bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–07–16
fifty-six papers selected by
Catalina Vasilescu, Helmholz Munich
  1. Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.
  2. Mitochondrial transport in symmetric and asymmetric axons with multiple branching junctions: a computational study.
  3. Recent advances in small molecules for improving mitochondrial disorders.
  4. Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation.
  5. Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
  6. Adenine nucleotide carrier protein dysfunction in human disease.
  7. Therapeutic potential of engineering the mitochondrial genome.
  8. Coenzyme Q-related compounds to maintain healthy mitochondria during aging.
  9. Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.
  10. Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit.
  11. Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.
  12. Defining NAD(P)(H) Catabolism.
  13. Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.
  14. Mitochondria as intracellular signalling organelles. An update.
  15. Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse.
  16. Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.
  17. Conduction Defects in Pediatric Patients with Pearson Syndrome: When to Pace?
  18. Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.
  19. Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.
  20. Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
  21. Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.
  22. Histological Examination of Mitochondrial Morphology in a Parkinson's Disease Model.
  23. A case of mitochondrial DNA depletion syndrome type 11 - expanding the genotype and phenotype.
  24. PHB2 ameliorates Doxorubicin-induced cardiomyopathy through interaction with NDUFV2 and restoration of mitochondrial complex I function.
  25. Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
  26. Deep structured learning for variant prioritization in Mendelian diseases.
  27. Metabolic flux in the driver's seat during cardiac health and disease.
  28. Editorial: Energy-producing organelles and the nucleus: a phenomenal genomic friendship.
  29. Mutant SPART causes defects in mitochondrial protein import and bioenergetics reversed by Coenzyme Q.
  30. Increased mitochondrial free Ca2+ during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca2+ uniporter.
  31. Mitochondrial DNA Analysis.
  32. Mitochondria-derived peptides in healthy ageing and therapy of age-related diseases.
  33. TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes.
  34. TUFM-variants lead to white matter abnormalities mimicking multiple sclerosis.
  35. Chasing the right tail: How the ER membrane complex recognizes its substrates.
  36. Aerobic Glycolysis in Photoreceptors Supports Energy Demand in the Absence of Mitochondrial Coupling.
  37. Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.
  38. Acyl-CoA thioesterase-2 facilitates β-oxidation in glycolytic skeletal muscle in a lipid supply dependent manner.
  39. Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae.
  40. TCA cycle deficiency in multiple sclerosis.
  41. Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
  42. Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons.
  43. Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.
  44. Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.
  45. Mitochondria-associated cellular senescence mechanisms: Biochemical and pharmacological perspectives.
  46. Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release.
  47. The role of mitochondria and mitophagy in cell senescence.
  48. The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.
  49. Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset.
  50. Democratising or disrupting diagnosis? Ethical issues raised by the use of AI tools for rare disease diagnosis.
  51. Axonal Transport Defects in Retinal Ganglion Cell Diseases.
  52. Mitochondrial Replacement Therapy: An Islamic Perspective.
  53. Changing ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics.
  54. NAD metabolism: Role in senescence regulation and aging.
  55. De novo design of protein structure and function with RFdiffusion.
  56. Single Extracellular Vesicle Analysis Using Droplet Microfluidics.
  1. EMBO J. 2023 Jul 13. e113256
    Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression.
    Nils Grotehans, Lynn McGarry, Hendrik Nolte, Vanessa Xavier, Moritz Kroker, Álvaro Jesús Narbona-Pérez, Soni Deshwal, Patrick Giavalisco, Thomas Langer, Thomas MacVicar.
      Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.
    Keywords:  NME6; mitochondria; mitochondrial DNA; mitochondrial transcription; nucleotide metabolism
    DOI:  https://doi.org/10.15252/embj.2022113256
  2. Comput Methods Biomech Biomed Engin. 2023 Jul 10. 1-20
    Mitochondrial transport in symmetric and asymmetric axons with multiple branching junctions: a computational study.
    Ivan A Kuznetsov, Andrey V Kuznetsov.
      Mitochondrial aging has been proposed to be involved in a variety of neurodegenerative disorders, such as Parkinson's disease. Here, we explore the impact of multiple branching junctions in axons on the mean age of mitochondria and their age density distributions in demand sites. The study examined mitochondrial concentration, mean age, and age density distribution in relation to the distance from the soma. We developed models for a symmetric axon containing 14 demand sites and an asymmetric axon containing 10 demand sites. We investigated how the concentration of mitochondria changes when an axon splits into two branches at the branching junction. Additionally, we studied whether mitochondrial concentrations in the branches are affected by what proportion of mitochondrial flux enters the upper branch versus the lower branch. Furthermore, we explored whether the distributions of mitochondrial mean age and age density in branching axons are affected by how the mitochondrial flux splits at the branching junction. When the mitochondrial flux is unevenly split at the branching junction of an asymmetric axon, with a greater proportion of the flux entering the longer branch, the average age of mitochondria (system age) in the axon increases. Our findings elucidate the effects of axonal branching on the mitochondrial age.
    Keywords:  Neurodegeneration; Parkinson’s disease; computational biology; large axonal arbors; mitochondrial aging
    DOI:  https://doi.org/10.1080/10255842.2023.2226787
  3. RSC Adv. 2023 Jul 07. 13(30): 20476-20485
    Recent advances in small molecules for improving mitochondrial disorders.
    Liying Meng, Guanzhao Wu.
      Mitochondrial disorders are observed in various human diseases, including rare genetic disorders and complex acquired pathologies. Recent advances in molecular biological techniques have dramatically expanded the understanding of multiple pathomechanisms involving mitochondrial disorders. However, the therapeutic methods for mitochondrial disorders are limited. For this reason, there is increasing interest in identifying safe and effective strategies to mitigate mitochondrial impairments. Small-molecule therapies hold promise for improving mitochondrial performance. This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.
    DOI:  https://doi.org/10.1039/d3ra03313a
  4. Nucleic Acids Res. 2023 Jul 13. pii: gkad591. [Epub ahead of print]
    Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation.
    Saori Ueda, Mikako Yagi, Ena Tomoda, Shinya Matsumoto, Yasushi Ueyanagi, Yura Do, Daiki Setoyama, Yuichi Matsushima, Asuteka Nagao, Tsutomu Suzuki, Tomomi Ide, Yusuke Mori, Noriko Oyama, Dongchon Kang, Takeshi Uchiumi.
      The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.
    DOI:  https://doi.org/10.1093/nar/gkad591
  5. EMBO J. 2023 Jul 10. e112446
    Local coordination of mRNA storage and degradation near mitochondria modulates C. elegans ageing.
    Ioanna Daskalaki, Maria Markaki, Ilias Gkikas, Nektarios Tavernarakis.
      Mitochondria are central regulators of healthspan and lifespan, yet the intricate choreography of multiple, tightly controlled steps regulating mitochondrial biogenesis remains poorly understood. Here, we uncover a pivotal role for specific elements of the 5'-3' mRNA degradation pathway in the regulation of mitochondrial abundance and function. We find that the mRNA degradation and the poly-A tail deadenylase CCR4-NOT complexes form distinct foci in somatic Caenorhabditis elegans cells that physically and functionally associate with mitochondria. Components of these two multi-subunit complexes bind transcripts of nuclear-encoded mitochondria-targeted proteins to regulate mitochondrial biogenesis during ageing in an opposite manner. In addition, we show that balanced degradation and storage of mitochondria-targeted protein mRNAs are critical for mitochondrial homeostasis, stress resistance and longevity. Our findings reveal a multifaceted role of mRNA metabolism in mitochondrial biogenesis and show that fine-tuning of mRNA turnover and local translation control mitochondrial abundance and promote longevity in response to stress and during ageing.
    Keywords:  ageing; mRNA metabolism; mitochondria; protein synthesis; stress
    DOI:  https://doi.org/10.15252/embj.2022112446
  6. IUBMB Life. 2023 Jul 14.
    Adenine nucleotide carrier protein dysfunction in human disease.
    Gargi Mishra, Liam P Coyne, Xin Jie Chen.
      Adenine nucleotide translocase (ANT) is the prototypical member of the mitochondrial carrier protein family, primarily involved in ADP/ATP exchange across the inner mitochondrial membrane. Several carrier proteins evolutionarily related to ANT, including SLC25A24 and SLC25A25, are believed to promote the exchange of cytosolic ATP-Mg2+ with phosphate in the mitochondrial matrix. They allow a net accumulation of adenine nucleotides inside mitochondria, which is essential for mitochondrial biogenesis and cell growth. In the last two decades, mutations in the heart/muscle isoform 1 of ANT (ANT1) and the ATP-Mg2+ transporters have been found to cause a wide spectrum of human diseases by a recessive or dominant mechanism. Although loss-of-function recessive mutations cause a defect in oxidative phosphorylation and an increase in oxidative stress which drives the pathology, it is unclear how the dominant missense mutations in these proteins cause human diseases. In this review, we focus on how yeast was productively used as a model system for the understanding of these dominant diseases. We also describe the relationship between the structure and function of ANT and how this may relate to various pathologies. Particularly, mutations in Aac2, the yeast homolog of ANT, were recently found to clog the mitochondrial protein import pathway. This leads to mitochondrial precursor overaccumulation stress (mPOS), characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. We anticipate that in coming years, yeast will continue to serve as a useful model system for the mechanistic understanding of mitochondrial protein import clogging and related pathologies in humans.
    DOI:  https://doi.org/10.1002/iub.2767
  7. Biochim Biophys Acta Mol Basis Dis. 2023 Jul 08. pii: S0925-4439(23)00170-9. [Epub ahead of print] 166804
    Therapeutic potential of engineering the mitochondrial genome.
    Mengmeng Liu, Wei Ji, Xin Zhao, Xiaoliang Liu, Ji-Fan Hu, Jiuwei Cui.
      Mitochondrial diseases are a group of clinical disorders caused by mutations in the genes encoded by either the nuclear or the mitochondrial genome involved in mitochondrial oxidative phosphorylation. Disorders become evident when mitochondrial dysfunction reaches a cell-specific threshold. Similarly, the severity of disorders is related to the degree of gene mutation. Clinical treatments for mitochondrial diseases mainly rely on symptomatic management. Theoretically, replacing or repairing dysfunctional mitochondria to acquire and preserve normal physiological functions should be effective. Significant advances have been made in gene therapies, including mitochondrial replacement therapy, mitochondrial genome manipulation, nuclease programming, mitochondrial DNA editing, and mitochondrial RNA interference. In this paper, we review the recent progress in these technologies by focusing on advancements that overcome limitations.
    Keywords:  Embryonic stem cell; Mitochondrial disorders; Mitochondrial replacement therapy; Programmable nucleases; mtDNA editing; mtDNA mutation
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166804
  8. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00035-4. [Epub ahead of print]136 277-308
    Coenzyme Q-related compounds to maintain healthy mitochondria during aging.
    Guillermo López-Lluch.
      Mitochondrial dysfunction is one of the main factors that affects aging progression and many age-related diseases. Accumulation of dysfunctional mitochondria can be driven by unbalanced mito/autophagy or by decrease in mitochondrial biosynthesis and turnover. Coenzyme Q is an essential component of the mitochondrial electron transport chain and a key factor in the protection of membrane and mitochondrial DNA against oxidation. Coenzyme Q levels decay during aging and this can be considered an accelerating factor in mitochondrial dysfunction and aging progression. Supplementation with coenzyme Q is successful for some tissues and organs but not for others. For this reason, the role of coenzyme Q in systemic aging is a complex picture that needs different strategies depending on the organ considered the main objective to be addressed. In this chapter we focus on the different effects of coenzyme Q and related compounds and the probable strategies to induce endogenous synthesis to maintain healthy aging.
    Keywords:  Aging; Antioxidant; Coenzyme Q; Health; Inflammation; Mitochondria
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.02.014
  9. Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00067-3. [Epub ahead of print]
    Mitochondrial respiratory complex I deficiency inhibits brown adipogenesis by limiting heme regulation of histone demethylation.
    Jingjing Liu, Wen Lu, Dongyue Yan, Junyuan Guo, Li Zhou, Bimin Shi, Xiong Su.
      Mitochondrial functions play a crucial role in determining the metabolic and thermogenic status of brown adipocytes. Increasing evidence reveals that the mitochondrial oxidative phosphorylation (OXPHOS) system plays an important role in brown adipogenesis, but the mechanistic insights are limited. Herein, we explored the potential metabolic mechanisms leading to OXPHOS regulation of brown adipogenesis in pharmacological and genetic models of mitochondrial respiratory complex I deficiency. OXPHOS deficiency inhibits brown adipogenesis through disruption of the brown adipogenic transcription circuit without affecting ATP levels. Neither blockage of calcium signaling nor antioxidant treatment can rescue the suppressed brown adipogenesis. Metabolomics analysis revealed a decrease in levels of tricarboxylic acid cycle intermediates and heme. Heme supplementation specifically enhances respiratory complex I activity without affecting complex II and partially reverses the inhibited brown adipogenesis by OXPHOS deficiency. Moreover, the regulation of brown adipogenesis by the OXPHOS-heme axis may be due to the suppressed histone methylation status by increasing histone demethylation. In summary, our findings identified a heme-sensing retrograde signaling pathway that connects mitochondrial OXPHOS to the regulation of brown adipocyte differentiation and metabolic functions.
    Keywords:  brown adipocytes; differentiation; heme; histone methylation; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.mito.2023.07.004
  10. Int J Mol Sci. 2023 Jun 27. pii: 10725. [Epub ahead of print]24(13):
    Succinyl-CoA Synthetase Dysfunction as a Mechanism of Mitochondrial Encephalomyopathy: More than Just an Oxidative Energy Deficit.
    Makayla S Lancaster, Brett H Graham.
      Biallelic pathogenic variants in subunits of succinyl-CoA synthetase (SCS), a tricarboxylic acid (TCA) cycle enzyme, are associated with mitochondrial encephalomyopathy in humans. SCS catalyzes the interconversion of succinyl-CoA to succinate, coupled to substrate-level phosphorylation of either ADP or GDP, within the TCA cycle. SCS-deficient encephalomyopathy typically presents in infancy and early childhood, with many patients succumbing to the disease during childhood. Common symptoms include abnormal brain MRI, basal ganglia lesions and cerebral atrophy, severe hypotonia, dystonia, progressive psychomotor regression, and growth deficits. Although subunits of SCS were first identified as causal genes for progressive metabolic encephalomyopathy in the early 2000s, recent investigations are now beginning to unravel the pathomechanisms underlying this metabolic disorder. This article reviews the current understanding of SCS function within and outside the TCA cycle as it relates to the complex and multifactorial mechanisms underlying SCS-related mitochondrial encephalomyopathy.
    Keywords:  encephalomyopathy; mitochondria; mitochondrial DNA; protein succinylation; succinyl-CoA synthetase; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3390/ijms241310725
  11. Sci Rep. 2023 Jul 14. 13(1): 11414
    Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency.
    K L Stauch, S Totusek, A J Trease, L D Estrella, K Emanuel, A Fangmeier, H S Fox.
      Our study utilizes a longitudinal isotopic metabolic labeling approach in vivo in combination with organelle fraction proteomics to address the role of parkin in mitochondrial protein turnover in mice. The use of metabolic labeling provides a method to quantitatively determine the global changes in protein half-lives whilst simultaneously assessing protein expression. Studying two diverse mitochondrial populations, we demonstrated the median half-life of brain striatal synaptic mitochondrial proteins is significantly greater than that of hepatic mitochondrial proteins (25.7 vs. 3.5 days). Furthermore, loss of parkin resulted in an overall, albeit modest, increase in both mitochondrial protein abundance and half-life. Pathway and functional analysis of our proteomics data identified both known and novel pathways affected by loss of parkin that are consistent with its role in both mitochondrial quality control and neurodegeneration. Our study therefore adds to a growing body of evidence suggesting dependence on parkin is low for basal mitophagy in vivo and provides a foundation for the investigation of novel parkin targets.
    DOI:  https://doi.org/10.1038/s41598-023-38484-0
  12. Nutrients. 2023 Jul 07. pii: 3064. [Epub ahead of print]15(13):
    Defining NAD(P)(H) Catabolism.
    Jyothi Dhuguru, Ryan W Dellinger, Marie E Migaud.
      Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD+). NAD+ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD+ levels through supplementation with NAD+ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD+ levels upon administration, although they initially generate NADH (the reduced form of NAD+). Other means to increase the combined levels of NAD+ and NADH, NAD(H), include the inhibition of NAD+-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.
    Keywords:  NAD(P)(H) catabolism; NAD+ metabolism; methyl-nicotinamide; niacin; nicotinamide; pyridone
    DOI:  https://doi.org/10.3390/nu15133064
  13. bioRxiv. 2023 Jun 26. pii: 2023.06.23.546087. [Epub ahead of print]
    Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.
    Hu Wang, Rong Chen, Liming Xiao, Manoj Kumar, Jesús Acevedo-Cintrón, Joanna Siuda, Dariusz Koziorowski, Zbigniew K Wszolek, Valina L Dawson, Ted M Dawson.
      Mutations and loss of activity in the protein kinase PINK1 play a role in the pathogenesis of Parkinson's disease (PD). PINK1 regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy), fission, fusion, transport, and biogenesis. Defects in mitophagy are though to play a predominant role in the loss of dopamine (DA) neurons in PD. Here we show that, although there are defects in mitophagy in human DA neurons lacking PINK1, mitochondrial deficits induced by the absence of PINK1 are primarily due to defects in mitochondrial biogenesis. Upregulation of PARIS and the subsequent down regulation of PGC-1α accounts for the mitochondrial biogenesis defects. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without impacting the deficits in mitophagy due to the absence of PINK1. These results highlight the importance mitochondrial biogenesis in the pathogenesis of PD due to inactivation or loss of PINK1 in human DA neurons.
    DOI:  https://doi.org/10.1101/2023.06.23.546087
  14. Cell Signal. 2023 Jul 06. pii: S0898-6568(23)00208-5. [Epub ahead of print]109 110794
    Mitochondria as intracellular signalling organelles. An update.
    Lucia-Doina Popov.
      Traditionally, mitochondria are known as "the powerhouse of the cell," responsible for energy (ATP) generation (by the electron transport chain, oxidative phosphorylation, the tricarboxylic acid cycle, and fatty acid ß-oxidation), and for the regulation of several metabolic processes, including redox homeostasis, calcium signalling, and cellular apoptosis. The extensive studies conducted in the last decades portray mitochondria as multifaceted signalling organelles that ultimately command cells' survival or death. Based on current knowledge, we'll outline the mitochondrial signalling to other intracellular compartments in homeostasis and pathology-related mitochondrial stress conditions here. The following topics are discussed: (i) oxidative stress and mtROS signalling in mitohormesis, (ii) mitochondrial Ca2+ signalling; (iii) the anterograde (nucleus-to-mitochondria) and retrograde (mitochondria-to-nucleus) signal transduction, (iv) the mtDNA role in immunity and inflammation, (v) the induction of mitophagy- and apoptosis - signalling cascades, (vi) the mitochondrial dysfunctions (mitochondriopathies) in cardiovascular, neurodegenerative, and malignant diseases. The novel insights into molecular mechanisms of mitochondria-mediated signalling can explain mitochondria adaptation to metabolic and environmental stresses to achieve cell survival.
    Keywords:  Mitochondriopathies; Mitophagy; Oxidative stress; Signal transduction; mtDNA
    DOI:  https://doi.org/10.1016/j.cellsig.2023.110794
  15. Int J Mol Sci. 2023 Jun 30. pii: 10973. [Epub ahead of print]24(13):
    Pathophysiology of Cerebellar Degeneration in Mitochondrial Disorders: Insights from the Harlequin Mouse.
    Miguel Fernández de la Torre, Carmen Fiuza-Luces, Sara Laine-Menéndez, Aitor Delmiro, Joaquín Arenas, Miguel Ángel Martín, Alejandro Lucia, María Morán.
      By means of a proteomic approach, we assessed the pathways involved in cerebellar neurodegeneration in a mouse model (Harlequin, Hq) of mitochondrial disorder. A differential proteomic profile study (iTRAQ) was performed in cerebellum homogenates of male Hq and wild-type (WT) mice 8 weeks after the onset of clear symptoms of ataxia in the Hq mice (aged 5.2 ± 0.2 and 5.3 ± 0.1 months for WT and Hq, respectively), followed by a biochemical validation of the most relevant changes. Additional groups of 2-, 3- and 6-month-old WT and Hq mice were analyzed to assess the disease progression on the proteins altered in the proteomic study. The proteomic analysis showed that beyond the expected deregulation of oxidative phosphorylation, the cerebellum of Hq mice showed a marked astroglial activation together with alterations in Ca2+ homeostasis and neurotransmission, with an up- and downregulation of GABAergic and glutamatergic neurotransmission, respectively, and the downregulation of cerebellar "long-term depression", a synaptic plasticity phenomenon that is a major player in the error-driven learning that occurs in the cerebellar cortex. Our study provides novel insights into the mechanisms associated with cerebellar degeneration in the Hq mouse model, including a complex deregulation of neuroinflammation, oxidative phosphorylation and glutamate, GABA and amino acids' metabolism.
    Keywords:  GABA; Harlequin mouse; OXPHOS disorders; ataxia; complex I; glutamate; long-term depression; mitochondrial diseases
    DOI:  https://doi.org/10.3390/ijms241310973
  16. Mitochondrion. 2023 Jul 12. pii: S1567-7249(23)00066-1. [Epub ahead of print]
    Mitochondrial Dysfunction and Skeletal Muscle Atrophy: Causes, Mechanisms, and Treatment Strategies.
    Gokhan Burcin Kubat, Esmaa Bouhamida, Oner Ulger, Ibrahim Turkel, Gaia Pedriali, Daniela Ramaccini, Ozgur Ekinci, Berkay Ozerklig, Ozbeyen Atalay, Simone Patergnani, Beyza Nur Sahin, Giampaolo Morciano, Meltem Tuncer, Elena Tremoli, Paolo Pinton.
      Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
    Keywords:  Skeletal muscle atrophy; cardiovascular diseases; exercise; mitochondria; mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.mito.2023.07.003
  17. Heart Rhythm. 2023 Jul 11. pii: S1547-5271(23)02414-1. [Epub ahead of print]
    Conduction Defects in Pediatric Patients with Pearson Syndrome: When to Pace?
    Saneeha Shahid, Iqbal El Assaad, Akash Patel, Sumit Parikh, Peter F Aziz.
      
    Keywords:  Pearson syndrome; conduction defect; heart block; mitochondrial disease; pacemaker
    DOI:  https://doi.org/10.1016/j.hrthm.2023.07.004
  18. Semin Cell Dev Biol. 2023 Jul 10. pii: S1084-9521(23)00141-6. [Epub ahead of print]
    Shedding light on mitochondrial outer-membrane permeabilization and membrane potential: State of the art methods and biosensors.
    Nikolay Popgeorgiev, Clara Gil, Kevin Berthenet, Giulia Bertolin, Gabriel Ichim.
      Membrane structural integrity is essential for optimal mitochondrial function. These organelles produce the energy needed for all vital processes, provided their outer and inner membranes are intact. This prevents the release of mitochondrial apoptogenic factors into the cytosol and ensures intact mitochondrial membrane potential (ΔΨm) to sustain ATP production. Cell death by apoptosis is generally triggered by outer mitochondrial membrane permeabilization (MOMP), tightly coupled with loss of ΔΨ m. As these two processes are essential for both mitochondrial function and cell death, researchers have devised various techniques to assess them. Here, we discuss current methods and biosensors available for detecting MOMP and measuring ΔΨ m, focusing on their advantages and limitations and discuss what new imaging tools are needed to improve our knowledge of mitochondrial function.
    Keywords:  Biosensor; MOMP; Microscopy; Mitochondrial membrane potential
    DOI:  https://doi.org/10.1016/j.semcdb.2023.07.003
  19. Nat Metab. 2023 Jul 10.
    Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.
    Yi-Heng Tai, Daniel Engels, Giuseppe Locatelli, Ioanna Emmanouilidis, Caroline Fecher, Delphine Theodorou, Stephan A Müller, Simon Licht-Mayer, Mario Kreutzfeldt, Ingrid Wagner, Natalia Prudente de Mello, Sofia-Natsouko Gkotzamani, Laura Trovò, Arek Kendirli, Almir Aljović, Michael O Breckwoldt, Ronald Naumann, Florence M Bareyre, Fabiana Perocchi, Don Mahad, Doron Merkler, Stefan F Lichtenthaler, Martin Kerschensteiner, Thomas Misgeld.
      Inflammation in the central nervous system can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell-type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.
    DOI:  https://doi.org/10.1038/s42255-023-00838-3
  20. Nat Commun. 2023 07 11. 14(1): 4105
    Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
    Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.
      Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.
    DOI:  https://doi.org/10.1038/s41467-023-39811-9
  21. Front Cell Dev Biol. 2023 ;11 1212779
    Regulation of mitochondrial morphology and cristae architecture by the TLR4 pathway in human skeletal muscle.
    Mauricio Castro-Sepulveda, Mauro Tuñón-Suárez, Giovanni Rosales-Soto, Ronald Vargas-Foitzick, Louise Deldicque, Hermann Zbinden-Foncea.
      In skeletal muscle (SkM), a reduced mitochondrial elongate phenotype is associated with several metabolic disorders like type 2 diabetes mellitus (T2DM). However, the mechanisms contributing to this reduction in mitochondrial elongate phenotype in SkM have not been fully elucidated. It has recently been shown in a SkM cell line that toll-like receptor 4 (TLR4) contributes to the regulation of mitochondrial morphology. However, this has not been investigated in human SkM. Here we found that in human SkM biopsies, TLR4 protein correlated negatively with Opa1 (pro-mitochondrial fusion protein). Moreover, the incubation of human myotubes with LPS reduced mitochondrial size and elongation and induced abnormal mitochondrial cristae, which was prevented with the co-incubation of LPS with TAK242. Finally, T2DM myotubes were found to have reduced mitochondrial elongation and mitochondrial cristae density. Mitochondrial morphology, membrane structure, and insulin-stimulated glucose uptake were restored to healthy levels in T2DM myotubes treated with TAK242. In conclusion, mitochondrial morphology and mitochondrial cristae seem to be regulated by the TLR4 pathway in human SkM. Those mitochondrial alterations might potentially contribute to insulin resistance in the SkM of patients with T2DM.
    Keywords:  Lipopolysaccharide; TAK242; mitochondrial dynamics; mitochondrial nanotunnels; skeletal muscle function; type 2 diabetes
    DOI:  https://doi.org/10.3389/fcell.2023.1212779
  22. J Vis Exp. 2023 06 23.
    Histological Examination of Mitochondrial Morphology in a Parkinson's Disease Model.
    Dalila Ciceri, Lierni Gregorio-Zabala, Xabier Llama-Pino, Begüm Kurt, Jon Olano-Bringas, Patricia Villegas-Zafra, Nora Bengoa-Vergniory.
      Mitochondria play a central role in the energy metabolism of cells, and their function is especially important for neurons due to their high energy demand. Therefore, mitochondrial dysfunction is a pathological hallmark of various neurological disorders, including Parkinson's disease. The shape and organization of the mitochondrial network is highly plastic, which allows the cell to respond to environmental cues and needs, and the structure of mitochondria is also tightly linked to their health. Here, we present a protocol to study mitochondrial morphology in situ based on immunostaining of the mitochondrial protein VDAC1 and subsequent image analysis. This tool could be particularly useful for the study of neurodegenerative disorders because it can detect subtle differences in mitochondrial counts and shape induced by aggregates of α-synuclein, an aggregation-prone protein heavily involved in the pathology of Parkinson's disease. This method allows one to report that substantia nigra pars compacta dopaminergic neurons harboring pS129 lesions show mitochondrial fragmentation (as suggested by their reduced Aspect Ratio, AR) compared to their healthy neighboring neurons in a pre-formed fibril intracranial injection Parkinson model.
    DOI:  https://doi.org/10.3791/65453
  23. Neuromuscul Disord. 2023 Jun 21. pii: S0960-8966(23)00152-9. [Epub ahead of print]
    A case of mitochondrial DNA depletion syndrome type 11 - expanding the genotype and phenotype.
    Emanuelle Bianchi da Silva Rocha, Ketteny de Lima Rodrigues, Laura Alonso Matheus Montouro, Érica Nogueira Coelho, João Aris Kouyoumdjian, Fernando Kok, Paulo Ribeiro Nóbrega, Carla Renata Graca, Maria da Penha Ananias Morita, Eduardo de Paula Estephan.
      Mitochondrial DNA depletion syndrome type 11 (MTDPS11) is caused by pathogenic variants in MGME1 gene. We report a woman, 40-year-old, who presented slow progressive drop eyelid at 11-year-old with, learning difficulty and frequent falls. Phisical examination revealed: mild scoliosis, elbow hyperextensibility, flat feet, chronic progressive external ophthalmoplegia with upper eyelid ptosis, diffuse hypotonia, and weakness of arm abduction and neck flexion. Investigation evidenced mild serum creatine kinase increase and glucose intolerance; second-degree atrioventricular block; mild mixed-type respiratory disorder and atrophy and granular appearance of the retinal pigment epithelium. Brain magnetic resonance showed cerebellar atrophy. Muscle biopsy was compatible with mitochondrial myopathy. Genetic panel revealed a homozygous pathogenic variant in the MGME1 gene, consistent with MTDPS11 (c.862C>T; p.Gln288*). This case of MTDPS11 can contribute to the phenotypic characterization of this ultra-rare mitochondrial disorder, presenting milder respiratory and nutritional involvement than the previously reported cases, with possible additional features.
    Keywords:  Chronic progressive external ophthalmoplegia; MGME1; Mitochondrial diseases; mtDNA depletion syndrome
    DOI:  https://doi.org/10.1016/j.nmd.2023.06.004
  24. Redox Biol. 2023 Jul 12. pii: S2213-2317(23)00213-6. [Epub ahead of print]65 102812
    PHB2 ameliorates Doxorubicin-induced cardiomyopathy through interaction with NDUFV2 and restoration of mitochondrial complex I function.
    Mingjie Yang, Miyesaier Abudureyimu, Xiang Wang, Yuan Zhou, Yingmei Zhang, Jun Ren.
       BACKGROUND: Doxorubicin (DOX) is among the most widely employed antitumor agents, although its clinical applications have been largely hindered by severe cardiotoxicity. Earlier studies described an essential role of mitochondrial injury in the pathogenesis of DOX cardiomyopathy. PHB2 (Prohibitin 2) is perceived as an essential regulator for mitochondrial dynamics and oxidative phosphorylation (OXPHOS) although its involvement in DOX cardiomyopathy remains elusive.
    METHODS: To decipher the possible role of PHB2 in DOX cardiomyopathy, tamoxifen-induced cardiac-specific PHB2 conditional knockout mice were generated and subjected to DOX challenge. Cardiac function and mitochondrial profiles were examined. Screening of downstream mediators of PHB2 was performed using proteomic profiling and bioinformatic analysis, and was further verified using co-immunoprecipitation and pulldown assays.
    RESULTS: Our data revealed significantly downregulated PHB2 expression in DOX-challenged mouse hearts. PHB2CKO mice were more susceptible to DOX cardiotoxicity compared with PHB2flox/flox mice, as evidenced by more pronounced cardiac atrophy, interstitial fibrosis and decrease in left ventricular ejection fraction and fractional shortening. Mechanistically, PHB2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that PHB2 interacted with NDUFV2 (NADH-ubiquinone oxidoreductase core subunit V2), a key subunit of mitochondrial respiratory Complex I to mediate regulatory property of PHB2 on mitochondrial metabolism. PHB2 governed the expression of NDUFV2 by promoting its stabilization, while PHB2 deficiency significantly downregulated NDUFV2 in DOX-challenged hearts. Cardiac overexpression of PHB2 alleviated mitochondrial defects in DOX cardiomyopathy both in vivo and in vitro.
    CONCLUSIONS: Our study defined a novel role for PHB2 in mitochondrial dynamics and energetic metabolism through interacting with NDUFV2 in DOX-challenged hearts. Forced overexpression of PHB2 may be considered a promising therapeutic approach for patients with DOX cardiomyopathy.
    Keywords:  Doxorubicin cardiotoxicity; Mitochondrial complex I; NDUFV2; PHB2
    DOI:  https://doi.org/10.1016/j.redox.2023.102812
  25. Nat Commun. 2023 07 11. 14(1): 4092
    Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction.
    Minji Kim, Remigiusz A Serwa, Lukasz Samluk, Ida Suppanz, Agata Kodroń, Tomasz M Stępkowski, Praveenraj Elancheliyan, Biniyam Tsegaye, Silke Oeljeklaus, Michal Wasilewski, Bettina Warscheid, Agnieszka Chacinska.
      Perturbed cellular protein homeostasis (proteostasis) and mitochondrial dysfunction play an important role in neurodegenerative diseases, however, the interplay between these two phenomena remains unclear. Mitochondrial dysfunction leads to a delay in mitochondrial protein import, causing accumulation of non-imported mitochondrial proteins in the cytosol and challenging proteostasis. Cells respond by increasing proteasome activity and molecular chaperones in yeast and C. elegans. Here, we demonstrate that in human cells mitochondrial dysfunction leads to the upregulation of a chaperone HSPB1 and, interestingly, an immunoproteasome-specific subunit PSMB9. Moreover, PSMB9 expression is dependent on the translation elongation factor EEF1A2. These mechanisms constitute a defense response to preserve cellular proteostasis under mitochondrial stress. Our findings define a mode of proteasomal activation through the change in proteasome composition driven by EEF1A2 and its spatial regulation, and are useful to formulate therapies to prevent neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-023-39642-8
  26. Nat Commun. 2023 Jul 13. 14(1): 4167
    Deep structured learning for variant prioritization in Mendelian diseases.
    Matt C Danzi, Maike F Dohrn, Sarah Fazal, Danique Beijer, Adriana P Rebelo, Vivian Cintra, Stephan Züchner.
      Effective computer-aided or automated variant evaluations for monogenic diseases will expedite clinical diagnostic and research efforts of known and novel disease-causing genes. Here we introduce MAVERICK: a Mendelian Approach to Variant Effect pRedICtion built in Keras. MAVERICK is an ensemble of transformer-based neural networks that can classify a wide range of protein-altering single nucleotide variants (SNVs) and indels and assesses whether a variant would be pathogenic in the context of dominant or recessive inheritance. We demonstrate that MAVERICK outperforms all other major programs that assess pathogenicity in a Mendelian context. In a cohort of 644 previously solved patients with Mendelian diseases, MAVERICK ranks the causative pathogenic variant within the top five variants in over 95% of cases. Seventy-six percent of cases were solved by the top-ranked variant. MAVERICK ranks the causative pathogenic variant in hitherto novel disease genes within the first five candidate variants in 70% of cases. MAVERICK has already facilitated the identification of a novel disease gene causing a degenerative motor neuron disease. These results represent a significant step towards automated identification of causal variants in patients with Mendelian diseases.
    DOI:  https://doi.org/10.1038/s41467-023-39306-7
  27. J Mol Cell Cardiol. 2023 Jul 12. pii: S0022-2828(23)00110-4. [Epub ahead of print]182 15-24
    Metabolic flux in the driver's seat during cardiac health and disease.
    E Douglas Lewandowski.
      Cardiac function is a dynamic process that must adjust efficiently to the immediate demands of physical state and activity. So too, the metabolic support of cardiac function is a dynamic process that must respond, in time, to the demands of cardiac function and viability. Flux through metabolic pathways provides chemical energy and generates signaling molecules that regulate activity among intracellular compartments to meet these demands. Thus, flux through metabolic pathways provides a dynamic mode of support of cardiomyocytes during physiological and pathophysiological challenges. Any inability of metabolic flux to keep pace with the demands of the cardiomyocyte results in progressive dysfunction that contributes to cardiac disease. Thus, the priority in maintaining and regulating flux through metabolic pathways in the cardiomyocyte cannot be understated. Great potential exists in current efforts to elucidate metabolic mechanisms as therapeutic targets for the diseased heart. As a consequence, detecting metabolic flux in the functioning myocardium of the heart, under normal and diseased conditions, is essential in elucidating the metabolic basis of contractile dysfunction. As a companion to the 2022 ISHR Research Achievement Award lecture, this review examines the use and applications of stable isotope kinetics to quantify metabolic flux through intermediary pathways and the exchange and transport of intermediates across the mitochondrial membrane and sarcolemma of intact functioning hearts in determining how these intracellular events are coordinated to support cardiac function and health. Finally, this work reviews recently demonstrated metabolic defects in diseased hearts and the potential for metabolic alleviation of heart disease.
    Keywords:  Fatty acids; Glucose; Heart failure; Ischemia/Reperfusion; Isotopes; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.yjmcc.2023.07.004
  28. Front Genet. 2023 ;14 1230032
    Editorial: Energy-producing organelles and the nucleus: a phenomenal genomic friendship.
    Dmytro V Gospodaryov, J William O Ballard, M Florencia Camus, Rob DeSalle, Michael R Garvin, Uwe Richter.
      
    Keywords:  Caenorhabditis elegans; Drosophila melanogaster; chloroplast; endosymbioses; mitochondria; mitochondrial genome; mitonuclear coadaptation; mitonuclear coevolution
    DOI:  https://doi.org/10.3389/fgene.2023.1230032
  29. Open Biol. 2023 07;13(7): 230040
    Mutant SPART causes defects in mitochondrial protein import and bioenergetics reversed by Coenzyme Q.
    Chiara Diquigiovanni, Nicola Rizzardi, Antje Kampmeier, Irene Liparulo, Francesca Bianco, Bianca De Nicolo, Erica Cataldi-Stagetti, Elisabetta Cuna, Giulia Severi, Marco Seri, Miriam Bertrand, Tobias B Haack, Adela Della Marina, Frederik Braun, Romana Fato, Alma Kuechler, Christian Bergamini, Elena Bonora.
      Pathogenic variants in SPART cause Troyer syndrome, characterized by lower extremity spasticity and weakness, short stature and cognitive impairment, and a severe mitochondrial impairment. Herein, we report the identification of a role of Spartin in nuclear-encoded mitochondrial proteins. SPART biallelic missense variants were detected in a 5-year-old boy with short stature, developmental delay and muscle weakness with impaired walking distance. Patient-derived fibroblasts showed an altered mitochondrial network, decreased mitochondrial respiration, increased mitochondrial reactive oxygen species and altered Ca2+ versus control cells. We investigated the mitochondrial import of nuclear-encoded proteins in these fibroblasts and in another cell model carrying a SPART loss-of-function mutation. In both cell models the mitochondrial import was impaired, leading to a significant decrease in different proteins, including two key enzymes involved in CoQ10 (CoQ) synthesis, COQ7 and COQ9, with a severe reduction in CoQ content, versus control cells. CoQ supplementation restored cellular ATP levels to the same extent shown by the re-expression of wild-type SPART, suggesting CoQ treatment as a promising therapeutic approach for patients carrying mutations in SPART.
    Keywords:  Coenzyme Q; SPG20; Spartin; bioenergetics; mitochondrial protein import
    DOI:  https://doi.org/10.1098/rsob.230040
  30. Cell Rep. 2023 Jul 07. pii: S2211-1247(23)00746-5. [Epub ahead of print]42(7): 112735
    Increased mitochondrial free Ca2+ during ischemia is suppressed, but not eliminated by, germline deletion of the mitochondrial Ca2+ uniporter.
    Courtney E Petersen, Junhui Sun, Kavisha Silva, Anna Kosmach, Robert S Balaban, Elizabeth Murphy.
      Mitochondrial Ca2+ overload is proposed to regulate cell death via opening of the mitochondrial permeability transition pore. It is hypothesized that inhibition of the mitochondrial Ca2+ uniporter (MCU) will prevent Ca2+ accumulation during ischemia/reperfusion and thereby reduce cell death. To address this, we evaluate mitochondrial Ca2+ in ex-vivo-perfused hearts from germline MCU-knockout (KO) and wild-type (WT) mice using transmural spectroscopy. Matrix Ca2+ levels are measured with a genetically encoded, red fluorescent Ca2+ indicator (R-GECO1) using an adeno-associated viral vector (AAV9) for delivery. Due to the pH sensitivity of R-GECO1 and the known fall in pH during ischemia, hearts are glycogen depleted to decrease the ischemic fall in pH. At 20 min of ischemia, there is significantly less mitochondrial Ca2+ in MCU-KO hearts compared with MCU-WT controls. However, an increase in mitochondrial Ca2+ is present in MCU-KO hearts, suggesting that mitochondrial Ca2+ overload during ischemia is not solely dependent on MCU.
    Keywords:  CP: Developmental biology; MCU; calcium; cardioprotection; ischemia-reperfusion; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.112735
  31. Methods Mol Biol. 2023 ;2685 331-349
    Mitochondrial DNA Analysis.
    Ashley M Cooley.
      Mitochondrial DNA (mtDNA) is a 16,569 base pair (bp) circular genome that is passed from generation to generation through the maternal line. mtDNA analysis in the context of the forensic science field usually involves unidentified human remains or missing persons. These cases tend to have more challenging sample types (e.g., rootless hairs, bone, blood, and saliva), and mtDNA analysis can be an additional method to assist in identification efforts. Due to the multifaceted protection of mtDNA within cells, mtDNA is able to be extracted even in cases of extreme degradation. mtDNA analysis for forensic science has been both peer-reviewed in academic journals and has been testified to in criminal court procedures since the late 1990s, allowing for consistent and reliable usage in casework. This chapter describes the general methodology of extracting, amplifying, quantifying, and analyzing an mtDNA sequence for use in forensic casework, specifically for these common items of evidence.
    Keywords:  Bone analysis; DNA sequencing; DNA typing; Forensic DNA analysis; Forensic science; Hair analysis; Mitochondrial DNA
    DOI:  https://doi.org/10.1007/978-1-0716-3295-6_20
  32. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00036-6. [Epub ahead of print]136 197-215
    Mitochondria-derived peptides in healthy ageing and therapy of age-related diseases.
    Siarhei A Dabravolski.
      Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by mitochondrial DNA and involved in various stress-protecting mechanisms. To date, eight mitochondrial-derived peptides have been identified: MOTS-c sequence is hidden in the 12 S rRNA gene (MT-RNR1), and the other 7 (humanin and small humanin-like peptides 1-6) are encoded by the 16 S rRNA (MT-RNR2) gene. While the anti-apoptotic, anti-inflammatory and cardioprotective activities of MDPs are well described, recent research suggests that MDPs are sensitive metabolic sensors, closely connected with mtDNA mutation-associated diseases and age-associated metabolic disorders. In this chapter, we focus on the recent progress in understanding the metabolo-protective properties of MDPs, their role in maintenance of the cellular and mitochondrial homeostasis associated with age-related diseases: Alzheimer's disease, cognitive decline, macular degeneration and cataracts. Also, we will discuss MDPs-based and MDPs-targeted interventions to treat age-related diseases and extend a healthy lifespan.
    Keywords:  Age-related macular degeneration; Ageing; Alzheimer’s disease; Healthspan; Humanin; Lifespan; MOTS-c; Mitochondria-derived peptides; SHLPs
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.02.015
  33. bioRxiv. 2023 Jun 26. pii: 2023.06.24.546411. [Epub ahead of print]
    TOMM40 and TOMM22 of the Translocase Outer Mitochondrial Membrane Complex rescue statin-impaired mitochondrial dynamics, morphology, and mitophagy in skeletal myotubes.
    Neil V Yang, Sean Rogers, Rachel Guerra, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss.
       Background: Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated as a cause of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates transcription of TOMM40 and TOMM22 , genes that encode major subunits of the translocase of outer mitochondrial membrane (TOM) complex which is responsible for importing nuclear-encoded proteins and maintaining mitochondrial function. We therefore investigated the role of TOMM40 and TOMM22 in mediating statin effects on mitochondrial function, dynamics, and mitophagy.
    Methods: Cellular and biochemical assays and transmission electron microscopy were used to investigate effects of simvastatin and TOMM40 and TOMM22 expression on measures of mitochondrial function and dynamics in C2C12 and primary human skeletal cell myotubes.
    Results: Knockdown of TOMM40 and TOMM22 in skeletal cell myotubes impaired mitochondrial oxidative function, increased production of mitochondrial superoxide, reduced mitochondrial cholesterol and CoQ levels, disrupted mitochondrial dynamics and morphology, and increased mitophagy, with similar effects resulting from simvastatin treatment. Overexpression of TOMM40 and TOMM22 in simvastatin-treated muscle cells rescued statin effects on mitochondrial dynamics, but not on mitochondrial function or cholesterol and CoQ levels. Moreover, overexpression of these genes resulted in an increase in number and density of cellular mitochondria.
    Conclusion: These results confirm that TOMM40 and TOMM22 are central in regulating mitochondrial homeostasis and demonstrate that downregulation of these genes by statin treatment mediates disruption of mitochondrial dynamics, morphology, and mitophagy, effects that may contribute to statin-induced myopathy.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2023.06.24.546411
  34. Eur J Neurol. 2023 Jul 11.
    TUFM-variants lead to white matter abnormalities mimicking multiple sclerosis.
    Shihan Chen, Grant A Mitchell, Jean-Francois Soucy, Julie Gauthier, Bernard Brais, Roberta La Piana.
       BACKGROUND: Defects in the mitochondrial respiratory chain (MRC) can lead to combined MRC dysfunctions (COXPDs) with heterogenous genotypes and clinical features. We report a patient carrying heterozygous variants in the TUFM gene who presented with clinical features compatible with COXPD4 and radiological findings mimicking multiple sclerosis (MS).
    METHODS: A 37-year-old French Canadian woman was investigated for recent onset of gait and balance problems. Her previous medical history included recurrent episodes of hyperventilation associated with lactic acidosis during infections, asymptomatic Wolff-Parkinson-White syndrome, and non-progressive sensorineural deafness.
    RESULTS: Neurological examinations revealed fine bilateral nystagmus, facial weakness, hypertonia, hyperreflexia, dysdiadochokinesia and dysmetria, and ataxic gait. Brain MRI showed multifocal white matter abnormalities in cerebral white matter as well as cerebellar hemispheres, brainstem, middle cerebellar peduncles, some of which mimicking MS. Analysis of native-state OXPHOS showed a combined decrease in CI/CII, CIV/CII, and CVI/CII. Exome sequencing detected two heterozygous TUFM gene variants. Little clinical progression was noted over a 5-year follow-up. Brain MRI remained unchanged.
    CONCLUSIONS: Our report broadens the phenotypic and radiological spectrum of TUFM-related disorders by adding milder, later-onset forms to the previously known early-onset, severe presentations. The presence of multifocal white matter abnormalities can be misinterpreted as due to acquired demyelinating diseases and thus, TUFM-related disorders should be added to the list of mitochondrial MS mimickers.
    Keywords:  TUFM; mitochondrial diseases; multiple sclerosis; white matter abnormalities
    DOI:  https://doi.org/10.1111/ene.15982
  35. J Cell Biol. 2023 08 07. pii: e202306035. [Epub ahead of print]222(8):
    Chasing the right tail: How the ER membrane complex recognizes its substrates.
    Doron Rapaport, Johannes M Herrmann.
      Tail-anchored proteins are tethered to membranes of the ER, mitochondria, and peroxisomes. In this issue, Pleiner and colleagues (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202212007) show that the ER membrane complex (EMC) uses an inbuilt charge-dependent selectivity filter to specifically insert ER tail-anchored proteins according to their topology signals and to prevent the misincorporation of mitochondrial proteins.
    DOI:  https://doi.org/10.1083/jcb.202306035
  36. Adv Exp Med Biol. 2023 ;1415 435-441
    Aerobic Glycolysis in Photoreceptors Supports Energy Demand in the Absence of Mitochondrial Coupling.
    Daniel T Hass, Celia M Bisbach, Martin Sadilek, Ian R Sweet, James B Hurley.
      Metabolism is adapted to meet energetic needs. Based on the amount of ATP required to maintain plasma membrane potential, photoreceptor energy demands must be high. The available evidence suggests that photoreceptors primarily generate metabolic energy through aerobic glycolysis, though this evidence is based primarily on protein expression and not measurement of metabolic flux. Aerobic glycolysis can be validated by measuring flux of glucose to lactate. Aerobic glycolysis is also inefficient and thus an unexpected adaptation for photoreceptors to make. We measured metabolic rates to determine the energy-generating pathways that support photoreceptor metabolism. We found that photoreceptors indeed perform aerobic glycolysis and this is associated with mitochondrial uncoupling.
    Keywords:  Aerobic glycolysis; Metabolic flux; Mitochondria; Photoreceptors; Retina; Uncoupling
    DOI:  https://doi.org/10.1007/978-3-031-27681-1_64
  37. PLoS Genet. 2023 Jul 13. 19(7): e1010828
    Loss of STING in parkin mutant flies suppresses muscle defects and mitochondria damage.
    Andrew T Moehlman, Gil Kanfer, Richard J Youle.
      The early pathogenesis and underlying molecular causes of motor neuron degeneration in Parkinson's Disease (PD) remains unresolved. In the model organism Drosophila melanogaster, loss of the early-onset PD gene parkin (the ortholog of human PRKN) results in impaired climbing ability, damage to the indirect flight muscles, and mitochondrial fragmentation with swelling. These stressed mitochondria have been proposed to activate innate immune pathways through release of damage associated molecular patterns (DAMPs). Parkin-mediated mitophagy is hypothesized to suppress mitochondrial damage and subsequent activation of the cGAS/STING innate immunity pathway, but the relevance of this interaction in the fly remains unresolved. Using a combination of genetics, immunoassays, and RNA sequencing, we investigated a potential role for STING in the onset of parkin-null phenotypes. Our findings demonstrate that loss of Drosophila STING in flies rescues the thorax muscle defects and the climbing ability of parkin-/- mutants. Loss of STING also suppresses the disrupted mitochondrial morphology in parkin-/- flight muscles, suggesting unexpected feedback of STING on mitochondria integrity or activation of a compensatory mitochondrial pathway. In the animals lacking both parkin and sting, PINK1 is activated and cell death pathways are suppressed. These findings support a unique, non-canonical role for Drosophila STING in the cellular and organismal response to mitochondria stress.
    DOI:  https://doi.org/10.1371/journal.pgen.1010828
  38. bioRxiv. 2023 Jun 27. pii: 2023.06.27.546724. [Epub ahead of print]
    Acyl-CoA thioesterase-2 facilitates β-oxidation in glycolytic skeletal muscle in a lipid supply dependent manner.
    Carmen Bekeova, Ji In Han, Heli Xu, Evan Kerr, Brittney Blackburne, Shannon C Lynch, Clementina Mesaros, Marta Murgia, Rajanikanth Vadigepalli, Joris Beld, Roberta Leonardi, Nathaniel W Snyder, Erin L Seifert.
      Acyl-Coenzyme A (acyl-CoA) thioesters are compartmentalized intermediates that participate in in multiple metabolic reactions within the mitochondrial matrix. The limited availability of free CoA (CoASH) in the matrix raises the question of how the local acyl-CoA concentration is regulated to prevent trapping of CoASH from overload of any specific substrate. Acyl-CoA thioesterase-2 (ACOT2) hydrolyzes long-chain acyl-CoAs to their constituent fatty acids and CoASH, and is the only mitochondrial matrix ACOT refractory to inhibition by CoASH. Thus, we reasoned that ACOT2 may constitutively regulate matrix acyl-CoA levels. Acot2 deletion in murine skeletal muscle (SM) resulted in acyl-CoA build-up when lipid supply and energy demands were modest. When energy demand and pyruvate availability were elevated, lack of ACOT2 activity promoted glucose oxidation. This preference for glucose over fatty acid oxidation was recapitulated in C2C12 myotubes with acute depletion of Acot2 , and overt inhibition of β-oxidation was demonstrated in isolated mitochondria from Acot2 -depleted glycolytic SM. In mice fed a high fat diet, ACOT2 enabled the accretion of acyl-CoAs and ceramide derivatives in glycolytic SM, and this was associated with worse glucose homeostasis compared to when ACOT2 was absent. These observations suggest that ACOT2 supports CoASH availability to facilitate β-oxidation in glycolytic SM when lipid supply is modest. However, when lipid supply is high, ACOT2 enables acyl-CoA and lipid accumulation, CoASH sequestration, and poor glucose homeostasis. Thus, ACOT2 regulates matrix acyl-CoA concentration in glycolytic muscle, and its impact depends on lipid supply.
    DOI:  https://doi.org/10.1101/2023.06.27.546724
  39. Int J Mol Sci. 2023 Jun 27. pii: 10696. [Epub ahead of print]24(13):
    Drug Drop Test: How to Quickly Identify Potential Therapeutic Compounds for Mitochondrial Diseases Using Yeast Saccharomyces cerevisiae.
    Martina Magistrati, Alexandru Ionut Gilea, Maria Carla Gerra, Enrico Baruffini, Cristina Dallabona.
      Mitochondrial diseases (MDs) refer to a group of clinically and genetically heterogeneous pathologies characterized by defective mitochondrial function and energy production. Unfortunately, there is no effective treatment for most MDs, and current therapeutic management is limited to relieving symptoms. The yeast Saccharomyces cerevisiae has been efficiently used as a model organism to study mitochondria-related disorders thanks to its easy manipulation and well-known mitochondrial biogenesis and metabolism. It has been successfully exploited both to validate alleged pathogenic variants identified in patients and to discover potential beneficial molecules for their treatment. The so-called "drug drop test", a phenotype-based high-throughput screening, especially if coupled with a drug repurposing approach, allows the identification of molecules with high translational potential in a cost-effective and time-saving manner. In addition to drug identification, S. cerevisiae can be used to point out the drug's target or pathway. To date, drug drop tests have been successfully carried out for a variety of disease models, leading to very promising results. The most relevant aspect is that studies on more complex model organisms confirmed the effectiveness of the drugs, strengthening the results obtained in yeast and demonstrating the usefulness of this screening as a novel approach to revealing new therapeutic molecules for MDs.
    Keywords:  Saccharomyces cerevisiae; drug drop test; drug repurposing; mitochondrial diseases; yeast model
    DOI:  https://doi.org/10.3390/ijms241310696
  40. Nat Metab. 2023 Jul 10.
    TCA cycle deficiency in multiple sclerosis.
    Swadha Mishra, Fabian den Brave, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s42255-023-00840-9
  41. Mov Disord. 2023 Jul 14.
    Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
    Dajana Grossmann, Nina Malburg, Hannes Glaß, Veronika Weeren, Verena Sondermann, Julia F Pfeiffer, Janine Petters, Jan Lukas, Philip Seibler, Christine Klein, Anne Grünewald, Andreas Hermann.
       BACKGROUND: It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the regulation of mitochondria-endoplasmic reticulum contact sites (MERCSs).
    OBJECTIVE: The aim of our study was to perform an in-depth analysis of the role of MERCSs and impaired calcium homeostasis in PINK1/Parkin-linked PD.
    METHODS: In our study, we used induced pluripotent stem cell-derived dopaminergic neurons from patients with PD with loss-of-function mutations in PINK1 or PRKN. We employed a split-GFP-based contact site sensor in combination with the calcium-sensitive dye Rhod-2 AM and applied Airyscan live-cell super-resolution microscopy to determine how MERCSs are involved in the regulation of mitochondrial calcium homeostasis.
    RESULTS: Our results showed that thapsigargin-induced calcium stress leads to an increase of the abundance of narrow MERCSs in wild-type neurons. Intriguingly, calcium levels at the MERCSs remained stable, whereas the increased net calcium influx resulted in elevated mitochondrial calcium levels. However, PINK1-PD or PRKN-PD neurons showed an increased abundance of MERCSs at baseline, accompanied by an inability to further increase MERCSs upon thapsigargin-induced calcium stress. Consequently, calcium distribution at MERCSs and within mitochondria was disrupted.
    CONCLUSIONS: Our results demonstrated how the endoplasmic reticulum and mitochondria work together to cope with calcium stress in wild-type neurons. In addition, our results suggests that PRKN deficiency affects the dynamics and composition of MERCSs differently from PINK1 deficiency, resulting in differentially affected calcium homeostasis. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
    Keywords:  PINK1; Parkin; Parkinson´s disease; calcium; mitochondria-ER contact sites
    DOI:  https://doi.org/10.1002/mds.29525
  42. iScience. 2023 Jul 21. 26(7): 107044
    Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons.
    Dayne A Beccano-Kelly, Marta Cherubini, Yassine Mousba, Kaitlyn M L Cramb, Stefania Giussani, Maria Claudia Caiazza, Pavandeep Rai, Siv Vingill, Nora Bengoa-Vergniory, Bryan Ng, Gabriele Corda, Abhirup Banerjee, Jane Vowles, Sally Cowley, Richard Wade-Martins.
      Parkinson's disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD.
    Keywords:  Cellular neuroscience; Pathophysiology; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2023.107044
  43. Psychoneuroendocrinology. 2023 Jun 14. pii: S0306-4530(23)00300-1. [Epub ahead of print]155 106322
    Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.
    Natalia Bobba-Alves, Gabriel Sturm, Jue Lin, Sarah A Ware, Kalpita R Karan, Anna S Monzel, Céline Bris, Vincent Procaccio, Guy Lenaers, Albert Higgins-Chen, Morgan Levine, Steve Horvath, Balaji S Santhanam, Brett A Kaufman, Michio Hirano, Elissa Epel, Martin Picard.
      Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.
    Keywords:  Aging; Allostatic load; Chronic stress; Epigenetic aging; Glucocorticoid; Hypermetabolism; Mitochondria; Telomere
    DOI:  https://doi.org/10.1016/j.psyneuen.2023.106322
  44. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00037-8. [Epub ahead of print]136 309-337
    Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.
    Komal Sharma, Joyobrata Sarkar, Anchal Trisal, Rishika Ghosh, Anubhuti Dixit, Abhishek Kumar Singh.
      Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.
    Keywords:  Mitochondrial dysfunction; Neurodegeneration; Senescence; Senolytics; Senotherapeutics
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.02.016
  45. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00045-7. [Epub ahead of print]136 117-155
    Mitochondria-associated cellular senescence mechanisms: Biochemical and pharmacological perspectives.
    Mehmet Can Atayik, Ufuk Çakatay.
      Initially, endosymbiotic relation of mitochondria and other cellular compartments had been continued mutually. However, that evolutionary adaptation impaired because of the deterioration of endosymbiotic crosstalk due to aging and several pathological consequences in cellular redox status are seen, such as deterioration in redox integrity of mitochondria, interfered inter-organelle redox signaling and inefficient antioxidant response element mediated gene expression. Although the dysfunction of mitochondria is known to be a classical pattern of senescence, it is unresolved that why dysfunctional mitochondria is the core of senescence-associated secretory phenotype (SASP). Redox impairment and SASP-related disease development are generally together with weaken immunity. Impaired mitochondrial redox integrity and its ineffectiveness in immunity control render elders to be more prone to age-related diseases. As senotherapeutic agents, senolytics remove senescent cells whilst senomorphics/senostatics inhibits the secretion of SASP. Senotherapeutics and the novel approaches for ameliorating SASP-related unfavorable effects are recently thought to be promising ways as mitochondria-targeted gerotherapeutic options.
    Keywords:  Adaptive redox response; Aging; Evolution; Mitochondria; Redox signaling; SASP; Senotherapeutics
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.003
  46. MedComm (2020). 2023 Aug;4(4): e314
    Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release.
    Xiang Li, Fangfang Zhou, Linghui Zeng.
      
    DOI:  https://doi.org/10.1002/mco2.314
  47. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00043-3. [Epub ahead of print]136 93-115
    The role of mitochondria and mitophagy in cell senescence.
    Tayyab Ali, Fatma Hussain, Haroon Ur Rashid Kayani, Muhammad Naeem, Fozia Anjum.
      Mitochondrial malfunction and cell senescence have been defined as the hallmarks of aging. Cell senescence leads to the loss of health allied with aging. While deciphering the complex association between mitochondria and cellular senescence, it is observed that senescence has a two-faced nature being beneficial and hazardous. This duality of cellular senescence is associated with circumstantial aspects. During the process of cellular senescence, dysfunctional mitochondria are accumulated, the efficiency of the oxidative phosphorylation process declines along with the enhanced synthesis of reactive oxygen species. It is suggested that reduction in the negative consequences of senescence throughout old age might be accomplished by targeting the mitochondria as all roads lead towards mitochondria. It is unclear how perturbation of mitophagy in senescence results in the accumulation of mitochondria, impairment of mitochondrial biogenesis and onset of diseases. Understanding this complex interplay will bring about a long yet healthy lifespan. But definitely casual and specific players contribute in the initiation and conservation of the cell senescence. Variations in metabolism, quality control and dynamics of mitochondria are observed during cell aging process. Several On-target and Off-target mechanisms can also cause side effects in cellular senescence. Translational research of these mechanisms may lead to effective clinical interventions. This chapter reviews the role of mitochondria, homeostatic mechanisms and mitophagy as drivers and effectors of cell senescence along with multiple signalling pathways that lead to the initiation, maintenance, induction and suppression of cellular aging process during health and disease.
    Keywords:  Autophagy; Cell senescence; Mitophagy; Signaling pathways
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.001
  48. Life Sci Alliance. 2023 Sep;pii: e202302149. [Epub ahead of print]6(9):
    The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.
    Panagiota Kolitsida, Vladimir Nolic, Jianwen Zhou, Michael Stumpe, Natalie M Niemi, Jörn Dengjel, Hagai Abeliovich.
      The mitophagic degradation of mitochondrial matrix proteins in Saccharomyces cerevisiae was previously shown to be selective, reflecting a pre-engulfment sorting step within the mitochondrial network. This selectivity is regulated through phosphorylation of mitochondrial matrix proteins by the matrix kinases Pkp1 and Pkp2, which in turn appear to be regulated by the phosphatase Aup1/Ptc6. However, these same proteins also regulate the phosphorylation status and catalytic activity of the yeast pyruvate dehydrogenase complex, which is critical for mitochondrial metabolism. To understand the relationship between these two functions, we evaluated the role of the pyruvate dehydrogenase complex in mitophagic selectivity. Surprisingly, we identified a novel function of the complex in regulating mitophagic selectivity, which is independent of its enzymatic activity. Our data support a model in which the pyruvate dehydrogenase complex directly regulates the activity of its associated kinases and phosphatases. This regulatory interaction then determines the phosphorylation state of mitochondrial matrix proteins and their mitophagic fates.
    DOI:  https://doi.org/10.26508/lsa.202302149
  49. Elife. 2023 Jul 11. pii: e81966. [Epub ahead of print]12
    Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset.
    Arian Mansur, Remi Joseph, Euri Kim, Pierre M Jean-Beltran, Namrata D Udeshi, Cadence Pearce, Hanjie Jiang, Reina Iwase, Miroslav P Milev, Hashem A Almousa, Elyshia McNamara, Jeffrey Widrick, Claudio Perez, Gianina Ravenscroft, Michael Sacher, Philip A Cole, Steven A Carr, Vandana A Gupta.
      Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases, including myopathies and muscular atrophy. However, the mechanistic understanding of specific components of the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein, result in severe congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive remain poorly understood. To characterize the KLHL40-regulated ubiquitin-modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40a mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy, biosynthetic metabolic processes, and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes, and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion-associated Ras-related GTPase1a (Sar1a). In KLHL40 deficient muscle, defects in ER exit site vesicle formation and downstream transport of extracellular cargo proteins result in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients.
    Keywords:  cell biology; developmental biology; zebrafish
    DOI:  https://doi.org/10.7554/eLife.81966
  50. SSM Qual Res Health. 2023 Jun;3 100240
    Democratising or disrupting diagnosis? Ethical issues raised by the use of AI tools for rare disease diagnosis.
    Nina Hallowell, Shirlene Badger, Francis McKay, Angeliki Kerasidou, Christoffer Nellåker.
      Computational phenotyping (CP) technology uses facial recognition algorithms to classify and potentially diagnose rare genetic disorders on the basis of digitised facial images. This AI technology has a number of research as well as clinical applications, such as supporting diagnostic decision-making. Using the example of CP, we examine stakeholders' views of the benefits and costs of using AI as a diagnostic tool within the clinic. Through a series of in-depth interviews (n ​= ​20) with: clinicians, clinical researchers, data scientists, industry and support group representatives, we report stakeholder views regarding the adoption of this technology in a clinical setting. While most interviewees were supportive of employing CP as a diagnostic tool in some capacity we observed ambivalence around the potential for artificial intelligence to overcome diagnostic uncertainty in a clinical context. Thus, while there was widespread agreement amongst interviewees concerning the public benefits of AI assisted diagnosis, namely, its potential to increase diagnostic yield and enable faster more objective and accurate diagnoses by up skilling non specialists and thereby enabling access to diagnosis that is potentially lacking, interviewees also raised concerns about ensuring algorithmic reliability, expunging algorithmic bias and that the use of AI could result in deskilling the specialist clinical workforce. We conclude that, prior to widespread clinical implementation, on-going reflection is needed regarding the trade-offs required to determine acceptable levels of bias and conclude that diagnostic AI tools should only be employed as an assistive technology within the dysmorphology clinic.
    Keywords:  AI; Computational phenotyping; Diagnosis; Qualitative interviews; Rare disease
    DOI:  https://doi.org/10.1016/j.ssmqr.2023.100240
  51. Adv Exp Med Biol. 2023 ;1415 223-227
    Axonal Transport Defects in Retinal Ganglion Cell Diseases.
    Iskalen Cansu Topcu Okan, Fatma Ozdemir, Cavit Agca.
      For the survival and maintenance of retinal ganglion cells (RGCs), axonal transportation is fundamental. Axonal transportation defects can cause severe neuropathies leading to neuronal loss. Axonal transport defects usually precede axonal degeneration and RGC loss in disease models. To date, the main causes of axonal transport defects have not been fully understood. Therefore, elucidation of the mechanisms that lead to transport defects will help us to develop novel therapeutic targets and early diagnostic tools. In this review, we provide an overview of optic neuropathies and axonal degeneration with a focus on axonal transport.
    Keywords:  Axonal degeneration; Axonal transport; Glaucoma; Mitochondria; OPA1
    DOI:  https://doi.org/10.1007/978-3-031-27681-1_32
  52. J Bioeth Inq. 2023 Jul 13.
    Mitochondrial Replacement Therapy: An Islamic Perspective.
    Abdul Halim Ibrahim, Noor Naemah Abdul Rahman, Shaikh Mohd Saifuddeen.
      Mitochondrial replacement technology (MRT) is an emerging and complex bioethical issue. This treatment aims to eliminate maternal inherited mitochondrial DNA (mtDNA) disorders. For Muslims, its introduction affects every aspect of human life, especially the five essential interests of human beings-namely, religion, life, lineage, intellect, and property. Thus, this technology must be assessed using a comprehensive and holistic approach addressing these human essential interests. Consequently, this article analyses and assesses tri-parent baby technology from the perspective of Maqasidic bioethics-that is, Islamic bioethics based on the framework of Maqasid al-Shariah. Using this analysis, this article suggests that tri-parent baby technology should not be permitted for Muslims due to the existence of third-party cell gametes which lead to lineage mixing and due to the uncertain safety of the therapy itself and because the major aim of the technology is to fulfil the affected couples interest to conceive their own genetically healthy child, not to treat and cure mtDNA disorders sufferers.
    Keywords:  Assisted reproduction; Islamic bioethics; Maqasid al-Shariah; Mitochondrial replacement therapy; Tri-parent baby
    DOI:  https://doi.org/10.1007/s11673-023-10279-y
  53. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00047-0. [Epub ahead of print]136 157-196
    Changing ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics.
    Oleh Lushchak, Dmytro Gospodaryov, Olha Strilbytska, Maria Bayliak.
      Lifespan of many organisms, from unicellular yeast to extremely complex human organism, strongly depends on the genetic background and environmental factors. Being among most influential target energy metabolism is affected by macronutrients, their caloric values, and peculiarities of catabolism. Mitochondria are central organelles that respond for energy metabolism in eukaryotic cells. Mitochondria generate reactive oxygen species (ROS), which are lifespan modifying metabolites and a kind of biological clock. Oxidized nicotinamide adenine dinucleotide (NAD+) and adenosine monophosphate (AMP) are important metabolic intermediates and molecules that trigger or inhibit several signaling pathways involved in gene silencing, nutrient allocation, and cell regeneration and programmed death. A part of NAD+ and AMP metabolism is tied to mitochondria. Using substances that able to target mitochondria, as well as allotopic expression of specific enzymes, are envisioned to be innovative approaches to prolong lifespan by modulation of ROS, NAD+, and AMP levels. Among substances, an anti-diabetic drug metformin is believed to increase NAD+ and AMP levels, indirectly influencing histone deacetylases, involved in gene silencing, and AMP-activated protein kinase, an energy sensor of cells. Mitochondrially targeted derivatives of ubiquinone were found to interact with ROS. A mitochondrially targeted non-proton-pumping NADH dehydrogenase may influence both ROS and NAD+ levels. Chapter describes putative how mitochondria-targeted drugs and NADH dehydrogenase extend lifespan, perspectives of creating drugs with similar properties and their usage as senotherapeutic pills are discussed in the chapter.
    Keywords:  Lifespan; Metabolism; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.005
  54. Aging Cell. 2023 Jul 09. e13920
    NAD metabolism: Role in senescence regulation and aging.
    Claudia Christiano Silva Chini, Heidi Soares Cordeiro, Ngan Le Kim Tran, Eduardo Nunes Chini.
      The geroscience hypothesis proposes that addressing the biology of aging could directly prevent the onset or mitigate the severity of multiple chronic diseases. Understanding the interplay between key aspects of the biological hallmarks of aging is essential in delivering the promises of the geroscience hypothesis. Notably, the nucleotide nicotinamide adenine dinucleotide (NAD) interfaces with several biological hallmarks of aging, including cellular senescence, and changes in NAD metabolism have been shown to be involved in the aging process. The relationship between NAD metabolism and cellular senescence appears to be complex. On the one hand, the accumulation of DNA damage and mitochondrial dysfunction induced by low NAD+ can promote the development of senescence. On the other hand, the low NAD+ state that occurs during aging may inhibit SASP development as this secretory phenotype and the development of cellular senescence are both highly metabolically demanding. However, to date, the impact of NAD+ metabolism on the progression of the cellular senescence phenotype has not been fully characterized. Therefore, to explore the implications of NAD metabolism and NAD replacement therapies, it is essential to consider their interactions with other hallmarks of aging, including cellular senescence. We propose that a comprehensive understanding of the interplay between NAD boosting strategies and senolytic agents is necessary to advance the field.
    Keywords:  NAD+ metabolism; SASP; aging; nicotinamide adenine dinucleotide; senescence
    DOI:  https://doi.org/10.1111/acel.13920
  55. Nature. 2023 Jul 11.
    De novo design of protein structure and function with RFdiffusion.
    Joseph L Watson, David Juergens, Nathaniel R Bennett, Brian L Trippe, Jason Yim, Helen E Eisenach, Woody Ahern, Andrew J Borst, Robert J Ragotte, Lukas F Milles, Basile I M Wicky, Nikita Hanikel, Samuel J Pellock, Alexis Courbet, William Sheffler, Jue Wang, Preetham Venkatesh, Isaac Sappington, Susana Vázquez Torres, Anna Lauko, Valentin De Bortoli, Emile Mathieu, Sergey Ovchinnikov, Regina Barzilay, Tommi S Jaakkola, Frank DiMaio, Minkyung Baek, David Baker.
      There has been considerable recent progress in designing new proteins using deep learning methods1-9. Despite this progress, a general deep learning framework for protein design that enables solution of a wide range of design challenges, including de novo binder design and design of higher order symmetric architectures, has yet to be described. Diffusion models10,11 have had considerable success in image and language generative modeling but limited success when applied to protein modeling, likely due to the complexity of protein backbone geometry and sequence-structure relationships. Here we show that by fine tuning the RoseTTAFold structure prediction network on protein structure denoising tasks, we obtain a generative model of protein backbones that achieves outstanding performance on unconditional and topology-constrained protein monomer design, protein binder design, symmetric oligomer design, enzyme active site scaffolding, and symmetric motif scaffolding for therapeutic and metal-binding protein design. We demonstrate the power and generality of the method, called RoseTTAFold Diffusion (RFdiffusion), by experimentally characterizing the structures and functions of hundreds of designed symmetric assemblies, metal binding proteins and protein binders. The accuracy of RFdiffusion is confirmed by the cryo-EM structure of a designed binder in complex with Influenza hemagglutinin which is nearly identical to the design model. In a manner analogous to networks which produce images from user-specified inputs, RFdiffusion enables the design of diverse functional proteins from simple molecular specifications.
    DOI:  https://doi.org/10.1038/s41586-023-06415-8
  56. Methods Mol Biol. 2023 ;2689 211-220
    Single Extracellular Vesicle Analysis Using Droplet Microfluidics.
    David Eun Reynolds, George Galanis, Yongcheng Wang, Jina Ko.
      Extracellular vesicles (EVs) are lipid-bound nanometer-sized vesicles released by all cell types that contain molecular payload such as proteins and/or nucleic acids. EVs are a key facet of cell-to-cell communication and have the potential to be used in the diagnosis of numerous diseases, chief among them being cancer. However, most methods of EV analysis struggle to identify the rare, malformed proteins indicative of tumor cells as tumor EVs represent only a tiny fraction of the bulk EVs present in the bloodstream. Here, we present a method of single EV analysis, utilizing droplet microfluidics to encapsulate EVs, which are labeled with DNA barcodes linked to antibodies, in droplets with the DNA extension used to amplify the signals associated with each EV. The amplified DNA can then be sequenced to assess the protein content of individual EVs, enabling the detection of rare proteins and EV subpopulations within a bulk EV sample.
    Keywords:  Droplet digital PCR; Droplet microfluidics; Extracellular vesicles; High-throughput; Multiplexing; Sequencing
    DOI:  https://doi.org/10.1007/978-1-0716-3323-6_16
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