bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–09–03
fifty-one papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
  2. Mitochondrial phospholipid metabolism in health and disease.
  3. The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.
  4. Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications.
  5. Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation.
  6. Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
  7. Mutation on MT-CO2 gene induces mitochondrial disease associated with neurodegeneration and intracerebral iron accumulation (NBIA).
  8. Structure and function of the human mitochondrial MRS2 channel.
  9. T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
  10. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
  11. Navigating Life With Primary Mitochondrial Myopathies: The Importance of the Patient Voice and Implications for Clinical Practice.
  12. A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes.
  13. Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary.
  14. Case report: Variability in clinical features as a potential pitfall for the diagnosis of Barth syndrome.
  15. Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
  16. Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.
  17. Mitochondrial double membrane fission: A mystery solved?
  18. AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations.
  19. Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase.
  20. Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
  21. The malate-aspartate shuttle is important for de novo serine biosynthesis.
  22. Mitophagy-promoting agents and their ability to promote healthy-aging.
  23. Strand-preferred base editing of organellar and nuclear genomes using CyDENT.
  24. Quantitative proteomic and phosphoproteomic analysis reveal the relationship between mitochondrial dysfunction and cytoskeletal remodeling in hiPSC-CMs deficient in PINK1.
  25. Insertases Scramble Lipids: Molecular Simulations of MTCH2.
  26. Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
  27. Resistance Exercise Training Rescues Mitochondrial Dysfunction in Skeletal Muscle of Patients with Myotonic Dystrophy Type 1.
  28. IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.
  29. PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
  30. A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
  31. Research progress in mitochondrial gene editing technology.
  32. Expanding the spectrum of neonatal-onset AIFM1-associated disorders.
  33. Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.
  34. Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.
  35. A blood-based marker of mitochondrial DNA damage in Parkinson's disease.
  36. Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data.
  37. Overcoming challenges in rare disease registry integration using the semantic web - a clinical research perspective.
  38. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
  39. Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism.
  40. Fully automated annotation of mitochondrial genomes using a cluster-based approach with de Bruijn graphs.
  41. Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.
  42. Parkinson's disease kinase LRRK2 coordinates a cell-intrinsic itaconate-dependent defence pathway against intracellular Salmonella.
  43. Fingerstick blood assay maps real-world NAD+ disparity across gender and age.
  44. Genome Sequencing for Newborn Screening-An Effective Approach for Tackling Rare Diseases.
  45. Foresight in clinical proteomics: current status, ethical considerations, and future perspectives.
  46. Identification of an alternative triglyceride biosynthesis pathway.
  47. Previously unknown pathway for lipid biosynthesis discovered.
  48. Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.
  49. Exogenous humanin and MOTS-c function as protective agents against gentamicin-induced hair cell damage.
  50. Parkinsonism in complex neurogenetic disorders: lessons from hereditary dementias, adult-onset ataxias and spastic paraplegias.
  51. A unique poly(A) tail profile uncovers the stability and translational activation of TOP transcripts during neuronal differentiation.
  1. Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]
    Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
    Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.
      The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.
    Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
  2. J Cell Sci. 2023 Sep 01. pii: jcs260857. [Epub ahead of print]136(17):
    Mitochondrial phospholipid metabolism in health and disease.
    Alaumy Joshi, Travis H Richard, Vishal M Gohil.
      Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.
    Keywords:  Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids
    DOI:  https://doi.org/10.1242/jcs.260857
  3. Am J Med Genet A. 2023 Aug 31.
    The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.
    Lauren Strasser, Asif Doja, Jorge Davila, Pranesh Chakraborty, Danielle K Bourque.
      Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.
    Keywords:  Leigh syndrome; heteroplasmy; lactic acidosis; mitochondrial disorders; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); phenotypic variability
    DOI:  https://doi.org/10.1002/ajmg.a.63378
  4. Expert Rev Mol Diagn. 2023 Jul-Dec;23(9):23(9): 797-814
    Enhanced mitochondrial genome analysis: bioinformatic and long-read sequencing advances and their diagnostic implications.
    William L Macken, Micol Falabella, Chiara Pizzamiglio, Cathy E Woodward, Elizabeth Scotchman, Lyn S Chitty, James M Polke, Enrico Bugiardini, Michael G Hanna, Jana Vandrovcova, Natalie Chandler, Robyn Labrum, Robert D S Pitceathly.
       INTRODUCTION: Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain.
    AREAS COVERED: In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics.
    EXPERT OPINION: We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants.
    Keywords:  Bioinformatics; large-scale rearrangements; long-read sequencing; mitochondrial DNA; primary mitochondrial diseases
    DOI:  https://doi.org/10.1080/14737159.2023.2241365
  5. Front Physiol. 2023 ;14 1164287
    Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation.
    Tongling Liufu, Haiyan Yu, Jiaxi Yu, Meng Yu, Yue Tian, Yichun Ou, Jianwen Deng, Guogang Xing, Zhaoxia Wang.
      Introduction: Mitochondrial disease is a spectrum of debilitating disorders caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA that compromises the respiratory chain. Mitochondrial 3243A>G (m.3243 A>G) is the most common mutation showing great heterogeneity in phenotype. Previous studies have indicated that NADH: ubiquinone oxidoreductase (complex I) deficiency accompanied by a decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio may play a pivotal role in the pathogenesis of m.3243A>G mutation. Methods: To evaluate the potential effects of strategies targeting the imbalanced NAD+/NADH ratio in m.3243A>G mutation, we treated fibroblasts derived from patients with the m.3243 A>G mutation using nicotinamide riboside (NR) or mitochondria-targeted H2O-forming NADH oxidase (mitoLbNOX). Results: M.3243 A>G fibroblasts showed a significant reduction in complex I core subunit 6, complex I enzymatic activity, complex I-dependent oxygen consumption rate (OCR), and adenosine triphosphate (ATP) production compared to the controls. The NAD+/NADH ratio was also significantly reduced in m.3243 A>G fibroblasts, and, using fluorescence lifetime imaging microscopy, we also found that the NADH level was elevated in m.3243 A>G fibroblasts. After NR treatment, the NAD+/NADH ratio, complex I-dependent OCR, and ATP levels increased, whereas NADH levels remained unchanged. More excitingly, after treatment with mitoLbNOX, the NAD+/NADH ratio, complex I-independent OCR, and ATP levels increased more pronouncedly compared with the NR treatment group, accompanied by significantly reduced NADH levels. Discussion: The present study suggests that compared with repletion of NAD+ alone, the combination of this therapeutic modality with alleviation of NADH overload may amplify the treatment effect of restoring NAD+/NADH balance in m.3243A>G fibroblasts.
    Keywords:  NADH; complex I; m.3243 A>G; mitoLbNOX; mitochondrial disease; nr
    DOI:  https://doi.org/10.3389/fphys.2023.1164287
  6. Biochem Soc Trans. 2023 Aug 29. pii: BST20230012. [Epub ahead of print]
    Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
    Sandra H Lee, Hannah E Duron, Dipayan Chaudhuri.
      While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.
    Keywords:  MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation
    DOI:  https://doi.org/10.1042/BST20230012
  7. Biochim Biophys Acta Mol Basis Dis. 2023 Aug 26. pii: S0925-4439(23)00222-3. [Epub ahead of print] 166856
    Mutation on MT-CO2 gene induces mitochondrial disease associated with neurodegeneration and intracerebral iron accumulation (NBIA).
    Sarah Courtois, Chloé Angelini, Christelle M Durand, Nivea Dias Amoedo, Armelle Courreges, Elodie Dumon, Mégane Le Quang, Cyril Goizet, Marie-Laure Martin-Negrier, Rodrigue Rossignol, Didier Lacombe, Isabelle Coupry, Aurélien Trimouille.
      Mitochondrial diseases are genetic disorders impairing mitochondrial functions. Here we describe a patient with a neurodegenerative condition associated with myopia, bilateral sensorineural hearing loss and motor disorders. Brain MRIs showed major cortico-subcortical and infra-tentorial atrophies, as well as intracerebral iron accumulation and central calcifications, compatible with a NBIA-like phenotype. Mitochondrial DNA analysis revealed an undescribed variant: m.8091G>A in the MT-CO2 gene, associated with a complex IV deficiency and a decrease of the mitochondrial respiratory chain capabilities. We report here this pathogenic variant, associated with a NBIA-like phenotype.
    Keywords:  Complex IV; MT-CO2; Mitochondriopathies; NBIA; iron accumulation
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166856
  8. bioRxiv. 2023 Aug 15. pii: 2023.08.12.553106. [Epub ahead of print]
    Structure and function of the human mitochondrial MRS2 channel.
    Zhihui He, Yung-Chi Tu, Chen-Wei Tsai, Jonathan Mount, Jingying Zhang, Ming-Feng Tsai, Peng Yuan.
      The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg 2+ transport across mitochondrial inner membranes, thus playing an important role in Mg 2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca 2+ -regulated, non-selective channel permeable to Mg 2+ , Ca 2+ , Na + and K + , which contrasts with its prokaryotic ortholog, CorA, operating as a Mg 2+ -gated Mg 2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.
    DOI:  https://doi.org/10.1101/2023.08.12.553106
  9. Life Sci Alliance. 2023 Nov;pii: e202302271. [Epub ahead of print]6(11):
    T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
    Imogen G Franklin, Paul Milne, Jordan Childs, Róisín M Boggan, Isabel Barrow, Conor Lawless, Gráinne S Gorman, Yi Shiau Ng, Matthew Collin, Oliver M Russell, Sarah J Pickett.
      Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.
    DOI:  https://doi.org/10.26508/lsa.202302271
  10. Nat Metab. 2023 Aug 31.
    A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
    Undiagnosed Diseases Network
      In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00873-0
  11. J Prim Care Community Health. 2023 Jan-Dec;14:14 21501319231193875
    Navigating Life With Primary Mitochondrial Myopathies: The Importance of the Patient Voice and Implications for Clinical Practice.
    Margaret Moore, Philip Yeske, Sumit Parikh.
      Primary mitochondrial myopathies (PMM) are rare disorders with diverse and progressive symptom presentations that cause a substantial, detrimental impact on the quality of life of patients and their caregivers. The burden of symptoms is compounded by their visibility and their unpredictable, progressive nature, leading to a sense of social stigmatization, limited autonomy, social isolation, and grief. There is also a lack of awareness and expertise in the medical community, which presents huge obstacles to diagnosis and provision of coordinated multidisciplinary care for these patients, along with a lack of disease-modifying treatments. The present commentary serves to raise awareness of the challenges faced by patients with PMM and their caregivers in their own words, including diagnostic delays, the burden of disease, and the need for further trials to develop disease-modifying treatments and improved understanding of the disease course. We also provide commentary on considerations for clinical practice, including the need for holistic care and multidisciplinary care teams, details of common 'red flag' symptoms, proposed diagnostic approaches, and suggested descriptions of multisystemic symptoms for physician-patient dialogue. In addition, we highlight the role patient advocacy and support groups play in supporting patients and providing access to reliable, up-to-date information and educational resources on these rare diseases.
    Keywords:  mitochondrial disorders; patient perspectives; patient-centeredness; practice management; primary mitochondrial disease; primary mitochondrial myopathies
    DOI:  https://doi.org/10.1177/21501319231193875
  12. Clin Genet. 2023 Aug 30.
    A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes.
    Leon Peifer-Weiß, Mazen Kurban, Céline David, Melissa Lubeck, Arun Kumar Kondadi, Georges Nemer, Andreas S Reichert, Ruchika Anand.
      APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.
    Keywords:  apolipoproteins; congenital disorder; mitochondria; mitochondrial disease; progeria
    DOI:  https://doi.org/10.1111/cge.14420
  13. Mitochondrion. 2023 Aug 25. pii: S1567-7249(23)00071-5. [Epub ahead of print]72 102-105
    Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary.
    Kumarie Latchman, Mario Saporta, Carlos T Moraes.
      Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.
    DOI:  https://doi.org/10.1016/j.mito.2023.08.003
  14. Front Pediatr. 2023 ;11 1250772
    Case report: Variability in clinical features as a potential pitfall for the diagnosis of Barth syndrome.
    Nicola Tovaglieri, Silvia Russo, Emanuele Micaglio, Angela Corcelli, Simona Lobasso.
       Background: Barth syndrome is a rare genetic disease characterized by cardiomyopathy, skeletal muscle weakness, neutropenia, growth retardation and organic aciduria. This variable phenotype is caused by pathogenic hemizygous variants of the TAFAZZIN gene on the X chromosome, which impair metabolism of the mitochondrial phospholipid cardiolipin. Although most patients are usually diagnosed in the first years of life, the extremely variable clinical picture and the wide range of clinical presentations may both delay diagnosis. This is the case reported here of a man affected with severe neutropenia, who was not diagnosed with Barth syndrome until adulthood.
    Case presentation: We describe herein a family case, specifically two Caucasian male cousins sharing the same mutation in the TAFAZZIN gene with a wide phenotypic variability: an infant who was early diagnosed with Barth syndrome due to heart failure, and his maternal cousin with milder and extremely different clinical features who has received the same diagnosis only at 33 years of age.
    Conclusions: Our report supports the underestimation of the prevalence of Barth syndrome, which should be always considered in the differential diagnosis of male patients with recurrent neutropenia with or without signs and symptoms of cardiomyopathy.
    Keywords:  TAFAZZIN; cardiolipin remodeling; cardiomyopathy; neutropenia; rare X-linked disease
    DOI:  https://doi.org/10.3389/fped.2023.1250772
  15. Am J Physiol Cell Physiol. 2023 Aug 29.
    Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
    Michael L Kamradt, Catherine A Makarewich.
      Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria (TOMM complex, TIMM complex, OXPHOS complexes, mitoribosomes). These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines; they also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.
    Keywords:  cell stress; microproteins; mitochondria; mitochondrial protein import; oxidative phosphorylation
    DOI:  https://doi.org/10.1152/ajpcell.00189.2023
  16. Metab Brain Dis. 2023 Aug 29.
    Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome.
    Rahma Felhi, Lamia Sfaihi, Majida Charif, Fakher Frikha, Nissaf Aoiadni, Thouraya Kamoun, Guy Lenaers, Faiza Fakhfakh.
      Leigh syndrome (LS) and Leigh-like spectrum are the most common infantile mitochondrial disorders characterized by heterogeneous neurologic and metabolic manifestations. Pathogenic variants in SLC carriers are frequently reported in LS given their important role in transporting various solutes across the blood-brain barrier. SLC19A3 (THTR2) is one of these carriers transporting vitamin-B1 (vitB1, thiamine) into the cell. Targeted NGS of nuclear genes involved in mitochondrial diseases was performed in a patient belonging to a consanguineous Tunisian family with LS and revealed a homozygous c.1264 A > G (p.T422A) variant in SLC19A3. Molecular docking revealed that the p.T422A aa change is located at a key position interacting with vitB1 and causes conformational changes compromising vitB1 import. We further disclosed decreased plasma antioxidant activities of CAT, SOD and GSH enzymes, and a 42% decrease of the mtDNA copy number in patient blood.Altogether, our results disclose that the c.1264 A > G (p.T422A) variant in SLC19A3 affects vitB1 transport, induces a mtDNA depletion and reduces the expression level of oxidative stress enzymes, altogether contributing to the LS phenotype of the patient.
    Keywords:  Antioxidant; Encephalopathy; Mitochondrial disorder; Molecular docking; Thiamine
    DOI:  https://doi.org/10.1007/s11011-023-01280-w
  17. J Cell Biol. 2023 Oct 02. pii: e202308119. [Epub ahead of print]222(10):
    Mitochondrial double membrane fission: A mystery solved?
    Benedikt Westermann.
      It has long been an unresolved question whether the division machineries that assemble on the mitochondrial surface cooperate with factors inside the organelle. Now, two studies by Connor et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202303147) and Fukuda et al. (2023. Mol. Cell.https://doi.org/10.1016/j.molcel.2023.04.022) have identified an intermembrane space protein that is crucial for mitochondrial double membrane division.
    DOI:  https://doi.org/10.1083/jcb.202308119
  18. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302490120
    AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations.
    Hu Zhang, Yunan Zhu, Yuji Suehiro, Shohei Mitani, Ding Xue.
      Pathological mutations in human mitochondrial genomes (mtDNA) can cause a series of neurological, behavioral, and developmental defects, but the underlying molecular mechanisms are poorly understood. We show here that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway plays a key role in mediating similar defects caused by different mtDNA mutations in Caenorhabditis elegans, including loss or reduction of osmotic, chemical and olfactory sensing, locomotion, and associative learning and memory, as well as increased embryonic lethality. mtDNA mutations cause reduced ATP (adenosine triphosphate) levels, activation of C. elegans AMPK AAK-2, and nuclear translocation of the FOXO transcription factor DAF-16. Activated DAF-16 up-regulates the expression of inositol triphosphate receptor ITR-1, an endoplasmic reticulum calcium channel, leading to increased basal cytosolic Ca2+ levels, decreased neuronal responsiveness, compromised synapses, and increased embryonic death. Treatment of mtDNA mutants with vitamin MK-4 restores cellular ATP and cytosolic Ca2+ levels, improves synaptic development, and suppresses sensory and behavioral defects and embryonic death. Our study provides crucial mechanistic insights into neuronal and developmental defects caused by mtDNA mutations and will improve understanding and treatment of related mitochondrial diseases.
    Keywords:  AMP-activated protein kinase; Caenorhabditis elegans; calcium homeostasis; mitochondrial genome mutations; neurological and developmental defects
    DOI:  https://doi.org/10.1073/pnas.2302490120
  19. Nucleic Acids Res. 2023 Aug 28. pii: gkad696. [Epub ahead of print]
    Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase.
    Bastiaan de Potter, Ingrid Vallee, Noelia Camacho, Luís Filipe Costa Póvoas, Aureliano Bonsembiante, Alba Pons I Pons, Ulrich Eckhard, Francesc-Xavier Gomis-Rüth, Xiang-Lei Yang, Paul Schimmel, Bernhard Kuhle, Lluís Ribas de Pouplana.
      Through their aminoacylation reactions, aminoacyl tRNA-synthetases (aaRS) establish the rules of the genetic code throughout all of nature. During their long evolution in eukaryotes, additional domains and splice variants were added to what is commonly a homodimeric or monomeric structure. These changes confer orthogonal functions in cellular activities that have recently been uncovered. An unusual exception to the familiar architecture of aaRSs is the heterodimeric metazoan mitochondrial SerRS. In contrast to domain additions or alternative splicing, here we show that heterodimeric metazoan mitochondrial SerRS arose from its homodimeric ancestor not by domain additions, but rather by collapse of an entire domain (in one subunit) and an active site ablation (in the other). The collapse/ablation retains aminoacylation activity while creating a new surface, which is necessary for its orthogonal function. The results highlight a new paradigm for repurposing a member of the ancient tRNA synthetase family.
    DOI:  https://doi.org/10.1093/nar/gkad696
  20. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120
    Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
    Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.
    Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2302360120
  21. Cell Rep. 2023 Aug 29. pii: S2211-1247(23)01054-9. [Epub ahead of print]42(9): 113043
    The malate-aspartate shuttle is important for de novo serine biosynthesis.
    Melissa H Broeks, Nils W F Meijer, Denise Westland, Marjolein Bosma, Johan Gerrits, Hannah M German, Jolita Ciapaite, Clara D M van Karnebeek, Ronald J A Wanders, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.
      The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.
    Keywords:  CP: Metabolism; NADH shuttle; central carbon metabolism; glycolysis; isotope-tracer analysis; malate dehydrogenase; malate-aspartate shuttle; metabolomics; serine biosynthesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113043
  22. Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]
    Mitophagy-promoting agents and their ability to promote healthy-aging.
    Vijigisha Srivastava, Einav Gross.
      The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.
    Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy
    DOI:  https://doi.org/10.1042/BST20221363
  23. Nat Biotechnol. 2023 Aug 28.
    Strand-preferred base editing of organellar and nuclear genomes using CyDENT.
    Jiacheng Hu, Yu Sun, Boshu Li, Zhen Liu, Zhiwei Wang, Qiang Gao, Mengyue Guo, Guanwen Liu, Kevin Tianmeng Zhao, Caixia Gao.
      Transcription-activator-like effector (TALE)-based tools for base editing of nuclear and organellar DNA rely on double-stranded DNA deaminases, which edit substrate bases on both strands of DNA, reducing editing precision. Here, we present CyDENT base editing, a CRISPR-free, strand-selective, modular base editor. CyDENT comprises a pair of TALEs fused with a FokI nickase, a single-strand-specific cytidine deaminase and an exonuclease to generate a single-stranded DNA substrate for deamination. We demonstrate effective base editing in nuclear, mitochondrial and chloroplast genomes. At certain mitochondrial sites, we show editing efficiencies of 14% and strand specificity of 95%. Furthermore, by exchanging the CyDENT deaminase with one that prefers editing GC motifs, we demonstrate up to 20% mitochondrial base editing at sites that are otherwise inaccessible to editing by other methods. The modular nature of CyDENT enables a suite of bespoke base editors for various applications.
    DOI:  https://doi.org/10.1038/s41587-023-01910-9
  24. J Transl Med. 2023 Aug 30. 21(1): 581
    Quantitative proteomic and phosphoproteomic analysis reveal the relationship between mitochondrial dysfunction and cytoskeletal remodeling in hiPSC-CMs deficient in PINK1.
    Huiwen Liu, Li Wang, Hao Xu, Bin Tan, Qin Yi, Hongrong Deng, Yunxia Chen, Bolin He, Jie Tian, Jing Zhu.
       BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are seed cells that can be used for alternative treatment of myocardial damage. However, their immaturity limits their clinical application. Mitochondrial development accompanies cardiomyocyte maturation, and PINK1 plays an important role in the regulation of mitochondrial quality. However, the role and mechanism of PINK1 in cardiomyocyte development remain unclear.
    METHODS: We used proteomic and phosphoproteomic to identify protein and phosphosite changes in hiPSC-CMs deficient in PINK1. Bioinformatics analysis was performed to identify the potential biological functions and regulatory mechanisms of these differentially expressed proteins and validate potential downstream mechanisms.
    RESULTS: Deletion of PINK1 resulted in mitochondrial structural breakdown and dysfunction, accompanied by disordered myofibrils arrangement. hiPSC-CMs deficient in PINK1 exhibited significantly decreased expression of mitochondrial ATP synthesis proteins and inhibition of the oxidative phosphorylation pathway. In contrast, the expression of proteins related to cardiac pathology was increased, and the phosphoproteins involved in cytoskeleton construction were significantly altered. Mechanistically, PINK1 deletion damaged the mitochondrial cristae of hiPSC-CMs and reduced the efficiency of mitochondrial respiratory chain assembly.
    CONCLUSION: The significantly differentially expressed proteins identified in this study highlight the important role of PINK1 in regulating mitochondrial quality in hiPSC-CMs. PINK1-mediated mitochondrial respiratory chain assembly is the basis for mitochondrial function. Whereas the cytoskeleton may be adaptively altered in response to mitochondrial dysfunction caused by PINK1 deletion, inadequate energy supply hinders myocardial development. These findings facilitate the exploration of the mechanism of PINK1 in cardiomyocyte development and guide efforts to promote the maturation of hiPSC-CMs.
    Keywords:  Cytoskeleton; Mitochondrial; PINK1; Phosphoproteomic; Proteomic; Respiratory chain; hiPSC-CMs
    DOI:  https://doi.org/10.1186/s12967-023-04467-y
  25. bioRxiv. 2023 Aug 14. pii: 2023.08.14.553169. [Epub ahead of print]
    Insertases Scramble Lipids: Molecular Simulations of MTCH2.
    Ladislav Bartoš, Anant K Menon, Robert Vácha.
      Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we now show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of VDAC, a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases.
    TOC Graphic:
    DOI:  https://doi.org/10.1101/2023.08.14.553169
  26. bioRxiv. 2023 Aug 17. pii: 2023.08.16.553624. [Epub ahead of print]
    Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
    Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman.
      Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse substrates remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways which act on substrates based on their topology. NAC is required for efficient targeting of polytopic proteins whereas signal-anchored proteins require TTC1, a novel cytosolic chaperone which physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.
    DOI:  https://doi.org/10.1101/2023.08.16.553624
  27. J Neuromuscul Dis. 2023 Aug 25.
    Resistance Exercise Training Rescues Mitochondrial Dysfunction in Skeletal Muscle of Patients with Myotonic Dystrophy Type 1.
    Valeria Di Leo, Conor Lawless, Marie-Pier Roussel, Tiago B Gomes, Gráinne S Gorman, Oliver M Russell, Helen A L Tuppen, Elise Duchesne, Amy E Vincent.
       BACKGROUND: Myotonic dystrophy type 1 (DM1) is a dominant autosomal neuromuscular disorder caused by the inheritance of a CTG triplet repeat expansion in the Dystrophia Myotonica Protein Kinase (DMPK) gene. At present, no cure currently exists for DM1 disease.
    OBJECTIVE: This study investigates the effects of 12-week resistance exercise training on mitochondrial oxidative phosphorylation in skeletal muscle in a cohort of DM1 patients (n = 11, men) in comparison to control muscle with normal oxidative phosphorylation.
    METHODS: Immunofluorescence was used to assess protein levels of key respiratory chain subunits of complex I (CI) and complex IV (CIV), and markers of mitochondrial mass and cell membrane in individual myofibres sampled from muscle biopsies. Using control's skeletal muscle fibers population, we classified each patient's fibers as having normal, low or high levels of CI and CIV and compared the proportions of fibers before and after exercise training. The significance of changes observed between pre- and post-exercise within patients was estimated using a permutation test.
    RESULTS: At baseline, DM1 patients present with significantly decreased mitochondrial mass, and isolated or combined CI and CIV deficiency. After resistance exercise training, in most patients a significant increase in mitochondrial mass was observed, and all patients showed a significant increase in CI and/or CIV protein levels. Moreover, improvements in mitochondrial mass were correlated with the one-repetition maximum strength evaluation.
    CONCLUSIONS: Remarkably, 12-week resistance exercise training is sufficient to partially rescue mitochondrial dysfunction in DM1 patients, suggesting that the response to exercise is in part be due to changes in mitochondria.
    Keywords:  Myotonic dystrophy type 1; mitochondrial dysfunction; myotonic dystrophy type 1 therapy; oxidative phosphorylation deficiency; resistance exercise training; skeletal muscle; strength training
    DOI:  https://doi.org/10.3233/JND-230099
  28. NAR Cancer. 2023 Sep;5(3): zcad046
    IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.
    Vasiliki Papadaki, Zoi Erpapazoglou, Maria Kokkori, Malgorzata Ewa Rogalska, Myrto Potiri, Andrada Birladeanu, Eleni N Tsakiri, Hassan Ashktorab, Duane T Smoot, Katerina Papanikolopoulou, Martina Samiotaki, Panagiota Kafasla.
      Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.
    DOI:  https://doi.org/10.1093/narcan/zcad046
  29. Cell. 2023 Aug 21. pii: S0092-8674(23)00862-0. [Epub ahead of print]
    PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
    Ruoxi Wang, Tina M Fortier, Fei Chai, Guangyan Miao, James L Shen, Lucas J Restrepo, Jeromy J DiGiacomo, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
    Keywords:  Drosophila; ER-phagy; Keap1; PINK1; Parkin; Rtnl1
    DOI:  https://doi.org/10.1016/j.cell.2023.08.008
  30. Commun Biol. 2023 08 29. 6(1): 890
    A G1528C Hadha knock-in mouse model recapitulates aspects of human clinical phenotypes for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.
    Garen Gaston, Shannon Babcock, Renee Ryals, Gabriela Elizondo, Tiffany DeVine, Dahlia Wafai, William Packwood, Sarah Holden, Jacob Raber, Jonathan R Lindner, Mark E Pennesi, Cary O Harding, Melanie B Gillingham.
      Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder (FAOD) caused by a pathogenic variant, c.1528 G > C, in HADHA encoding the alpha subunit of trifunctional protein (TFPα). Individuals with LCHADD develop chorioretinopathy and peripheral neuropathy not observed in other FAODs in addition to the more ubiquitous symptoms of hypoketotic hypoglycemia, rhabdomyolysis and cardiomyopathy. We report a CRISPR/Cas9 generated knock-in murine model of G1528C in Hadha that recapitulates aspects of the human LCHADD phenotype. Homozygous pups are less numerous than expected from Mendelian probability, but survivors exhibit similar viability with wildtype (WT) littermates. Tissues of LCHADD homozygotes express TFPα protein, but LCHADD mice oxidize less fat and accumulate plasma 3-hydroxyacylcarnitines compared to WT mice. LCHADD mice exhibit lower ketones with fasting, exhaust earlier during treadmill exercise and develop a dilated cardiomyopathy compared to WT mice. In addition, LCHADD mice exhibit decreased visual performance, decreased cone function, and disruption of retinal pigment epithelium. Neurological function is affected, with impaired motor function during wire hang test and reduced open field activity. The G1528C knock-in mouse exhibits a phenotype similar to that observed in human patients; this model will be useful to explore pathophysiology and treatments for LCHADD in the future.
    DOI:  https://doi.org/10.1038/s42003-023-05268-1
  31. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Aug 25. pii: 1008-9292(2023)04-0460-13. [Epub ahead of print]52(4): 460-472
    Research progress in mitochondrial gene editing technology.
    Yichen Wang, Ying Wang, Yu Chen, Qingfeng Yan, Aifu Lin.
      Mitochondrial DNA (mtDNA) mutations result in a variety of genetic diseases. As an emerging therapeutic method, mtDNA editing technology recognizes targets more based on the protein and less on the nucleic acid. Although the protein recognition type mtDNA editing technology represented by zinc finger nuclease technology, transcription activator like effector nuclease technology and base editing technology has made some progress, the disadvantages of complex recognition sequence design hinder further popularization. Gene editing based on nucleic acid recognition by the CRISPR system shows superiority due to the simple structure, easy design and modification. However, the lack of effective means to deliver nucleic acids into mitochondria limits application in the field of mtDNA editing. With the advances in the study of endogenous and exogenous import pathways and the deepening understanding of DNA repair mechanisms, growing evidence shows the feasibility of nucleic acid delivery and the broad application prospects of nucleic acid recognition type mtDNA editing technology. Based on the classification of recognition elements, this article summarizes the current principles and development of mitochondrial gene editing technology, and discusses its application prospects.
    Keywords:  CRISPR; Gene editing; Mitochondrion; Nucleic acid delivery; Review
    DOI:  https://doi.org/10.3724/zdxbyxb-2023-0129
  32. Ann Clin Transl Neurol. 2023 Aug 29.
    Expanding the spectrum of neonatal-onset AIFM1-associated disorders.
    Alberto A Zambon, Daniele Ghezzi, Cristina Baldoli, Gianni Cutillo, Katia Fontana, Valentina Sofia, Maria Grazia Patricelli, Alessia Nasca, Stefano Vinci, Ivana Spiga, Eleonora Lamantea, Giovanna F Fanelli, Maria Grazia Natali Sora, Rosanna Rovelli, Antonella Poloniato, Paola Carrera, Massimo Filippi, Graziano Barera.
       OBJECTIVES: Pathogenic variants in AIFM1 have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on AIFM1-related disorders.
    METHODS: We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy.
    RESULTS: The patient presented with drug-resistant, electro-clinical, multifocal seizures 6 h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T>C; p.(Phe2Ser) in the AIFM1 gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6 months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy.
    INTERPRETATION: This is the first AIFM1 case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.
    DOI:  https://doi.org/10.1002/acn3.51876
  33. Basic Res Cardiol. 2023 Aug 28. 118(1): 34
    Preventing mitochondrial reverse electron transport as a strategy for cardioprotection.
    Hiran A Prag, Michael P Murphy, Thomas Krieg.
      In the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.
    Keywords:  Malonate; Mitochondria; Reactive oxygen species; Reverse electron transport; Succinate; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s00395-023-01002-4
  34. Ann Med. 2023 ;55(2): 2240707
    Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link.
    Lubing Cai, Luze Shi, Zhen Peng, Yaying Sun, Jiwu Chen.
      Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.
    Keywords:  Ageing; extracellular matrix; mitochondria; reactive oxygen species; sarcopenia
    DOI:  https://doi.org/10.1080/07853890.2023.2240707
  35. Sci Transl Med. 2023 Aug 30. 15(711): eabo1557
    A blood-based marker of mitochondrial DNA damage in Parkinson's disease.
    Rui Qi, Esther Sammler, Claudia P Gonzalez-Hunt, Ivana Barraza, Nicholas Pena, Jeremy P Rouanet, Yahaira Naaldijk, Steven Goodson, Marie Fuzzati, Fabio Blandini, Kirk I Erickson, Andrea M Weinstein, Michael W Lutz, John B Kwok, Glenda M Halliday, Nicolas Dzamko, Shalini Padmanabhan, Roy N Alcalay, Cheryl Waters, Penelope Hogarth, Tanya Simuni, Danielle Smith, Connie Marras, Francesca Tonelli, Dario R Alessi, Andrew B West, Sruti Shiva, Sabine Hilfiker, Laurie H Sanders.
      Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.
    DOI:  https://doi.org/10.1126/scitranslmed.abo1557
  36. Am J Hum Genet. 2023 Aug 22. pii: S0002-9297(23)00281-1. [Epub ahead of print]
    Advanced variant classification framework reduces the false positive rate of predicted loss-of-function variants in population sequencing data.
    Moriel Singer-Berk, Sanna Gudmundsson, Samantha Baxter, Eleanor G Seaby, Eleina England, Jordan C Wood, Rachel G Son, Nicholas A Watts, Konrad J Karczewski, Steven M Harrison, Daniel G MacArthur, Heidi L Rehm, Anne O'Donnell-Luria.
      Predicted loss of function (pLoF) variants are often highly deleterious and play an important role in disease biology, but many pLoF variants may not result in loss of function (LoF). Here we present a framework that advances interpretation of pLoF variants in research and clinical settings by considering three categories of LoF evasion: (1) predicted rescue by secondary sequence properties, (2) uncertain biological relevance, and (3) potential technical artifacts. We also provide recommendations on adjustments to ACMG/AMP guidelines' PVS1 criterion. Applying this framework to all high-confidence pLoF variants in 22 genes associated with autosomal-recessive disease from the Genome Aggregation Database (gnomAD v.2.1.1) revealed predicted LoF evasion or potential artifacts in 27.3% (304/1,113) of variants. The major reasons were location in the last exon, in a homopolymer repeat, in a low proportion expressed across transcripts (pext) scored region, or the presence of cryptic in-frame splice rescues. Variants predicted to evade LoF or to be potential artifacts were enriched for ClinVar benign variants. PVS1 was downgraded in 99.4% (162/163) of pLoF variants predicted as likely not LoF/not LoF, with 17.2% (28/163) downgraded as a result of our framework, adding to previous guidelines. Variant pathogenicity was affected (mostly from likely pathogenic to VUS) in 20 (71.4%) of these 28 variants. This framework guides assessment of pLoF variants beyond standard annotation pipelines and substantially reduces false positive rates, which is key to ensure accurate LoF variant prediction in both a research and clinical setting.
    Keywords:  PVS1; gnomAD; pLoF; population data; predicted loss-of-function variants; variant classification; variant interpretation
    DOI:  https://doi.org/10.1016/j.ajhg.2023.08.005
  37. Orphanet J Rare Dis. 2023 Aug 29. 18(1): 253
    Overcoming challenges in rare disease registry integration using the semantic web - a clinical research perspective.
    Karl Gisslander, Aladdin J Mohammad, Augusto Vaglio, Mark A Little.
      The growing number of disease-specific patient registries for rare diseases has highlighted the need for registry interoperability and data linkage, leading to large-scale rare disease data integration projects using Semantic Web based solutions. These technologies may be difficult to grasp for rare disease experts, leading to limited involvement by domain expertise in the data integration process. Here, we propose a data integration framework starting from the perspective of the clinical researcher, allowing for purposeful rare disease registry integration driven by clinical research questions.
    Keywords:  Data integration; FAIRification; Rare disease; Registry; Semantic web; Vasculitis
    DOI:  https://doi.org/10.1186/s13023-023-02841-z
  38. bioRxiv. 2023 Aug 16. pii: 2023.08.15.553413. [Epub ahead of print]
    The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
    Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.
      Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
    DOI:  https://doi.org/10.1101/2023.08.15.553413
  39. Mol Psychiatry. 2023 Aug 30.
    Crif1 deficiency in dopamine neurons triggers early-onset parkinsonism.
    Jun Young Heo, Ah Hyung Park, Min Joung Lee, Min Jeong Ryu, Yong Kyung Kim, Yun Seon Jang, Soo Jeong Kim, So Yeon Shin, Hyo Jin Son, Thor D Stein, Yang Hoon Huh, Sookja K Chung, Song Yi Choi, Jin Man Kim, Onyou Hwang, Minho Shong, Seung Jae Hyeon, Junghee Lee, Hoon Ryu, Daesoo Kim, Gi Ryang Kweon.
      Mitochondrial dysfunction has been implicated in Parkinson's Disease (PD) progression; however, the mitochondrial factors underlying the development of PD symptoms remain unclear. One candidate is CR6-interacting factor1 (CRIF1), which controls translation and membrane insertion of 13 mitochondrial proteins involved in oxidative phosphorylation. Here, we found that CRIF1 mRNA and protein expression were significantly reduced in postmortem brains of elderly PD patients compared to normal controls. To evaluate the effect of Crif1 deficiency, we produced mice lacking the Crif1 gene in dopaminergic neurons (DAT-CRIF1-KO mice). From 5 weeks of age, DAT-CRIF1-KO mice began to show decreased dopamine production with progressive neuronal degeneration in the nigral area. At ~10 weeks of age, they developed PD-like behavioral deficits, including gait abnormalities, rigidity, and resting tremor. L-DOPA, a medication used to treat PD, ameliorated these defects at an early stage, although it was ineffective in older mice. Taken together, the observation that CRIF1 expression is reduced in human PD brains and deletion of CRIF1 in dopaminergic neurons leads to early-onset PD with stepwise PD progression support the conclusion that CRIF1-mediated mitochondrial function is important for the survival of dopaminergic neurons.
    DOI:  https://doi.org/10.1038/s41380-023-02234-5
  40. Front Genet. 2023 ;14 1250907
    Fully automated annotation of mitochondrial genomes using a cluster-based approach with de Bruijn graphs.
    Lisa Fiedler, Martin Middendorf, Matthias Bernt.
      A wide range of scientific fields, such as forensics, anthropology, medicine, and molecular evolution, benefits from the analysis of mitogenomic data. With the development of new sequencing technologies, the amount of mitochondrial sequence data to be analyzed has increased exponentially over the last few years. The accurate annotation of mitochondrial DNA is a prerequisite for any mitogenomic comparative analysis. To sustain with the growth of the available mitochondrial sequence data, highly efficient automatic computational methods are, hence, needed. Automatic annotation methods are typically based on databases that contain information about already annotated (and often pre-curated) mitogenomes of different species. However, the existing approaches have several shortcomings: 1) they do not scale well with the size of the database; 2) they do not allow for a fast (and easy) update of the database; and 3) they can only be applied to a relatively small taxonomic subset of all species. Here, we present a novel approach that does not have any of these aforementioned shortcomings, (1), (2), and (3). The reference database of mitogenomes is represented as a richly annotated de Bruijn graph. To generate gene predictions for a new user-supplied mitogenome, the method utilizes a clustering routine that uses the mapping information of the provided sequence to this graph. The method is implemented in a software package called DeGeCI (De Bruijn graph Gene Cluster Identification). For a large set of mitogenomes, for which expert-curated annotations are available, DeGeCI generates gene predictions of high conformity. In a comparative evaluation with MITOS2, a state-of-the-art annotation tool for mitochondrial genomes, DeGeCI shows better database scalability while still matching MITOS2 in terms of result quality and providing a fully automated means to update the underlying database. Moreover, unlike MITOS2, DeGeCI can be run in parallel on several processors to make use of modern multi-processor systems.
    Keywords:  Metazoa; annotation; clustering; de Bruijn graph; gene prediction; genome; mitochondria; mitogenome
    DOI:  https://doi.org/10.3389/fgene.2023.1250907
  41. Life Sci Alliance. 2023 Nov;pii: e202302036. [Epub ahead of print]6(11):
    Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.
    Lilli Ikonen, Sini Pirnes-Karhu, Swagat Pradhan, Howard T Jacobs, Marten Szibor, Anu Suomalainen.
      Energetic insufficiency, excess production of reactive oxygen species (ROS), and aberrant signaling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem cell pools, could modify somatic stem cell homeostasis remains unknown. Previous data from mitochondrial DNA mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mitochondrial DNA mutator mice how ubiquitous expression of the Ciona intestinalis alternative oxidase (AOX), which attenuates ROS production, affects murine stem cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell type-specific findings demonstrate that AOX expression is not a global panacea for curing mitochondrial dysfunction. ROS attenuation must be carefully studied regarding specific underlying defects before AOX can be safely used in therapy.
    DOI:  https://doi.org/10.26508/lsa.202302036
  42. Nat Microbiol. 2023 Aug 28.
    Parkinson's disease kinase LRRK2 coordinates a cell-intrinsic itaconate-dependent defence pathway against intracellular Salmonella.
    Huan Lian, Donghyun Park, Meixin Chen, Florian Schueder, Maria Lara-Tejero, Jun Liu, Jorge E Galán.
      Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen Salmonella, through delivery of antimicrobial itaconate. Here we show that the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) orchestrates this defence response by scaffolding a complex between RAB32 and aconitate decarboxylase 1, which synthesizes itaconate from mitochondrial precursors. Itaconate delivery to Salmonella-containing vacuoles was impaired and Salmonella replication increased in LRRK2-deficient cells. Loss of LRRK2 also restored virulence of a Salmonella mutant defective in neutralizing this RAB32-dependent host defence pathway in mice. Cryo-electron tomography revealed tether formation between Salmonella-containing vacuoles and host mitochondria upon Salmonella infection, which was significantly impaired in LRRK2-deficient cells. This positions LRRK2 centrally within a host defence mechanism, which may have favoured selection of a common familial Parkinson's disease mutant allele in the human population.
    DOI:  https://doi.org/10.1038/s41564-023-01459-y
  43. Aging Cell. 2023 Aug 28. e13965
    Fingerstick blood assay maps real-world NAD+ disparity across gender and age.
    Pei Wang, Meiting Chen, Yaying Hou, Jun Luan, Ruili Liu, Liuqing Chen, Min Hu, Qiuliyang Yu.
      Nicotinamide adenine dinucleotide (NAD+ ) level has been associated with various age-related diseases and its pharmacological modulation emerges as a potential approach for aging intervention. But human NAD+ landscape exhibits large heterogeneity. The lack of rapid, low-cost assays limits the establishment of whole-blood NAD+ baseline and the development of personalized therapies, especially for those with poor responses towards conventional NAD+ supplementations. Here, we developed an automated NAD+ analyzer for the rapid measurement of NAD+ with 5 μL of capillary blood using recombinant bioluminescent sensor protein and automated optical reader. The minimal invasiveness of the assay allowed a frequent and decentralized mapping of real-world NAD+ dynamics. We showed that aerobic sport and NMN supplementation increased whole-blood NAD+ and that male on average has higher NAD+ than female before the age of 50. We further revealed the long-term stability of human NAD+ baseline over 100 days and identified major real-world NAD+ -modulating behaviors.
    Keywords:   nicotinamide mononucleotide ; NAD+; aging; point-of care
    DOI:  https://doi.org/10.1111/acel.13965
  44. JAMA Netw Open. 2023 Sep 05. 6(9): e2331141
    Genome Sequencing for Newborn Screening-An Effective Approach for Tackling Rare Diseases.
    Shan Jiang, Haiyin Wang, Yuanyuan Gu.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2023.31141
  45. Open Res Eur. 2023 ;3 59
    Foresight in clinical proteomics: current status, ethical considerations, and future perspectives.
    Filip Mundt, Nicolai J Wewer Albrechtsen, Sebastian Porsdam Mann, Peter Treit, Medini Ghodgaonkar-Steger, Martina O'Flaherty, Reinout Raijmakers, Juan Antonio Vizcaíno, Albert J R Heck, Matthias Mann.
      With the advent of robust and high-throughput mass spectrometric technologies and bioinformatics tools to analyze large data sets, proteomics has penetrated broadly into basic and translational life sciences research. More than 95% of FDA-approved drugs currently target proteins, and most diagnostic tests are protein-based. The introduction of proteomics to the clinic, for instance to guide patient stratification and treatment, is already ongoing. Importantly, ethical challenges come with this success, which must also be adequately addressed by the proteomics and medical communities. Consortium members of the H2020 European Union-funded proteomics initiative: European Proteomics Infrastructure Consortium-providing access (EPIC-XS) met at the Core Technologies for Life Sciences (CTLS) conference to discuss the emerging role and implementation of proteomics in the clinic. The discussion, involving leaders in the field, focused on the current status, related challenges, and future efforts required to make proteomics a more mainstream technology for translational and clinical research. Here we report on that discussion and provide an expert update concerning the feasibility of clinical proteomics, the ethical implications of generating and analyzing large-scale proteomics clinical data, and recommendations to ensure both ethical and effective implementation in real-world applications.
    Keywords:  Clinical proteomics; clinical research; ethical challenges
    DOI:  https://doi.org/10.12688/openreseurope.15810.1
  46. Nature. 2023 Aug 30.
    Identification of an alternative triglyceride biosynthesis pathway.
    Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.
      Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
    DOI:  https://doi.org/10.1038/s41586-023-06497-4
  47. Nature. 2023 Sep;621(7977): 47-48
    Previously unknown pathway for lipid biosynthesis discovered.
    Jean E Schaffer.
      
    Keywords:  Biochemistry; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-02502-y
  48. Cell Rep. 2023 Aug 31. pii: S2211-1247(23)01065-3. [Epub ahead of print]42(9): 113054
    Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.
    San Joon Lee, Douglas Emery, Eric Vukmanic, Yekai Wang, Xiaoqin Lu, Wei Wang, Enzo Fortuny, Robert James, Henry J Kaplan, Yongqing Liu, Jianhai Du, Douglas C Dean.
      Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.
    Keywords:  CP: Neuroscience; cone metabolism; glucose transport; lactate metabolism; photoreceptor metabolic and epigenetic transcriptomes; retinitis pigmentosa; rod metabolism; single cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.celrep.2023.113054
  49. Biochem Biophys Res Commun. 2023 Aug 17. pii: S0006-291X(23)00979-8. [Epub ahead of print]678 115-121
    Exogenous humanin and MOTS-c function as protective agents against gentamicin-induced hair cell damage.
    Dominique Waldmann, Yu Lu, Maurizio Cortada, Daniel Bodmer, Soledad Levano Huaman.
      Loss of hair cells can lead to irreversible sensorineural hearing loss. Therefore, hair cell preservation is critical for hearing. Mitochondrial derived peptides (MDPs) are bioactive peptides and prominent members of this family are humanin (HN) and the mitochondrial-open-reading frame of the twelve S c (MOTS-c). The protective roles of HN and MOTS-c in age-related diseases and in various tissues exposed to cellular stresses have been demonstrated. The involvement of MDPs in the inner ear remains to be investigated. Therefore, we determined the expression of rattin, the homolog of humanin, in inner ear tissues. Then, we found that HN and MOTS-c showed a significant protective effect on hair cells in organ of Corti explants exposed to gentamicin. Treatment with HN decreased gentamicin-induced phosphorylation of AKT, whereas treatment with MOTS-c increased phosphorylation of AMPKα in explants. Our data indicate that MDPs exert a protective function in gentamicin-induced hair cell damage. Therefore, MDPs may contribute to design new preventive strategies against hearing loss.
    Keywords:  Cochlea; Gentamicin; Hair cells; Humanin; MOTS-C; Mitochondrial derived peptides
    DOI:  https://doi.org/10.1016/j.bbrc.2023.08.033
  50. Neurol Sci. 2023 Aug 30.
    Parkinsonism in complex neurogenetic disorders: lessons from hereditary dementias, adult-onset ataxias and spastic paraplegias.
    Simone Aloisio, Sara Satolli, Gabriele Bellini, Piervito Lopriore.
      Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson's disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism's clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.
    Keywords:  Familial Alzheimer’s disease; Frontotemporal dementia; Hereditary ataxia; Hereditary spastic paraplegia; Neurogenetics; Parkinsonism
    DOI:  https://doi.org/10.1007/s10072-023-07044-9
  51. iScience. 2023 Sep 15. 26(9): 107511
    A unique poly(A) tail profile uncovers the stability and translational activation of TOP transcripts during neuronal differentiation.
    Marine Baptissart, Brian N Papas, Ru-Pin Alicia Chi, Yin Li, Dongwon Lee, Bhairavy Puviindran, Marcos Morgan.
      Cell differentiation is associated with global changes in translational activity. Here, we characterize how mRNA poly(A) tail processing supports this dynamic. We observe that decreased translation during neuronal differentiation of P19 cells correlates with the downregulation of 5'-terminal oligopyrimidine (TOP) transcripts which encode the translational machinery. Despite their downregulation, TOP transcripts remain highly stable and show increased translation as cells differentiate. Changes in TOP mRNA metabolism are reflected by their accumulation with poly(A) tails ∼60-nucleotide (nt) long. The dynamic changes in poly(A) processing can be partially recapitulated by depleting LARP1 or activating the mTOR pathway in undifferentiated cells. Although mTOR-induced accumulation of TOP mRNAs with tails ∼60-nt long does not trigger differentiation, it is associated with reduced proliferation of neuronal progenitors. We propose that while TOP mRNAs are transcriptionally silenced, their post-transcriptional regulation mediated by a specific poly(A) processing ensures an adequate supply of ribosomes to complete differentiation.
    Keywords:  Cell biology; Developmental neuroscience; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107511
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