bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–06–26
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes.
  2. Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective.
  3. Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.
  4. Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant.
  5. Mitochondria transplantation/transfer between single cells.
  6. Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.
  7. Disease causing mutation (P178L) in mitochondrial transcription factor A results in impaired mitochondrial transcription initiation.
  8. Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.
  9. The doxycycline paradox in primary mitochondrial diseases.
  10. Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy.
  11. Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle.
  12. The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.
  13. Coordination of metal center biogenesis in human cytochrome c oxidase.
  14. A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome.
  15. Shaping fuel utilization by mitochondria.
  16. Clinical and genetic spectrum of Mitochondrial DNA depletion syndromes: a report of 6 cases with 4 novel variants.
  17. TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.
  18. Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S-adenosylmethionine, and related diseases: A review†.
  19. Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress.
  20. Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration.
  21. Unraveling mitochondrial piRNAs in mouse embryonic gonadal cells.
  22. Is Drp1 sufficient to catalyze membrane fission?
  23. Protocol for engineering and validating a synthetic mitochondrial intermembrane bridge in mammalian cells.
  24. PGC-1α-Mediated Mitochondrial Quality Control: Molecular Mechanisms and Implications for Heart Failure.
  25. Fission Impossible (?)-New Insights into Disorders of Peroxisome Dynamics.
  26. Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming.
  27. Immunomodulatory role of mitochondrial damps: A missing link in pathology?
  28. Methodology for measuring oxidative capacity of isolated peroxisomes in the Seahorse assay.
  29. Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases.
  1. Membranes (Basel). 2022 Jun 15. pii: 625. [Epub ahead of print]12(6):
    Mitochondrial Membranes and Mitochondrial Genome: Interactions and Clinical Syndromes.
    Mohammed Almannai, Azza Salah, Ayman W El-Hattab.
      Mitochondria are surrounded by two membranes; the outer mitochondrial membrane and the inner mitochondrial membrane. They are unique organelles since they have their own DNA, the mitochondrial DNA (mtDNA), which is replicated continuously. Mitochondrial membranes have direct interaction with mtDNA and are therefore involved in organization of the mitochondrial genome. They also play essential roles in mitochondrial dynamics and the supply of nucleotides for mtDNA synthesis. In this review, we will discuss how the mitochondrial membranes interact with mtDNA and how this interaction is essential for mtDNA maintenance. We will review different mtDNA maintenance disorders that result from defects in this crucial interaction. Finally, we will review therapeutic approaches relevant to defects in mitochondrial membranes.
    Keywords:  IMM; OMM; fission; fusion; mitochondria; mtDNA
    DOI:  https://doi.org/10.3390/membranes12060625
  2. Pharmaceutics. 2022 Jun 17. pii: 1287. [Epub ahead of print]14(6):
    Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective.
    Alessia Di Donfrancesco, Giulia Massaro, Ivano Di Meo, Valeria Tiranti, Emanuela Bottani, Dario Brunetti.
      Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field.
    Keywords:  gene therapy; mitochondria; mitochondrial DNA; mitochondrial disease; precision medicine
    DOI:  https://doi.org/10.3390/pharmaceutics14061287
  3. Commun Biol. 2022 Jun 23. 5(1): 620
    Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit.
    David Molina-Granada, Emiliano González-Vioque, Marris G Dibley, Raquel Cabrera-Pérez, Antoni Vallbona-Garcia, Javier Torres-Torronteras, Leonid A Sazanov, Michael T Ryan, Yolanda Cámara, Ramon Martí.
      Imbalanced mitochondrial dNTP pools are known players in the pathogenesis of multiple human diseases. Here we show that, even under physiological conditions, dGTP is largely overrepresented among other dNTPs in mitochondria of mouse tissues and human cultured cells. In addition, a vast majority of mitochondrial dGTP is tightly bound to NDUFA10, an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFA10 shares a deoxyribonucleoside kinase (dNK) domain with deoxyribonucleoside kinases in the nucleotide salvage pathway, though no specific function beyond stabilizing the complex I holoenzyme has been described for this subunit. We mutated the dNK domain of NDUFA10 in human HEK-293T cells while preserving complex I assembly and activity. The NDUFA10E160A/R161A shows reduced dGTP binding capacity in vitro and leads to a 50% reduction in mitochondrial dGTP content, proving that most dGTP is directly bound to the dNK domain of NDUFA10. This interaction may represent a hitherto unknown mechanism regulating mitochondrial dNTP availability and linking oxidative metabolism to DNA maintenance.
    DOI:  https://doi.org/10.1038/s42003-022-03568-6
  4. Front Genet. 2022 ;13 887696
    Case Report: Optic Atrophy and Nephropathy With m.13513G>A/MT-ND5 mtDNA Pathogenic Variant.
    Valentina Barone, Chiara La Morgia, Leonardo Caporali, Claudio Fiorini, Michele Carbonelli, Laura Ludovica Gramegna, Fiorina Bartiromo, Caterina Tonon, Luca Morandi, Rocco Liguori, Aurelia Petrini, Rachele Brugnano, Rachele Del Sordo, Carla Covarelli, Manrico Morroni, Raffaele Lodi, Valerio Carelli.
      Isolated complex I deficiency represents the most common mitochondrial respiratory chain defect involved in mitochondrial disorders. Among these, the mitochondrial DNA (mtDNA) m.13513G>A pathogenic variant in the NADH dehydrogenase 5 subunit gene (MT-ND5) has been associated with heterogenous manifestations, including phenotypic overlaps of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, Leigh syndrome, and Leber's hereditary optic neuropathy (LHON). Interestingly, this specific mutation has been recently described in patients with adult-onset nephropathy. We, here, report the unique combination of LHON, nephropathy, sensorineural deafness, and subcortical and cerebellar atrophy in association with the m.13513G>A variant.
    Keywords:  LHON; MT-ND5; Mitochondrial nephropathy; cerebellum; m.13513G>A mutation
    DOI:  https://doi.org/10.3389/fgene.2022.887696
  5. J Cereb Blood Flow Metab. 2022 Jun 21. 271678X221109685
    Mitochondria transplantation/transfer between single cells.
    Qin Hu, Jianfei Lu, Xiaohua Zhang, Ran Liu, Shao-Hua Yang.
      Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al. reported a novel method for single cells mitochondria transplantation using "nanosyringe". This technique combines atomic force microscopy, optical microscopy, and nanofluidics that enable intra- and intercellular organelle micromanipulation and cell-to-cell mitochondria transplantation with up to 95% success rate. The transferred mitochondria fuse to the host mitochondrial network and donor mtDNA incorporate into the recipient mitochondrial genome. The nanosyringe technique provides a novel tool for future mitochondrial research to offer insight into mitochondrial replacement therapy for stroke and fundamental mitochondrial biology.
    Keywords:  Mitochondria; mitochondrial transfer; mitochondrial transplantation; nanosyringe; revitalization
    DOI:  https://doi.org/10.1177/0271678X221109685
  6. Trends Endocrinol Metab. 2022 Jun 17. pii: S1043-2760(22)00099-6. [Epub ahead of print]
    Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.
    Sotiria Tavoulari, Denis Lacabanne, Chancievan Thangaratnarajah, Edmund R S Kunji.
      Citrin deficiency is a pan-ethnic and highly prevalent mitochondrial disease with three different stages: neonatal intrahepatic cholestasis (NICCD), a relatively mild adaptation stage, and type II citrullinemia in adulthood (CTLN2). The cause is the absence or dysfunction of the calcium-regulated mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also called citrin, which imports glutamate into the mitochondrial matrix and exports aspartate to the cytosol. In citrin deficiency, these missing transport steps lead to impairment of the malate-aspartate shuttle, gluconeogenesis, amino acid homeostasis, and the urea cycle. In this review, we describe the geological spread and occurrence of citrin deficiency, the metabolic consequences and use our current knowledge of the structure to predict the impact of the known pathogenic mutations on the calcium-regulatory and transport mechanism of citrin.
    Keywords:  SLC25A12; SLC25A13; calcium regulation; mitochondrial carrier family; transport; urea cycle disorders
    DOI:  https://doi.org/10.1016/j.tem.2022.05.002
  7. Biochim Biophys Acta Mol Basis Dis. 2022 Jun 15. pii: S0925-4439(22)00138-7. [Epub ahead of print] 166467
    Disease causing mutation (P178L) in mitochondrial transcription factor A results in impaired mitochondrial transcription initiation.
    Majda Mehmedović, Martial Martucci, Henrik Spåhr, Layal Ishak, Anup Mishra, Maria Eugenia Sanchez-Sandoval, Carlos Pardo-Hernández, Bradley Peter, Siet M van den Wildenberg, Maria Falkenberg, Geraldine Farge.
      Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression, and packaging of mitochondrial DNA (mtDNA). Recently, a pathogenic homozygous variant in TFAM (P178L) has been associated with a severe mtDNA depletion syndrome leading to neonatal liver failure and early death. We have performed a biochemical characterization of the TFAM variant P178L in order to understand the molecular basis for the pathogenicity of this mutation. We observe no effects on DNA binding, and compaction of DNA is only mildly affected by the P178L amino acid change. Instead, the mutation severely impairs mtDNA transcription initiation at the mitochondrial heavy and light strand promoters. Molecular modeling suggests that the P178L mutation affects promoter sequence recognition and the interaction between TFAM and the tether helix of POLRMT, thus explaining transcription initiation deficiency.
    Keywords:  Disease causing mutation; Mitochondria; TFAM; Transcription initiation; mtDNA depletion
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166467
  8. Free Radic Biol Med. 2022 Jun 21. pii: S0891-5849(22)00460-9. [Epub ahead of print]
    Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress.
    Tingting Peng, Yinyin Xie, Hanqing Sheng, Cui Wang, Yajun Lian, Nanchang Xie.
      Mitochondrial quality control (MQC) mechanisms are a series of adaptive responses that ensure the relative stability of mitochondrial morphology, quantity, and quality to preserve cellular survival and function. While MQC mechanisms range from mitochondrial biogenesis and fusion/fission to mitophagy, mitochondrial-derived vesicles (MDVs) may represent an essential component of MQC. MDVs precede mitochondrial autophagy and serve as the first line of defense against oxidative stress by selectively transferring damaged mitochondrial substances to the lysosome for degradation. In fact, the function of MDVs is dependent on the cargo, the shuttle route, and the ultimate destination. Abnormal MDVs disrupt metabolite clearance and the immune response, predisposing to pathological conditions, including neurodegeneration, cardiovascular diseases, and cancers. Therefore, MDV regulation may be a potential therapeutic for the therapy of these diseases. In this review, we highlight recent advances in the study of MDVs and their misregulation in various diseases from the perspectives of formation, cargo selection, regulation, and transportation.
    Keywords:  Aging; Diseases; Mitochondria; Mitochondrial quality control; Mitochondrial-derived vesicle; Therapeutics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.233
  9. J Inherit Metab Dis. 2022 Jun 23.
    The doxycycline paradox in primary mitochondrial diseases.
    Tamas Kozicz, Shamima Rahman, Eva Morava.
      
    DOI:  https://doi.org/10.1002/jimd.12531
  10. BMB Rep. 2022 Jun 21. pii: 5590. [Epub ahead of print]
    Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy.
    Seunghee Lee, Sangguk Lee, Seon-Jin Lee, Su Wol Chung.
      MitoNEET, a mitochondrial outer membrane protein containing the Asn-Glu-Glu-Thr (NEET) sequence, controls the formation of intermitochondrial junctions and confers autophagy resistance. Moreover, mitoNEET as a mitochondrial substrate undergoes ubiquitination by activated Parkin during the initiation of mitophagy. Therefore, mitoNEET is linked to the regulation of autophagy and mitophagy. Mitophagy is the selective removal of the damaged or unnecessary mitochondria, which is crucial to sustaining mitochondrial quality control. In numerous human diseases, the accumulation of damaged mitochondria by impaired mitophagy has been observed. However, the therapeutic strategy targeting of mitoNEET as a mitophagy-enhancing mediator requires further research. Herein, we confirmed that mitophagy is indeed activated by mitoNEET inhibition. CCCP (carbonyl cyanide m-chlorophenyl hydrazone), which leads to mitochondrial depolarization, induces mitochondrial dysfunction and superoxide production. This, in turn, contributes to the induction of mitophagy; mitoNEET protein levels were initially increased before an increase in LC3-Ⅱ protein following CCCP treatment. Pharmacological inhibition of mitoNEET using mitoNEET Ligand-1 (NL-1) promoted accumulation of Pink1 and Parkin, which are mitophagy-associated proteins, and activation of mitochondria-lysosome crosstalk, in comparison to CCCP alone. Inhibition of mitoNEET using NL-1, or mitoNEET shRNA transfected into RAW264.7 cells, abrogated CCCP-induced ROS and mitochondrial cell death; additionally, it activated the expression of PGC-1α and SOD2, regulators of oxidative metabolism. In particular, the increase in PGC-1α, which is a major regulator of mitochondrial biogenesis, promotes mitochondrial quality control. These results indicated that mitoNEET is a potential therapeutic target in numerous human diseases to enhance mitophagy and protect cells by maintaining a network of healthy mitochondria.
  11. Nat Commun. 2022 Jun 23. 13(1): 3585
    Substrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle.
    Vasiliki Mavridou, Martin S King, Sotiria Tavoulari, Jonathan J Ruprecht, Shane M Palmer, Edmund R S Kunji.
      Mitochondrial ADP/ATP carriers import ADP into the mitochondrial matrix and export ATP to the cytosol to fuel cellular processes. Structures of the inhibited cytoplasmic- and matrix-open states have confirmed an alternating access transport mechanism, but the molecular details of substrate binding remain unresolved. Here, we evaluate the role of the solvent-exposed residues of the translocation pathway in the process of substrate binding. We identify the main binding site, comprising three positively charged and a set of aliphatic and aromatic residues, which bind ADP and ATP in both states. Additionally, there are two pairs of asparagine/arginine residues on opposite sides of this site that are involved in substrate binding in a state-dependent manner. Thus, the substrates are directed through a series of binding poses, inducing the conformational changes of the carrier that lead to their translocation. The properties of this site explain the electrogenic and reversible nature of adenine nucleotide transport.
    DOI:  https://doi.org/10.1038/s41467-022-31366-5
  12. Free Radic Biol Med. 2022 Jun 16. pii: S0891-5849(22)00238-6. [Epub ahead of print]
    The decylTPP mitochondria-targeting moiety lowers electron transport chain supercomplex levels in primary human skin fibroblasts.
    Elianne P Bulthuis, Claudia Einer, Felix Distelmaier, Laszlo Groh, Sjenet E van Emst-de Vries, Els van de Westerlo, Melissa van de Wal, Jori Wagenaars, Richard J Rodenburg, Jan A M Smeitink, Niels P Riksen, Peter H G M Willems, Merel J W Adjobo-Hermans, Hans Zischka, Werner J H Koopman.
      Attachment of cargo molecules to lipophilic triphenylphosphonium (TPP+) cations is a widely applied strategy for mitochondrial targeting. We previously demonstrated that the vitamin E-derived antioxidant Trolox increases the levels of active mitochondrial complex I (CI), the first complex of the electron transport chain (ETC), in primary human skin fibroblasts (PHSFs) of Leigh Syndrome (LS) patients with isolated CI deficiency. Primed by this finding, we here studied the cellular effects of mitochondria-targeted Trolox (MitoE10), mitochondria-targeted ubiquinone (MitoQ10) and their mitochondria-targeting moiety decylTPP (C10-TPP+). Chronic treatment (96 h) with these molecules of PHSFs from a healthy subject and an LS patient with isolated CI deficiency (NDUFS7-V122 M mutation) did not greatly affect cell number. Unexpectedly, this treatment reduced CI levels/activity, lowered the amount of ETC supercomplexes, inhibited mitochondrial oxygen consumption, increased extracellular acidification, altered mitochondrial morphology and stimulated hydroethidine oxidation. We conclude that the mitochondria-targeting decylTPP moiety is responsible for the observed effects and advocate that every study employing alkylTPP-mediated mitochondrial targeting should routinely include control experiments with the corresponding alkylTPP moiety.
    Keywords:  Complex I; Glycolysis; Mitochondrial targeting; Supercomplexes; Trolox; decylTPP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.011
  13. Nat Commun. 2022 Jun 24. 13(1): 3615
    Coordination of metal center biogenesis in human cytochrome c oxidase.
    Eva Nývltová, Jonathan V Dietz, Javier Seravalli, Oleh Khalimonchuk, Antoni Barrientos.
      Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa3-copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbors the CuB site that tightly associates with heme a3 while the COX2 subunit contains the binuclear CuA site. Here, we report that in human cells the CcO copper chaperones form macromolecular assemblies and cooperate with several twin CX9C proteins to control heme a biosynthesis and coordinate copper transfer sequentially to the CuA and CuB sites. These data on CcO illustrate a mechanism that regulates the biogenesis of macromolecular enzymatic assemblies with several catalytic metal redox centers and prevents the accumulation of cytotoxic reactive assembly intermediates.
    DOI:  https://doi.org/10.1038/s41467-022-31413-1
  14. J Hum Genet. 2022 Jun 21.
    A novel homozygous missense mutation in the FASTKD2 gene leads to Lennox-Gastaut syndrome.
    Tenghui Wu, Leilei Mao, Chen Chen, Fei Yin, Jing Peng.
      FASTKD2 encodes an RNA-binding protein, which is a key post-transcriptional regulator of mitochondrial gene expression. Mutations in FASTKD2 have recently been found in mitochondrial encephalomyopathy, which is characterized by a deficiency in mitochondrial function. To date, seven patients have been reported. Six patients were identified with nonsense or frameshift mutations in the FASTKD2 gene, and only one patient harbored a missense mutation and a nonsense mutation. Here, we identified a novel FASTKD2 homozygous mutation, c.911 T > C, in a patient diagnosed with Lennox-Gastaut syndrome. We observed that the expression of FASTKD2 and the levels of mitochondrial 16 S rRNA were lower in the patient than in the unaffected controls. In conclusion, the missense mutation c.911 T > C caused loss of function in FASTKD2, which was associated with a new phenotype, Lennox-Gastaut syndrome.
    DOI:  https://doi.org/10.1038/s10038-022-01056-7
  15. Curr Biol. 2022 Jun 20. pii: S0960-9822(22)00765-5. [Epub ahead of print]32(12): R618-R623
    Shaping fuel utilization by mitochondria.
    Lukas Alan, Luca Scorrano.
      Mitochondria are central to cellular metabolism. They provide intermediate metabolites that are used in biosynthetic pathways and they process diet-derived nutrients into the energy-rich compound ATP. Mitochondrial ATP biosynthesis is a marvel of thermodynamic efficiency. Via the tricarboxylic acid cycle (TCA) and fatty acid β-oxidation, mitochondria extract electrons from dietary carbon compounds and pass them to nucleotides that ultimately deliver them to the respiratory chain complexes located in invaginations in the inner mitochondrial membrane (IMM) known as cristae. The respiratory chain complexes donate electrons in stepwise redox reactions to molecular oxygen and, with the exception of complex II, use the liberated energy to pump protons across the proton-impermeable IMM, generating a proton electrochemical gradient. This gradient is then utilized by the ATP synthase, which, in a rotary mechanism, catalyzes the formation of the high-energy γ-phosphate chemical bond between ADP and inorganic phosphate. The conversion of the chemical energy of carbon compounds into a physical, vectorial form of energy (the electrochemical gradient) maximizes the yield of the ATP biosynthetic process and is perhaps one of the foundations of life as we know it.
    DOI:  https://doi.org/10.1016/j.cub.2022.05.006
  16. Mitochondrion. 2022 Jun 21. pii: S1567-7249(22)00052-6. [Epub ahead of print]
    Clinical and genetic spectrum of Mitochondrial DNA depletion syndromes: a report of 6 cases with 4 novel variants.
    Nihal Al Menabawy, Hebatallah M Hassaan, Manal Ramadan, Iman Ehsan Abdel Meguid, Hala Ahmed El Gindy, Christian Beetz, Laila Selim.
      Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a heterogeneous group of rare autosomal recessive genetic disorders characterized by a decrease in the number of mtDNA copies inside the organ involved. There are three distinct forms of MDS including the hepatocerebral, the myopathic and the encephalomyopathic forms. The diversity in the clinical and genetic spectrum of these disorders makes the diagnosis challenging. Here, we describe the clinical phenotype and the genetic spectrum of 6 patients with MDS including 4 novel variants and compare them with previously reported cases. Subject and Methods Six patients from six unrelated families were included in this study. All the patients were subjected to a detailed history, thorough general and neurologic examination, basic laboratory investigations including lactic acid and ammonia, amino acids, acylcarnitine profiles and brain MRI. Whole-exome sequencing was performed for all of them to confirm the suspicion of mitochondrial disorder. RESULTS: In our series, four patients presented with the hepatocerebral form of MDS with the major presenting manifestation of progressive liver cell failure with severe hypotonia and global developmental delay. Four variants in the DGUOK gene and the MPV17 have been identified including 2 novel variants. One patient was identified in the myopathic form presenting with myopathy associated with two novel variants in the TK2 gene. One patient was diagnosed with encephalomyopathic form presenting with persistent lactic acidosis and global delay due to a homozygous variant in the FBXL4 gene. CONCLUSION: MDS has a wide spectrum of heterogeneous clinical presentations and about nine different genes involved. Whole exome sequencing (WES) has resulted in faster diagnosis of these challenging cases as the phenotype overlap with many other disorders. This should be considered the first-tier diagnostic test obviating the need for more invasive testing like muscle biopsies.
    DOI:  https://doi.org/10.1016/j.mito.2022.06.004
  17. Brain. 2022 Jun 20. pii: awac123. [Epub ahead of print]
    TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia.
    Luis Carlos Tábara, Fatema Al-Salmi, Reza Maroofian, Amna Mohammed Al-Futaisi, Fathiya Al-Murshedi, Joanna Kennedy, Jacob O Day, Thomas Courtin, Aisha Al-Khayat, Hamid Galedari, Neda Mazaheri, Margherita Protasoni, Mark Johnson, Joseph S Leslie, Claire G Salter, Lettie E Rawlins, James Fasham, Almundher Al-Maawali, Nikol Voutsina, Perrine Charles, Laura Harrold, Boris Keren, Edmund R S Kunji, Barbara Vona, Gholamreza Jelodar, Alireza Sedaghat, Gholamreza Shariati, Henry Houlden, Andrew H Crosby, Julien Prudent, Emma L Baple.
      The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.
    Keywords:  TMEM63C; endoplasmic reticulum/ER; hereditary spastic paraplegia/HSP; mitochondria; mitochondria-ER contact sites/MERCs
    DOI:  https://doi.org/10.1093/brain/awac123
  18. IUBMB Life. 2022 Jun 22.
    Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S-adenosylmethionine, and related diseases: A review†.
    Magnus Monné, Carlo M T Marobbio, Gennaro Agrimi, Luigi Palmieri, Ferdinando Palmieri.
      S-adenosyl-L-methionine (SAM) is a coenzyme and the most commonly used methyl-group donor for the modification of metabolites, DNA, RNA and proteins. SAM biosynthesis and SAM regeneration from the methylation reaction product S-adenosyl-L-homocysteine (SAH) take place in the cytoplasm. Therefore, the intramitochondrial SAM-dependent methyltransferases require the import of SAM and export of SAH for recycling. Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1-2 in plants. In mitochondria SAM is used by a vast number of enzymes implicated in the following processes: the regulation of replication, transcription, translation, and enzymatic activities; the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin. Mutations in SLC25A26 and mitochondrial SAM-dependent enzymes have been found to cause human diseases, which emphasizes the physiological importance of these proteins.
    Keywords:  S-adenosyl-L-methionine; diseases; metabolism; methyltransferase; mitochondria; mitochondrial carrier; mitochondrial transport
    DOI:  https://doi.org/10.1002/iub.2658
  19. Biomedicines. 2022 Jun 10. pii: 1375. [Epub ahead of print]10(6):
    Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress.
    Giovanni Fajardo, Michael Coronado, Melia Matthews, Daniel Bernstein.
      Alterations in mitochondrial function and morphology are critical adaptations to cardiovascular stress, working in concert in an attempt to restore organelle-level and cellular-level homeostasis. Processes that alter mitochondrial morphology include fission, fusion, mitophagy, and biogenesis, and these interact to maintain mitochondrial quality control. Not all cardiovascular stress is pathologic (e.g., ischemia, pressure overload, cardiotoxins), despite a wealth of studies to this effect. Physiological stress, such as that induced by aerobic exercise, can induce morphologic adaptations that share many common pathways with pathological stress, but in this case result in improved mitochondrial health. Developing a better understanding of the mechanisms underlying alterations in mitochondrial quality control under diverse cardiovascular stressors will aid in the development of pharmacologic interventions aimed at restoring cellular homeostasis.
    Keywords:  biogenesis; fission; fusion; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines10061375
  20. Biology (Basel). 2022 Jun 20. pii: 943. [Epub ahead of print]11(6):
    Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration.
    Giacoma Galizzi, Marta Di Carlo.
      Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer's disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.
    Keywords:  insulin; insulin resistance; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/biology11060943
  21. Sci Rep. 2022 Jun 24. 12(1): 10730
    Unraveling mitochondrial piRNAs in mouse embryonic gonadal cells.
    Odei Barreñada, Eduardo Larriba, Daniel Fernández-Pérez, Miguel Ángel Brieño-Enríquez, Jesús Del Mazo Martínez.
      Although mitochondria are widely studied organelles, the recent interest in the role of mitochondrial small noncoding RNAs (sncRNAs), miRNAs, and more recently, piRNAs, is providing new functional perspectives in germ cell development and differentiation. piRNAs (PIWI-interacting RNAs) are single-stranded sncRNAs of mostly about 20-35 nucleotides, generated from the processing of pre-piRNAs. We leverage next-generation sequencing data obtained from mouse primordial germ cells and somatic cells purified from early-differentiating embryonic ovaries and testis from 11.5 to 13.5 days postcoitum. Using bioinformatic tools, we elucidate (i) the origins of piRNAs as transcribed from mitochondrial DNA fragments inserted in the nucleus or from the mitochondrial genome; (ii) their levels of expression; and (iii) their potential roles, as well as their association with genomic regions encoding other sncRNAs (such as tRNAs and rRNAs) and the mitochondrial regulatory region (D-loop). Finally, our results suggest how nucleo-mitochondrial communication, both anterograde and retrograde signaling, may be mediated by mitochondria-associated piRNAs.
    DOI:  https://doi.org/10.1038/s41598-022-14414-4
  22. Proc Natl Acad Sci U S A. 2022 Jul 05. 119(27): e2201709119
    Is Drp1 sufficient to catalyze membrane fission?
    Krishnendu Roy, Thomas J Pucadyil.
      
    DOI:  https://doi.org/10.1073/pnas.2201709119
  23. STAR Protoc. 2022 Sep 16. 3(3): 101454
    Protocol for engineering and validating a synthetic mitochondrial intermembrane bridge in mammalian cells.
    Gunjan Purohit, Martonio Ponte Viana, Oleh Khalimonchuk.
      Membrane contact sites are recognized as critical means of intercompartmental communication. Here, we describe a protocol for engineering and validating a synthetic bridge between the inner and outer mitochondrial membranes to support functioning of the endogenous mitochondrial contact site and cristae organizing system (MICOS). A chimeric protein, MitoT, is stably expressed in cultured mammalian cells to bridge the mitochondrial membranes. This approach can be a valuable tool to study the function of the MICOS complex and associated proteins. For complete details on the use and execution of this protocol, please refer to Viana et al. (2021).
    Keywords:  Biotechnology and bioengineering; Cell Biology; Cell Membrane; Cell culture; Cell isolation; Flow Cytometry/Mass Cytometry; Metabolism; Microscopy; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101454
  24. Front Cell Dev Biol. 2022 ;10 871357
    PGC-1α-Mediated Mitochondrial Quality Control: Molecular Mechanisms and Implications for Heart Failure.
    Lei Chen, Yuan Qin, Bilin Liu, Meng Gao, Anqi Li, Xue Li, Guohua Gong.
      Mitochondria with structural and functional integrity are essential for maintaining mitochondrial function and cardiac homeostasis. It is involved in the pathogenesis of many diseases. Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), acted as a transcriptional cofactor, is abundant in the heart, which modulates mitochondrial biogenesis and mitochondrial dynamics and mitophagy to sustain a steady-state of mitochondria. Cumulative evidence suggests that dysregulation of PGC-1α is closely related to the onset and progression of heart failure. PGC-1α deficient-mice can lead to worse cardiac function under pressure overload compared to sham. Here, this review mainly focuses on what is known about its regulation in mitochondrial functions, as well as its crucial role in heart failure.
    Keywords:  PGC-1α; heart failure; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fcell.2022.871357
  25. Cells. 2022 Jun 14. pii: 1922. [Epub ahead of print]11(12):
    Fission Impossible (?)-New Insights into Disorders of Peroxisome Dynamics.
    Ruth E Carmichael, Markus Islinger, Michael Schrader.
      Peroxisomes are highly dynamic and responsive organelles, which can adjust their morphology, number, intracellular position, and metabolic functions according to cellular needs. Peroxisome multiplication in mammalian cells involves the concerted action of the membrane-shaping protein PEX11β and division proteins, such as the membrane adaptors FIS1 and MFF, which recruit the fission GTPase DRP1 to the peroxisomal membrane. The latter proteins are also involved in mitochondrial division. Patients with loss of DRP1, MFF or PEX11β function have been identified, showing abnormalities in peroxisomal (and, for the shared proteins, mitochondrial) dynamics as well as developmental and neurological defects, whereas the metabolic functions of the organelles are often unaffected. Here, we provide a timely update on peroxisomal membrane dynamics with a particular focus on peroxisome formation by membrane growth and division. We address the function of PEX11β in these processes, as well as the role of peroxisome-ER contacts in lipid transfer for peroxisomal membrane expansion. Furthermore, we summarize the clinical phenotypes and pathophysiology of patients with defects in the key division proteins DRP1, MFF, and PEX11β as well as in the peroxisome-ER tether ACBD5. Potential therapeutic strategies for these rare disorders with limited treatment options are discussed.
    Keywords:  ACBD5; FIS1; PEX11β; division defects; dynamin-related protein 1; membrane fission; mitochondria; mitochondrial fission factor; organelle dynamics; peroxisomes
    DOI:  https://doi.org/10.3390/cells11121922
  26. Cell Reprogram. 2022 Jun 24.
    Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming.
    Emilie M Legault, Julie Bouquety, Janelle Drouin-Ouellet.
      Understanding the pathophysiology of CNS-associated neurological diseases has been hampered by the inaccessibility of patient brain tissue to perform live analyses at the molecular level. To this end, neural cells obtained by differentiation of patient-derived induced pluripotent stem cells (iPSCs) are considerably helpful, especially in the context of monogenic-based disorders. More recently, the use of direct reprogramming to convert somatic cells to neural cells has emerged as an alternative to iPSCs to generate neurons, astrocytes, and oligodendrocytes. This review focuses on the different studies that used direct neural reprogramming to study disease-associated phenotypes in the context of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
    Keywords:  direct neural reprogramming; disease modeling; iPSCs; induced neurons; neurodegenerative diseases
    DOI:  https://doi.org/10.1089/cell.2021.0172
  27. FEBS J. 2022 Jun 22.
    Immunomodulatory role of mitochondrial damps: A missing link in pathology?
    Mayank Garg, Saumya Johri, Krishnendu Chakraborty.
      In accordance with the endosymbiotic theory, mitochondrial components bear characteristic prokaryotic signatures which act as immunomodulatory molecules when released into the extramitochondrial compartment. These endogenous immune triggers, called mitochondrial Damage Associated Molecular Patterns (mtDAMPs) have been implicated in the pathogenesis of various diseases, yet their role remains largely unexplored. In this review, we summarize the available literature on mtDAMPs in diseases, with a special focus on respiratory diseases. We highlight the need to bolster mtDAMP research using a multipronged approach, to study their effect on specific cell types, receptors and machinery in pathologies. We emphasise the lacunae in the current understanding of mtDAMPs, particularly in their cellular release as well as the chemical modifications they undergo. Finally, we conclude by proposing additional effects of mtDAMPs in diseases, specifically their role in modulating the immune system.
    Keywords:  ATP; Cardiolipin; Cytochrome c (Cyt c); Inflammation; N-Formyl peptides (NFP); acute respiratory distress syndrome (ARDS); immunometabolism; mitochondrial DAMPs; mtDNA
    DOI:  https://doi.org/10.1111/febs.16563
  28. J Biol Methods. 2022 ;9(2): e160
    Methodology for measuring oxidative capacity of isolated peroxisomes in the Seahorse assay.
    Brittany A Stork, Adam Dean, Brian York.
      The regulation of cellular energetics is a complex process that requires the coordinated function of multiple organelles. Historically, studies focused on understanding cellular energy utilization and production have been overwhelmingly concentrated on the mitochondria. While mitochondria account for the majority of intracellular energy production, they alone are incapable of maintaining the variable energetic demands of the cell. The peroxisome has recently emerged as a secondary metabolic organelle that complements and improves mitochondrial performance. Although mitochondria and peroxisomes are structurally distinct organelles, they share key functional similarities that allows for the potential to repurpose readily available tools initially developed for mitochondrial assessment to interrogate peroxisomal metabolic function in a novel manner. To this end, we report here on procedures for the isolation, purification and real-time metabolic assessment of peroxisomal β-oxidation using the Agilent Seahorse® system. When used together, these protocols provide a straightforward, reproducible and highly quantifiable method for measuring the contributions of peroxisomes to cellular and organismal metabolism.
    Keywords:  fatty acid metabolism; peroxisome; seahorse assay
    DOI:  https://doi.org/10.14440/jbm.2022.374
  29. Cell Mol Life Sci. 2022 Jun 21. 79(7): 374
    Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases.
    Elena Abati, Arianna Manini, Giacomo Pietro Comi, Stefania Corti.
      Myostatin is a negative regulator of skeletal muscle growth secreted by skeletal myocytes. In the past years, myostatin inhibition sparked interest among the scientific community for its potential to enhance muscle growth and to reduce, or even prevent, muscle atrophy. These characteristics make it a promising target for the treatment of muscle atrophy in motor neuron diseases, namely, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), which are rare neurological diseases, whereby the degeneration of motor neurons leads to progressive muscle loss and paralysis. These diseases carry a huge burden of morbidity and mortality but, despite this unfavorable scenario, several therapeutic advancements have been made in the past years. Indeed, a number of different curative therapies for SMA have been approved, leading to a revolution in the life expectancy and outcomes of SMA patients. Similarly, tofersen, an antisense oligonucleotide, is now undergoing clinical trial phase for use in ALS patients carrying the SOD1 mutation. However, these therapies are not able to completely halt or reverse progression of muscle damage. Recently, a trial evaluating apitegromab, a myostatin inhibitor, in SMA patients was started, following positive results from preclinical studies. In this context, myostatin inhibition could represent a useful strategy to tackle motor symptoms in these patients. The aim of this review is to describe the myostatin pathway and its role in motor neuron diseases, and to summarize and critically discuss preclinical and clinical studies of myostatin inhibitors in SMA and ALS. Then, we will highlight promises and pitfalls related to the use of myostatin inhibitors in the human setting, to aid the scientific community in the development of future clinical trials.
    Keywords:  Activin receptors, type II; Monoclonal antibodies; Motor neuron diseases; Muscle atrophy; Myostatin
    DOI:  https://doi.org/10.1007/s00018-022-04408-w
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