
      Mitochondrial DNA (mtDNA) is a potent agonist of the innate immune system; however, the exact immunostimulatory features of mtDNA and the kinetics of detection by cytosolic nucleic acid sensors remain poorly defined. Here, we show that mitochondrial genome instability promotes Z-form DNA accumulation. Z-DNA binding protein 1 (ZBP1) stabilizes Z-form mtDNA and nucleates a cytosolic complex containing cGAS, RIPK1, and RIPK3 to sustain STAT1 phosphorylation and type I interferon (IFN-I) signaling. Elevated Z-form mtDNA, ZBP1 expression, and IFN-I signaling are observed in cardiomyocytes after exposure to Doxorubicin, a first-line chemotherapeutic agent that induces frequent cardiotoxicity in cancer patients. Strikingly, mice lacking ZBP1 or IFN-I signaling are protected from Doxorubicin-induced cardiotoxicity. Our findings reveal ZBP1 as a cooperative partner for cGAS that sustains IFN-I responses to mitochondrial genome instability and highlight ZBP1 as a potential target in heart failure and other disorders where mtDNA stress contributes to interferon-related pathology.
    Keywords:  STING; Z-DNA; ZBP1; cGAS; cardiotoxicity; heart failure; mitochondrial DNA; type I interferon
    DOI:  https://doi.org/10.1016/j.cell.2023.05.039
  15. Antioxid Redox Signal. 2023 Jun 19.
    NAD+ Precursors in Human Health and Disease: Current Status and Future Prospects.
    Keisuke Yaku, Takashi Nakagawa.
       SIGNIFICANCE: Nicotinamide adenine dinucleotide (NAD+) acts as a cofactor in many important biological processes. The administration of NAD+ precursors increases the intracellular NAD+ pool and has beneficial effects on physiological changes and diseases associated with aging in various organisms, including rodents and humans.
    RECENT ADVANCES: Evidence from pre-clinical studies demonstrating the beneficial effects of NAD+ precursors has rapidly increased in the last decade. The results of these studies have prompted the development of clinical trials using NAD+ precursors, particularly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Additionally, in vivo studies of NAD+ metabolism have rapidly progressed. Critical issue: Several studies have demonstrated that the oral administration of NAD+ precursors, such as NR and NMN, is safe and significantly increases NAD+ levels in humans. However, the efficacy of these NAD+ precursors is lower than expected from the results of pre-clinical studies. In addition, the identification of the contribution of the host-gut microbiota interactions to NR and NMN metabolism has added to the complexity of NAD+ metabolism.
    FUTURE DIRECTIONS: Further studies are required to determine the efficacy of NAD+ precursors in humans. Further in vivo studies of NAD+ metabolism are required to optimize the effects of NAD+ supplementation. There is also a need for methods of delivering NAD+ precursors to target organs or tissues to increase the outcomes of clinical trials.
    DOI:  https://doi.org/10.1089/ars.2023.0354
  16. Theranostics. 2023 ;13(10): 3165-3187
    Mitochondrial supercomplex assembly regulates metabolic features and glutamine dependency in mammalian cells.
    Kun Zhang, Linjie Chen, Bo Wang, Deyu Chen, Xianglai Ye, Xinyu Han, Quan Fang, Can Yu, Jia Wu, Sihan Guo, Lifang Chen, Yu Shi, Lan Wang, Huang Cheng, Hao Li, Lu Shen, Qiongya Zhao, Liqin Jin, Jianxin Lyu, Hezhi Fang.
      Rationale: Mitochondria generate ATP via the oxidative phosphorylation system, which mainly comprises five respiratory complexes found in the inner mitochondrial membrane. A high-order assembly of respiratory complexes is called a supercomplex. COX7A2L is a supercomplex assembly factor that has been well-investigated for studying supercomplex function and assembly. To date, the effects of mitochondrial supercomplexes on cell metabolism have not been elucidated. Methods: We depleted COX7A2L or Cox7a2l in human and mouse cells to generate cell models lacking mitochondrial supercomplexes as well as in DBA/2J mice as animal models. We tested the effect of impaired supercomplex assembly on cell proliferation with different nutrient supply. We profiled the metabolic features in COX7A2L-/- cells and Cox7a2l-/- mice via the combined use of targeted and untargeted metabolic profiling and metabolic flux analysis. We further tested the role of mitochondrial supercomplexes in pancreatic ductal adenocarcinoma (PDAC) through PDAC cell lines and a nude mouse model. Results: Impairing mitochondrial supercomplex assembly by depleting COX7A2L in human cells reprogrammed metabolic pathways toward anabolism and increased glutamine metabolism, cell proliferation and antioxidative defense. Similarly, knockout of Cox7a2l in DBA/2J mice promoted the use of proteins/amino acids as oxidative carbon sources. Mechanistically, impaired supercomplex assembly increased electron flux from CII to CIII/CIV and promoted CII-dependent respiration in COX7A2L-/- cells which further upregulated glutaminolysis and glutamine oxidation to accelerate the reactions of the tricarboxylic acid cycle. Moreover, the proliferation of PDAC cells lacking COX7A2L was inhibited by glutamine deprivation. Conclusion: Our results reveal the regulatory role of mitochondrial supercomplexes in glutaminolysis which may fine-tune the fate of cells with different nutrient availability.
    Keywords:  COX7A2L; PDAC; SCAF1; metabolism; mitochondrial supercomplex
    DOI:  https://doi.org/10.7150/thno.78292
  17. Nat Rev Drug Discov. 2023 Jun 23.
    FDA grants accelerated approval to first gene therapy for Duchenne muscular dystrophy, despite internal objections.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-023-00103-y
  18. Nature. 2023 Jun 21.
    Structural basis of mitochondrial protein import by the TIM23 complex.
    Sue Im Sim, Yuanyuan Chen, Diane L Lynch, James C Gumbart, Eunyong Park.
      Mitochondria import nearly all of their approximately 1,000-2,000 constituent proteins from the cytosol across their double-membrane envelope1-5. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM23 complex, mediates import of presequence-containing proteins (preproteins) into the mitochondrial matrix and inner membrane. Among about ten different subunits of the TIM23 complex, the essential multipass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel6-11. However, the mechanism by which these subunits form a translocation path in the membrane and enable the import process remains unclear due to a lack of structural information. Here we determined the cryo-electron microscopy structure of the core TIM23 complex (heterotrimeric Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. Contrary to the prevailing model, Tim23 and Tim17 themselves do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Our structural and biochemical analyses show that the cavity of Tim17, but not Tim23, forms the protein translocation path, whereas Tim23 probably has a structural role. The results further suggest that, during translocation of substrate polypeptides, the nonessential subunit Mgr2 seals the lateral opening of the Tim17 cavity to facilitate the translocation process. We propose a new model for the TIM23-mediated protein import and sorting mechanism, a central pathway in mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s41586-023-06239-6
  19. Methods Mol Biol. 2023 Jun 24.
    Generation of Human Blastoids from Naive Pluripotent Stem Cells.
    Yulei Wei, Kun Liu, Carlos A Pinzon-Arteaga, Deirdre Logsdon, Leqian Yu, Ye Yuan, Jun Wu.
      Under certain culture conditions, naive human pluripotent stem cells can generate human blastocyst-like structures (called human blastoids). Human blastoids serve as an accessible model for human blastocysts and are amenable for large-scale production. Here, we describe a detailed step-by-step protocol for the robust and high-efficient generation of human blastoids from naive human pluripotent stem cells.
    Keywords:  Human blastoids; Human extraembryonic cell types; Human implantation model; Hypoblast cells; Integrated models of human embryos; Naive human pluripotent stem cells; The generation of blastocyst-like structures; Trophoblast cells
    DOI:  https://doi.org/10.1007/7651_2023_485
  20. Science. 2023 Jun 23. 380(6651): 1206-1207
    Human stem cells turned into detailed lab replicas of embryos.
    Mitch Leslie.
      Mock embryos created by multiple groups recapitulate developmental events beyond implantation.
    DOI:  https://doi.org/10.1126/science.adj3373
  21. Ann Clin Transl Neurol. 2023 Jun 23.
    Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.
    Duchenne Muscular Dystrophy Pilot Study Group
       OBJECTIVE: Duchenne muscular dystrophy (DMD) is an X-linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre-symptomatic diagnosis.
    METHODS: At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first-tier screen measured creatine kinase-MM (CK-MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK-MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next-generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene.
    RESULTS: In the two-year pilot study, 36,781 newborns were screened with CK-MM. Forty-two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified.
    INTERPRETATION: This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.
    DOI:  https://doi.org/10.1002/acn3.51829
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