bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–07–09
33 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Disease models of mitochondrial aminoacyl-tRNA synthetase defects.
  2. Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.
  3. Mitochondrial quality control: prime targets for antiviral therapy?
  4. Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.
  5. Ferroptosis in mitochondrial cardiomyopathy.
  6. Tissue specific differences in the assembly of mitochondrial complex I is revealed by a novel ENU mutation in ECSIT.
  7. Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target.
  8. Age-related advanced glycation end-product accumulation impairs mitochondrial regulation after vitrification.
  9. Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms.
  10. An Improved Method to Isolate Mitochondrial Contact Sites.
  11. Uncharacterized protein C17orf80: A novel interactor of human mitochondrial nucleoids.
  12. CISD3 is required for Complex I function, mitochondrial integrity, and skeletal muscle maintenance.
  13. Developing human embryos imaged at highest-ever resolution.
  14. Genetically Engineered Triple MAPT-Mutant Human-Induced Pluripotent Stem Cells (N279K, P301L, and E10+16 Mutations) Exhibit Impairments in Mitochondrial Bioenergetics and Dynamics.
  15. Blood-based bioenergetics: a liquid biopsy of mitochondrial dysfunction in disease.
  16. Regulation of electron transfer in the terminal step of the respiratory chain.
  17. Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.
  18. Age and sex dependent effects of metabolic response to muscle contraction.
  19. Deletion of Nmnat1 in Skeletal Muscle Leads to the Reduction of NAD+ Levels but Has No Impact on Skeletal Muscle Morphology and Fiber Types.
  20. Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.
  21. Heart failure in patients is associated with downregulation of mitochondrial quality control genes.
  22. N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.
  23. Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.
  24. NRF1-mediated mitochondrial biogenesis antagonizes innate antiviral immunity.
  25. Spatial mapping of cellular senescence: emerging challenges and opportunities.
  26. High-resolution visualization and assessment of basal and OXPHOS-induced mitophagy in H9c2 cardiomyoblasts.
  27. Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.
  28. Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth.
  29. Natural compounds targeting mitochondrial dysfunction: emerging therapeutics for target organ damage in hypertension.
  30. The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer's Disease.
  31. Quantifying mitochondrial redox and bilirubin content in intact primary hepatocytes of obese mice using fluorescent reporters.
  32. A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes.
  33. Mitochondrial homeostasis: a potential target for delaying renal aging.
  1. J Inherit Metab Dis. 2023 Jul 06.
    Disease models of mitochondrial aminoacyl-tRNA synthetase defects.
    Henna Tyynismaa.
      Mitochondrial aminoacyl-tRNA synthetases (mtARS) are enzymes critical for the first step of mitochondrial protein synthesis by charging mitochondrial tRNAs with their cognate amino acids. Pathogenic variants in all nineteen nuclear mtARS genes are now recognized as causing recessive mitochondrial diseases. Most mtARS disorders affect the nervous system, but the phenotypes range from multisystem diseases to tissue-specific manifestations. However, the mechanisms behind the tissue-specificities are poorly understood, and challenges remain in obtaining accurate disease models for developing and testing treatments. Here some of the currently existing disease models that have increased our understanding of mtARS defects are discussed. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/jimd.12652
  2. PLoS Genet. 2023 Jul 03. 19(7): e1010793
    Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.
    Lucy Granat, Debbra Y Knorr, Daniel C Ranson, Emma L Hamer, Ram Prosad Chakrabarty, Francesca Mattedi, Laura Fort-Aznar, Frank Hirth, Sean T Sweeney, Alessio Vagnoni, Navdeep S Chandel, Joseph M Bateman.
      Mutations in subunits of the mitochondrial NADH dehydrogenase cause mitochondrial complex I deficiency, a group of severe neurological diseases that can result in death in infancy. The pathogenesis of complex I deficiency remain poorly understood, and as a result there are currently no available treatments. To better understand the underlying mechanisms, we modelled complex I deficiency in Drosophila using knockdown of the mitochondrial complex I subunit ND-75 (NDUFS1) specifically in neurons. Neuronal complex I deficiency causes locomotor defects, seizures and reduced lifespan. At the cellular level, complex I deficiency does not affect ATP levels but leads to mitochondrial morphology defects, reduced endoplasmic reticulum-mitochondria contacts and activation of the endoplasmic reticulum unfolded protein response (UPR) in neurons. Multi-omic analysis shows that complex I deficiency dramatically perturbs mitochondrial metabolism in the brain. We find that expression of the yeast non-proton translocating NADH dehydrogenase NDI1, which reinstates mitochondrial NADH oxidation but not ATP production, restores levels of several key metabolites in the brain in complex I deficiency. Remarkably, NDI1 expression also reinstates endoplasmic reticulum-mitochondria contacts, prevents UPR activation and rescues the behavioural and lifespan phenotypes caused by complex I deficiency. Together, these data show that metabolic disruption due to loss of neuronal NADH dehydrogenase activity cause UPR activation and drive pathogenesis in complex I deficiency.
    DOI:  https://doi.org/10.1371/journal.pgen.1010793
  3. Trends Pharmacol Sci. 2023 Jul 04. pii: S0165-6147(23)00133-5. [Epub ahead of print]
    Mitochondrial quality control: prime targets for antiviral therapy?
    Yijin Wang, Peicong Ji, Qiuwei Pan.
      Mitochondrial quality control (MQC) plays a crucial role in maintaining mitochondrial health. Mitochondrial dynamics and mitophagy are two intricate processes of the MQC machinery acting at the organelle level to orchestrate mitochondrial homeostasis. Here, we discuss how viruses perturb these two processes to facilitate their infections and emphasize the rationale and challenges of therapeutically targeting MQC for treating viral diseases.
    DOI:  https://doi.org/10.1016/j.tips.2023.06.006
  4. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 29. pii: S0925-4439(23)00164-3. [Epub ahead of print]1869(7): 166798
    Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease.
    Jasvinder Singh Bhatti, Satinder Kaur, Jayapriya Mishra, Harikrishnareddy Dibbanti, Arti Singh, Arubala P Reddy, Gurjit Kaur Bhatti, P Hemachandra Reddy.
      Alzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid β (Aβ) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with Aβ and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with Aβ and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology.
    Keywords:  Alzheimer's disease; Amyloid beta; Mitochondria; Protein folding; Tau hyperphosphorylation
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166798
  5. Trends Cell Biol. 2023 Jul 05. pii: S0962-8924(23)00125-3. [Epub ahead of print]
    Ferroptosis in mitochondrial cardiomyopathy.
    Sofia Ahola, Thomas Langer.
      Ferroptosis is a form of necrotic cell death characterized by iron-dependent lipid peroxidation culminating in membrane rupture. Accumulating evidence links ferroptosis to multiple cardiac diseases and identifies mitochondria as important regulators of ferroptosis. Mitochondria are not only a major source of reactive oxygen species (ROS) but also counteract ferroptosis by preserving cellular redox balance and oxidative defense. Recent evidence has revealed that the mitochondrial integrated stress response limits oxidative stress and ferroptosis in oxidative phosphorylation (OXPHOS)-deficient cardiomyocytes and protects against mitochondrial cardiomyopathy. We summarize the multiple ways in which mitochondria modulate the susceptibility of cells to ferroptosis, and discuss the implications of ferroptosis for cardiomyopathies in mitochondrial disease.
    Keywords:  Gpx4; ferroptosis; integrated stress response; mitochondrial cardiomyopathy
    DOI:  https://doi.org/10.1016/j.tcb.2023.06.002
  6. Cardiovasc Res. 2023 Jul 03. pii: cvad101. [Epub ahead of print]
    Tissue specific differences in the assembly of mitochondrial complex I is revealed by a novel ENU mutation in ECSIT.
    Thomas Nicol, Sara Falcone, Andrew Blease, Pratik Vikhe, Gabriele Civiletto, Saleh Salman Omairi, Carlo Viscomi, Ketan Patel, Paul K Potter.
       AIMS: Mitochondrial complex I assembly is a multi-step process which necessitates the involvement of a variety of assembly factors and chaperones to ensure the final active enzyme is correctly assembled. The role of the assembly factor ECSIT was studied across various murine tissues to determine its role in this process and how this varied between tissues of varying energetic demands. We hypothesised that many of the known functions of ECSIT were unhindered by the introduction of an ENU induced mutation, whilst it's role in complex I assembly was affected on a tissue specific basis.
    METHODS AND RESULTS: Here we describe a mutation in the mitochondrial complex I assembly factor ECSIT which reveals tissue specific requirements for ECSIT in complex I assembly. Mitochondrial complex I assembly is a multi-step process dependent on assembly factors that organise and arrange the individual subunits, allowing for their incorporation into the complete enzyme complex. We have identified an ENU induced mutation in ECSIT (N209I) that exhibits a profound effect on complex I component expression and assembly in heart tissue, resulting in hypertrophic cardiomyopathy in the absence of other phenotypes. The dysfunction of complex I appears to be cardiac specific, leading to a loss of mitochondrial output as measured by Seahorse extracellular flux and various biochemical assays in heart tissue, whilst mitochondria from other tissues were unaffected.
    CONCLUSIONS: These data suggest that the mechanisms underlying complex I assembly and activity may have tissue specific elements tailored to the specific demands of cells and tissues. Our data suggest that tissues with high energy demands, such as the heart, may utilise assembly factors in different ways to low energy tissues in order to improve mitochondrial output. This data have implications for the diagnosis and treatment of various disorders of mitochondrial function as well as cardiac hypertrophy with no identifiable underlying genetic cause.
    TRANSLATIONAL PERSPECTIVE: Mitochondrial diseases often present as multi system disorders with far reaching implications to the health and well being of patients. Diagnoses are often undertaken by characterisation of mitochondrial function from skin or muscle biopsy, with the expectation that any affect on mitochondrial function will be recognisable in all cell types. However, this study demonstrates that mitochondrial function may differ between cell types with the involvement of tissue specific proteins or isoforms, as such, current diagnostic techniques may miss diagnoses of a more specific mitochondrial dysfunction.
    DOI:  https://doi.org/10.1093/cvr/cvad101
  7. iScience. 2023 Jul 21. 26(7): 107014
    Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target.
    Ira Buntenbroich, Vincent Anton, Daniel Perez-Hernandez, Tânia Simões, Felix Gaedke, Astrid Schauss, Gunnar Dittmar, Jan Riemer, Mafalda Escobar-Henriques.
      Defects in mitochondrial fusion are at the base of many diseases. Mitofusins power membrane-remodeling events via self-interaction and GTP hydrolysis. However, how exactly mitofusins mediate fusion of the outer membrane is still unclear. Structural studies enable tailored design of mitofusin variants, providing valuable tools to dissect this stepwise process. Here, we found that the two cysteines conserved between yeast and mammals are required for mitochondrial fusion, revealing two novel steps of the fusion cycle. C381 is dominantly required for the formation of the trans-tethering complex, before GTP hydrolysis. C805 allows stabilizing the Fzo1 protein and the trans-tethering complex, just prior to membrane fusion. Moreover, proteasomal inhibition rescued Fzo1 C805S levels and membrane fusion, suggesting a possible application for clinically approved drugs. Together, our study provides insights into how assembly or stability defects in mitofusins might cause mitofusin-associated diseases and uncovers potential therapeutic intervention by proteasomal inhibition.
    Keywords:  Biological sciences; Cell biology; Genetics; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107014
  8. Biol Reprod. 2023 Jul 03. pii: ioad070. [Epub ahead of print]
    Age-related advanced glycation end-product accumulation impairs mitochondrial regulation after vitrification.
    Jun Ito, Hisataka Iwata.
      Vitrification is an important assisted reproductive technology, although it induces mitochondrial dysfunction in embryos. Herein, we aimed to investigate whether age-associated accumulation of advanced glycation end-products (AGEs) in oocytes impairs the recovery of embryos from cryopreservation-induced mitochondrial dysfunction/damage. Mouse 8-cell stage embryos developed in vitro were vitrified and warmed and incubated up to the blastocyst stage. AGE levels in oocytes were higher in both aged mice and AGE accumulation mouse models (MGO-mice) than those in young and control mice. Additionally, the level of SIRT1 upregulation was lower for embryos of aged and MGO-mice than that for embryos of young and control mice. The highest mtDNA content was detected in blastocysts derived from vitrified embryos of aged and MGO-mice. The spent culture medium of blastocysts derived from both aged and MGO-mice contained higher mtDNA content than that of the blastocysts derived from young and control mice. EX527 increased mtDNA content in the spent culture medium of vitrified embryos derived from young mice. In addition, p62 aggregate levels were higher in vitrified embryos of control mice than those in vitrified embryos of MGO-mice. The SIRT1 activator, resveratrol, increased p62 aggregation levels in vitrified embryos derived from young and aged mice, whereas vitrification did not affect p62 aggregation levels in embryos from aged mice. Therefore, age-associated AGE accumulation induces decreased responsive SIRT1 upregulation following vitrified-warmed treatment and impairs mitochondrial quality control activity in vitrified embryos.
    Keywords:  advanced glycation end-products; embryos; maternal aging; mitochondrial quality control; oocytes; vitrification
    DOI:  https://doi.org/10.1093/biolre/ioad070
  9. Biochim Biophys Acta Mol Basis Dis. 2023 Jul 04. pii: S0925-4439(23)00168-0. [Epub ahead of print] 166802
    Mitochondrial dysfunction in the offspring of obese mothers and it's transmission through damaged oocyte mitochondria: Integration of mechanisms.
    A L Elías-López, O Vázquez-Mena, A N Sferruzzi-Perri.
      In vivo and in vitro studies demonstrate that mitochondria in the oocyte, are susceptible to damage by suboptimal pre/pregnancy conditions, such as obesity. These suboptimal conditions have been shown to induce mitochondrial dysfunction (MD) in multiple tissues of the offspring, suggesting that mitochondria of oocytes that pass from mother to offspring, can carry information that can programme mitochondrial and metabolic dysfunction of the next generation. They also suggest that transmission of MD could increase the risk of obesity and other metabolic diseases in the population inter- and trans-generationally. In this review, we examined whether MD observed in offspring tissues of high energetic demand, is the result of the transmission of damaged mitochondria from obese mothers' oocytes to the offspring. The contribution of genome-independent mechanisms (namely mitophagy) in this transmission were also explored. Finally, potential interventions aimed at improving oocyte/embryo health were investigated, to see if they may provide an opportunity to halter the generational effects of MD.
    Keywords:  Downregulated mitophagy; Maternal obesity; Metabolic dysfunction; Milpa diet; Mitochondrial metabolic dysfunction; Mitophagy; Offspring mitochondrial dysfunction; Oocyte mitochondria; Preconceptional interventions; Traditional diet
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166802
  10. J Vis Exp. 2023 06 16.
    An Improved Method to Isolate Mitochondrial Contact Sites.
    Siavash Khosravi, Johanna Frickel, Max E Harner.
      Mitochondria are present in virtually all eukaryotic cells and perform essential functions that go far beyond energy production, for instance, the synthesis of iron-sulfur clusters, lipids, or proteins, Ca2+ buffering, and the induction of apoptosis. Likewise, mitochondrial dysfunction results in severe human diseases such as cancer, diabetes, and neurodegeneration. In order to perform these functions, mitochondria have to communicate with the rest of the cell across their envelope, which consists of two membranes. Therefore, these two membranes have to interact constantly. Proteinaceous contact sites between the mitochondrial inner and outer membranes are essential in this respect. So far, several contact sites have been identified. In the method described here, Saccharomyces cerevisiae mitochondria are used to isolate contact sites and, thus, identify candidates that qualify for contact site proteins. We used this method to identify the mitochondrial contact site and cristae organizing system (MICOS) complex, one of the major contact site-forming complexes in the mitochondrial inner membrane, which is conserved from yeast to humans. Recently, we further improved this method to identify a novel contact site consisting of Cqd1 and the Por1-Om14 complex.
    DOI:  https://doi.org/10.3791/65444
  11. J Cell Sci. 2023 Jul 04. pii: jcs.260822. [Epub ahead of print]
    Uncharacterized protein C17orf80: A novel interactor of human mitochondrial nucleoids.
    Alisa Potter, Anu Hangas, Steffi Goffart, Martijn A Huynen, Alfredo Cabrera-Orefice, Johannes N Spelbrink.
      Molecular functions of many human proteins remain unstudied, despite the demonstrated association with diseases or pivotal molecular structures, such as mitochondrial DNA (mtDNA). This small genome is crucial for proper functioning of mitochondria, the energy-converting organelles. In mammals, mtDNA is arranged into macromolecular complexes called nucleoids that serve as functional stations for its maintenance and expression. Here, we aimed to explore an uncharacterized protein C17orf80, which was previously detected close to the nucleoid components by proximity-labelling mass spectrometry. To investigate the subcellular localization and function of C17orf80, we took an advantage of immunofluorescence microscopy, interaction proteomics and several biochemical assays. We demonstrate that C17orf80 is a mitochondrial membrane-associated protein that interacts with nucleoids even when mtDNA replication is inhibited. In addition, we show that C17orf80 is not essential for mtDNA maintenance and mitochondrial gene expression in cultured human cells. These results provide a basis for uncovering the molecular function of C17orf80 and the nature of its association with nucleoids, possibly leading to new insights about mtDNA and its expression.
    Keywords:  2'; 3'-dideoxycytidine; C17orf80; Mitochondria; Mitochondrial nucleoid; mtDNA
    DOI:  https://doi.org/10.1242/jcs.260822
  12. bioRxiv. 2023 Jun 04. pii: 2023.06.03.543558. [Epub ahead of print]
    CISD3 is required for Complex I function, mitochondrial integrity, and skeletal muscle maintenance.
    Henri-Baptiste Marjault, Ola Karmi, Linda Rowland, Thi Thao Nguyen, DeAna Grant, Camila Manrique-Acevedo, Rachel Nechushtai, Ron Mittler.
      Mitochondria play a central role in muscle metabolism and function. In skeletal muscles, a unique family of iron-sulfur proteins, termed CISD proteins, support mitochondrial function. The abundance of these proteins declines with aging leading to muscle degeneration. Although the function of the outer mitochondrial proteins CISD1 and CISD2 has been defined, the role of the inner mitochondrial protein CISD3, is currently unknown. Here we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne Muscular Dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscle mitochondria, and that CISD3 interacts with, and donates its clusters to, Complex I respiratory chain subunit NDUFV2. These findings reveal that CISD3 is important for supporting the biogenesis and function of Complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact muscle degeneration syndromes, aging, and related conditions.
    DOI:  https://doi.org/10.1101/2023.06.03.543558
  13. Nature. 2023 Jul 06.
    Developing human embryos imaged at highest-ever resolution.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Imaging
    DOI:  https://doi.org/10.1038/d41586-023-02222-3
  14. Cells. 2023 May 13. pii: 1385. [Epub ahead of print]12(10):
    Genetically Engineered Triple MAPT-Mutant Human-Induced Pluripotent Stem Cells (N279K, P301L, and E10+16 Mutations) Exhibit Impairments in Mitochondrial Bioenergetics and Dynamics.
    Leonora Szabo, Amandine Grimm, Juan Antonio García-León, Catherine M Verfaillie, Anne Eckert.
      Pathological abnormalities in the tau protein give rise to a variety of neurodegenerative diseases, conjointly termed tauopathies. Several tau mutations have been identified in the tau-encoding gene MAPT, affecting either the physical properties of tau or resulting in altered tau splicing. At early disease stages, mitochondrial dysfunction was highlighted with mutant tau compromising almost every aspect of mitochondrial function. Additionally, mitochondria have emerged as fundamental regulators of stem cell function. Here, we show that compared to the isogenic wild-type triple MAPT-mutant human-induced pluripotent stem cells, bearing the pathogenic N279K, P301L, and E10+16 mutations, exhibit deficits in mitochondrial bioenergetics and present altered parameters linked to the metabolic regulation of mitochondria. Moreover, we demonstrate that the triple tau mutations disturb the cellular redox homeostasis and modify the mitochondrial network morphology and distribution. This study provides the first characterization of disease-associated tau-mediated mitochondrial impairments in an advanced human cellular tau pathology model at early disease stages, ranging from mitochondrial bioenergetics to dynamics. Consequently, comprehending better the influence of dysfunctional mitochondria on the development and differentiation of stem cells and their contribution to disease progression may thus assist in the potential prevention and treatment of tau-related neurodegeneration.
    Keywords:  bioenergetics; dynamics; induced pluripotent stem cells; mitochondria; oxidative stress; tau protein
    DOI:  https://doi.org/10.3390/cells12101385
  15. Trends Endocrinol Metab. 2023 Jul 04. pii: S1043-2760(23)00115-7. [Epub ahead of print]
    Blood-based bioenergetics: a liquid biopsy of mitochondrial dysfunction in disease.
    Mia S Wilkinson, Kimberly J Dunham-Snary.
      Mitochondria operate as hubs of cellular metabolism that execute important regulatory functions. Damaged/dysfunctional mitochondria are recognized as major pathogenic contributors to many common human diseases. Assessment of mitochondrial function relies upon invasive tissue biopsies; peripheral blood cells, specifically platelets, have emerged as an ideal candidate for mitochondrial function assessment. Accessibility and documented pathology-related dysfunction have prompted investigation into the role of platelets in disease, the contribution of platelet mitochondria to pathophysiology, and the capacity of platelets to reflect systemic mitochondrial health. Platelet mitochondrial bioenergetics are being investigated in neurodegenerative and cardiopulmonary diseases, infection, diabetes, and other (patho)physiological states such as aging and pregnancy. Early findings support the use of platelets as a biomarker for mitochondrial functional health.
    Keywords:  bioenergetics; biomarker; metabolism; mitochondria; platelet
    DOI:  https://doi.org/10.1016/j.tem.2023.06.004
  16. Biochem Soc Trans. 2023 Jul 06. pii: BST20221449. [Epub ahead of print]
    Regulation of electron transfer in the terminal step of the respiratory chain.
    Wataru Sato, Koichiro Ishimori.
      In mitochondria, electrons are transferred along a series of enzymes and electron carriers that are referred to as the respiratory chain, leading to the synthesis of cellular ATP. The series of the interprotein electron transfer (ET) reactions is terminated by the reduction in molecular oxygen at Complex IV, cytochrome c oxidase (CcO) that is coupled with the proton pumping from the matrix to the inner membrane space. Unlike the ET reactions from Complex I to Complex III, the ET reaction to CcO, mediated by cytochrome c (Cyt c), is quite specific in that it is irreversible with suppressed electron leakage, which characterizes the ET reactions in the respiratory chain and is thought to play a key role in the regulation of mitochondrial respiration. In this review, we summarize the recent findings regarding the molecular mechanism of the ET reaction from Cyt c to CcO in terms of specific interaction between two proteins, a molecular breakwater, and the effects of the conformational fluctuation on the ET reaction, conformational gating. Both of these are essential factors, not only in the ET reaction from Cyt c to CcO, but also in the interprotein ET reactions in general. We also discuss the significance of a supercomplex in the terminal ET reaction, which provides information on the regulatory factors of the ET reactions that are specific to the mitochondrial respiratory chain.
    Keywords:  breakwater; complex IV; conformational gating; cytochrome c; electron transfer; supercomplex
    DOI:  https://doi.org/10.1042/BST20221449
  17. Cell Death Discov. 2023 Jul 01. 9(1): 217
    Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.
    Marian León, Javier Prieto, María Micaela Molina-Navarro, Francisco García-García, Manuela Barneo-Muñoz, Xavier Ponsoda, Rosana Sáez, Francesc Palau, Joaquín Dopazo, Juan Carlos Izpisua Belmonte, Josema Torres.
      Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1-/- motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1-/- iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.
    DOI:  https://doi.org/10.1038/s41420-023-01531-w
  18. bioRxiv. 2023 Jun 01. pii: 2023.05.30.542769. [Epub ahead of print]
    Age and sex dependent effects of metabolic response to muscle contraction.
    Matthew D Campbell, Danijel Djukovic, Daniel Raftery, David Marcinek.
      Sarcopenia, the age-related loss of muscle mass and function, contributes to decreased quality of life in the elderly and increased healthcare costs. Decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance are all associated with increased oxidative stress and the decline in mitochondrial function with age. We hypothesized that elevated mitochondrial stress with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we designed two in vivo muscle-stimulation protocols to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise to characterize the effect of age and sex on mitochondrial substrate utilization in skeletal muscle following muscle contraction. Following HII stimulation, mitochondria from young skeletal muscle increased fatty acid oxidation compared to non-stimulated control muscle; however, mitochondria from aged muscle decreased fatty acid oxidation. In contrast, following LISS, mitochondrial from young skeletal muscle decreased fatty acid oxidation, whereas aged mitochondria increased fatty acid oxidation. We also found that HII can inhibit mitochondrial oxidation of glutamate in both stimulated and non-stimulated aged muscle, suggesting HII initiates circulation of an exerkine capable of altering whole-body metabolism. Analyses of the muscle metabolome indicates that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. Treatment with elamipretide, a mitochondrially targeted peptide, restored glutamate oxidation and metabolic pathway changes following HII suggesting rescuing redox status and improving mitochondrial function in aged muscle enhances the metabolic response to muscle contraction.
    DOI:  https://doi.org/10.1101/2023.05.30.542769
  19. J Nutr Sci Vitaminol (Tokyo). 2023 ;69(3): 184-189
    Deletion of Nmnat1 in Skeletal Muscle Leads to the Reduction of NAD+ Levels but Has No Impact on Skeletal Muscle Morphology and Fiber Types.
    Mariam Karim, Tooba Iqbal, Allah Nawaz, Keisuke Yaku, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) is a coenzyme that mediates many redox reactions in energy metabolism. NAD+ is also a substrate for ADP-ribosylation and deacetylation by poly (ADP-ribose) polymerase and sirtuin, respectively. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is a NAD+ biosynthesizing enzyme found in the nucleus. Recent research has shown that the maintaining NAD+ levels is critical for sustaining muscle functions both in physiological and pathological conditions. However, the role of Nmnat1 in skeletal muscle remains unexplored. In this study, we generated skeletal muscle-specific Nmnat1 knockout (M-Nmnat1 KO) mice and investigated its role in skeletal muscle. We found that NAD+ levels were significantly lower in the skeletal muscle of M-Nmnat1 KO mice than in control mice. M-Nmnat1 KO mice, in contrast, had similar body weight and normal muscle histology. Furthermore, the distribution of muscle fiber size and gene expressions of muscle fiber type gene expression were comparable in M-Nmnat1 KO and control mice. Finally, we investigated the role of Nmnat1 in muscle regeneration using cardiotoxin-induced muscle injury model, but muscle regeneration appeared almost normal in M-Nmnat1 KO mice. These findings imply that Nmnat1 has a redundancy in the pathophysiology of skeletal muscle.
    Keywords:  NAD+; Nmnat1; fiber type; muscle injury; skeletal muscle
    DOI:  https://doi.org/10.3177/jnsv.69.184
  20. Nat Cell Biol. 2023 Jul 03.
    Arf1 coordinates fatty acid metabolism and mitochondrial homeostasis.
    Ludovic Enkler, Viktoria Szentgyörgyi, Mirjam Pennauer, Cristina Prescianotto-Baschong, Isabelle Riezman, Aneta Wiesyk, Reut Ester Avraham, Martin Spiess, Einat Zalckvar, Roza Kucharczyk, Howard Riezman, Anne Spang.
      Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts in the peroxisome from where β-oxidation products enter mitochondria and fuel the tricarboxylic acid cycle. Little is known about the physical and metabolic cooperation between these organelles. Here we found that expression of fatty acid transporters and of the rate-limiting enzyme involved in β-oxidation is decreased in cells expressing a hyperactive mutant of the small GTPase Arf1, leading to an accumulation of fatty acids in lipid droplets. Consequently, mitochondria became fragmented and ATP synthesis decreased. Genetic and pharmacological depletion of fatty acids phenocopied the arf1 mutant mitochondrial phenotype. Although β-oxidation occurs in both mitochondria and peroxisomes in mammals, Arf1's role in fatty acid metabolism is conserved. Together, our results indicate that Arf1 integrates metabolism into energy production by regulating fatty acid storage and utilization, and presumably organelle contact sites.
    DOI:  https://doi.org/10.1038/s41556-023-01180-2
  21. Eur J Clin Invest. 2023 Jul 04. e14054
    Heart failure in patients is associated with downregulation of mitochondrial quality control genes.
    T Svagusa, S Sikiric, M Milavic, A Sepac, S Seiwerth, D Milicic, H Gasparovic, B Biocina, I Rudez, Z Sutlic, S Manola, J Varvodic, M Udovicic, M Urlic, S Ivankovic, S Plestina, F Paic, A Kulic, P Bakovic, F Sedlic.
       BACKGROUND: Mitochondrial dysfunction is one of key factors causing heart failure. We performed a comprehensive analysis of expression of mitochondrial quality control (MQC) genes in heart failure.
    METHODS: Myocardial samples were obtained from patients with ischemic and dilated cardiomyopathy in a terminal stage of heart failure and donors without heart disease. Using quantitative real-time PCR, we analysed a total of 45 MQC genes belonging to mitochondrial biogenesis, fusion-fission balance, mitochondrial unfolded protein response (UPRmt), translocase of the inner membrane (TIM) and mitophagy. Protein expression was analysed by ELISA and immunohistochemistry.
    RESULTS: The following genes were downregulated in ischemic and dilated cardiomyopathy: COX1, NRF1, TFAM, SIRT1, MTOR, MFF, DNM1L, DDIT3, UBL5, HSPA9, HSPE1, YME1L, LONP1, SPG7, HTRA2, OMA1, TIMM23, TIMM17A, TIMM17B, TIMM44, PAM16, TIMM22, TIMM9, TIMM10, PINK1, PARK2, ROTH1, PARL, FUNDC1, BNIP3, BNIP3L, TPCN2, LAMP2, MAP1LC3A and BECN1. Moreover, MT-ATP8, MFN2, EIF2AK4 and ULK1 were downregulated in heart failure from dilated, but not ischemic cardiomyopathy. VDAC1 and JUN were only genes that exhibited significantly different expression between ischemic and dilated cardiomyopathy. Expression of PPARGC1, OPA1, JUN, CEBPB, EIF2A, HSPD1, TIMM50 and TPCN1 was not significantly different between control and any form of heart failure. TOMM20 and COX proteins were downregulated in ICM and DCM.
    CONCLUSIONS: Heart failure in patients with ischemic and dilated cardiomyopathy is associated with downregulation of large number of UPRmt, mitophagy, TIM and fusion-fission balance genes. This indicates multiple defects in MQC and represents one of potential mechanisms underlying mitochondrial dysfunction in patients with heart failure.
    Keywords:  MQC; TIM; UPRmt; heart; mitochondria; mitophagy
    DOI:  https://doi.org/10.1111/eci.14054
  22. Mitochondrion. 2023 Jul 05. pii: S1567-7249(23)00056-9. [Epub ahead of print]
    N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.
    Winston Tse-Hou Kwok, Haejin Angela Kwak, Ana Cristina Andreazza.
      Mitochondrial Complex I dysfunction and oxidative stress have been part of the pathophysiology of several diseases ranging from mitochondrial disease to chronic diseases such as diabetes, mood disorders and Parkinson's Disease. Nonetheless, to investigate the potential of mitochondria-targeted therapeutic strategies for these conditions, there is a need further our understanding on how cells respond and adapt in the presence of Complex I dysfunction. In this study, we used low doses of rotenone, a classical inhibitor of mitochondrial complex I, to mimic peripheral mitochondrial dysfunction in THP-1 cells, a human monocytic cell line, and explored the effects of N-acetylcysteine on preventing this rotenone-induced mitochondrial dysfunction. Our results show that in THP-1 cells, rotenone exposure led to increases in mitochondrial superoxide, levels of cell-free mitochondrial DNA, and protein levels of the NDUFS7 subunit. N-acetylcysteine (NAC) pre-treatment ameliorated the rotenone-induced increase of cell-free mitochondrial DNA and NDUFS7 protein levels, but not mitochondrial superoxide. Furthermore, rotenone exposure did not affect protein levels of the NDUFV1 subunit but induced NDUFV1 glutathionylation. In summary, NAC may help to mitigate the effects of rotenone on Complex I and preserve the normal function of mitochondria in THP-1 cells.
    Keywords:  Cell model; Complex I; Mitochondrial; N-acetylcysteine; Reactive oxygen species; Rotenone
    DOI:  https://doi.org/10.1016/j.mito.2023.07.001
  23. iScience. 2023 Jul 21. 26(7): 107136
    Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.
    Shixuan Zhang, Junrou Zhang, Luli Wu, Li Chen, Piye Niu, Jie Li.
      Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.
    Keywords:  Biochemistry; Cell biology; Metabolomics; Toxicology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2023.107136
  24. EMBO J. 2023 Jul 06. e113258
    NRF1-mediated mitochondrial biogenesis antagonizes innate antiviral immunity.
    Tian Zhao, Jiaojiao Zhang, Hong Lei, Yuanyuan Meng, Hongcheng Cheng, Yanping Zhao, Guangfeng Geng, Chenglong Mu, Linbo Chen, Qiangqiang Liu, Qian Luo, Chuanmei Zhang, Yijia Long, Jingyi Su, Yinhao Wang, Zhuoya Li, Jiaxing Sun, Guo Chen, Yanjun Li, Xudong Liao, Yingli Shang, Gang Hu, Quan Chen, Yushan Zhu.
      Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor-1 (NRF1), a vital transcriptional factor involved in nuclear-mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV-1) virus-induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1-mediated mitochondrial biogenesis aggravated virus-induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus-activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1-TFAM axis during HSV-1 infection. A knock-in (KI) strategy that mimicked TBK1-NRF1 signaling revealed that interrupting the TBK1-NRF1 connection ablated mtDNA release and thereby attenuated the HSV-1-induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1-mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response.
    Keywords:  NRF1; TBK1; innate immunity; mitochondrial biogenesis
    DOI:  https://doi.org/10.15252/embj.2022113258
  25. Nat Aging. 2023 Jul 03.
    Spatial mapping of cellular senescence: emerging challenges and opportunities.
    Aditi U Gurkar, Akos A Gerencser, Ana L Mora, Andrew C Nelson, Anru R Zhang, Anthony B Lagnado, Archibald Enninful, Christopher Benz, David Furman, Delphine Beaulieu, Diana Jurk, Elizabeth L Thompson, Fei Wu, Fernanda Rodriguez, Grant Barthel, Hao Chen, Hemali Phatnani, Indra Heckenbach, Jeffrey H Chuang, Jeremy Horrell, Joana Petrescu, Jonathan K Alder, Jun Hee Lee, Laura J Niedernhofer, Manoj Kumar, Melanie Königshoff, Marta Bueno, Miiko Sokka, Morten Scheibye-Knudsen, Nicola Neretti, Oliver Eickelberg, Peter D Adams, Qianjiang Hu, Quan Zhu, Rebecca A Porritt, Runze Dong, Samuel Peters, Stella Victorelli, Thomas Pengo, Timur Khaliullin, Vidyani Suryadevara, Xiaonan Fu, Ziv Bar-Joseph, Zhicheng Ji, João F Passos.
      Cellular senescence is a well-established driver of aging and age-related diseases. There are many challenges to mapping senescent cells in tissues such as the absence of specific markers and their relatively low abundance and vast heterogeneity. Single-cell technologies have allowed unprecedented characterization of senescence; however, many methodologies fail to provide spatial insights. The spatial component is essential, as senescent cells communicate with neighboring cells, impacting their function and the composition of extracellular space. The Cellular Senescence Network (SenNet), a National Institutes of Health (NIH) Common Fund initiative, aims to map senescent cells across the lifespan of humans and mice. Here, we provide a comprehensive review of the existing and emerging methodologies for spatial imaging and their application toward mapping senescent cells. Moreover, we discuss the limitations and challenges inherent to each technology. We argue that the development of spatially resolved methods is essential toward the goal of attaining an atlas of senescent cells.
    DOI:  https://doi.org/10.1038/s43587-023-00446-6
  26. Autophagy. 2023 Jul 05. 1-20
    High-resolution visualization and assessment of basal and OXPHOS-induced mitophagy in H9c2 cardiomyoblasts.
    Gustav Godtliebsen, Kenneth Bowitz Larsen, Zambarlal Bhujabal, Ida S Opstad, Mireia Nager, Abhinanda R Punnakkal, Trine B Kalstad, Randi Olsen, Trine Lund, Dilip K Prasad, Krishna Agarwal, Truls Myrmel, Asa Birna Birgisdottir.
      Mitochondria are susceptible to damage resulting from their activity as energy providers. Damaged mitochondria can cause harm to the cell and thus mitochondria are subjected to elaborate quality-control mechanisms including elimination via lysosomal degradation in a process termed mitophagy. Basal mitophagy is a house-keeping mechanism fine-tuning the number of mitochondria according to the metabolic state of the cell. However, the molecular mechanisms underlying basal mitophagy remain largely elusive. In this study, we visualized and assessed the level of mitophagy in H9c2 cardiomyoblasts at basal conditions and after OXPHOS induction by galactose adaptation. We used cells with a stable expression of a pH-sensitive fluorescent mitochondrial reporter and applied state-of-the-art imaging techniques and image analysis. Our data showed a significant increase in acidic mitochondria after galactose adaptation. Using a machine-learning approach we also demonstrated increased mitochondrial fragmentation by OXPHOS induction. Furthermore, super-resolution microscopy of live cells enabled capturing of mitochondrial fragments within lysosomes as well as dynamic transfer of mitochondrial contents to lysosomes. Applying correlative light and electron microscopy we revealed the ultrastructure of the acidic mitochondria confirming their proximity to the mitochondrial network, ER and lysosomes. Finally, exploiting siRNA knockdown strategy combined with flux perturbation with lysosomal inhibitors, we demonstrated the importance of both canonical as well as non-canonical autophagy mediators in lysosomal degradation of mitochondria after OXPHOS induction. Taken together, our high-resolution imaging approaches applied on H9c2 cells provide novel insights on mitophagy during physiologically relevant conditions. The implication of redundant underlying mechanisms highlights the fundamental importance of mitophagy.Abbreviations: ATG: autophagy related; ATG7: autophagy related 7; ATP: adenosine triphosphate; BafA1: bafilomycin A1; CLEM: correlative light and electron microscopy; EGFP: enhanced green fluorescent protein; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; OXPHOS: oxidative phosphorylation; PepA: pepstatin A; PLA: proximity ligation assay; PRKN: parkin RBR E3 ubiquitin protein ligase; RAB5A: RAB5A, member RAS oncogene family; RAB7A: RAB7A, member RAS oncogene family; RAB9A: RAB9A, member RAS oncogene family; ROS: reactive oxygen species; SIM: structured illumination microscopy; siRNA: short interfering RNA; SYNJ2BP: synaptojanin 2 binding protein; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.
    Keywords:  CLEM; SIM; deep learning; lysosomes; mitochondria; quality control
    DOI:  https://doi.org/10.1080/15548627.2023.2230837
  27. Eur J Med Res. 2023 Jul 01. 28(1): 209
    Abnormal expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium.
    Chaoshuang Ye, Pei Chen, Bingning Xu, Yang Jin, Yongchao Pan, Tianyu Wu, Yongjiang Du, Jingxia Mao, Ruijin Wu.
      Mitochondria play a pivotal role in physiological and metabolic function of the cell. Mitochondrial dynamics orchestrate mitochondrial function and morphology, involving fission and fusion as well as ultrastructural remodeling. Mounting evidence unravels the close link between mitochondria and endometriosis. However, how mitochondrial architecture changes through fission and fusion in eutopic and ectopic tissues of women with ovarian endometriosis remains unknown. We detected the expression of fission and fusion genes and the morphology of mitochondria in eutopic and ectopic endometrium in ovarian endometriosis. The results showed that the expression of DRP1 and LCLAT1 was upregulated in eutopic endometrial stromal cells (ESCs), and the expression of DRP1, OPA1, MFN1, MFN2, and LCLAT1 was significantly downregulated in ectopic ESCs, and reduced number of mitochondria, wider cristae width and narrower cristae junction width was observed, but there was no difference in cell survival rate. The altered mitochondrial dynamics and morphology might, respectively, provide an advantage for migration and adhesion in eutopic ESCs and be the adaptive response in ectopic endometrial cells to survive under hypoxic and oxidative stress environment.
    Keywords:  Cristae; Endometriosis; Fission; Fusion; Mitochondria; Mitochondrial morphology
    DOI:  https://doi.org/10.1186/s40001-023-01180-w
  28. Placenta. 2023 Jun 22. pii: S0143-4004(23)00145-5. [Epub ahead of print]139 148-158
    Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth.
    Nykola L Kent, Sharat C Atluri, Karen M Moritz, James S M Cuffe.
       INTRODUCTION: Hypothyroidism during pregnancy is associated with fetal growth restriction (FGR). FGR is commonly caused by placental insufficiency and yet the role of hypothyroidism in placental regulation of fetal growth is unknown. This study aimed to investigate the effects of maternal hypothyroidism on placental nutrient transporter expression, placental morphology, and placental metabolism.
    METHODS: Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. Maternal and fetal tissues were collected on embryonic day 20 (E20).
    RESULTS: Hypothyroidism reduced fetal weight (PTrt<0.001) despite causing fetal hyperglycaemia (PTrt = 0.016). Placental weight was not affected by hypothyroidism however placental efficiency was reduced (PTrt<0.001), as was the junctional zone (JZ):labyrinth zone (LZ) weight ratio (PTrt = 0.005). LZ glycogen content was increased (PTrt = 0.029) and while mRNA expression of glucose transporters was reduced by hypothyroidism, only GLUT1 protein expression was reduced in male LZs. Maternal hypothyroidism reduced mitochondrial content (PTrt = 0.031), particularly in SEV males relative to CON males (P = 0.004). Protein expression of Complex V (P < 0.001) and Complex III (P = 0.002) of the electron transport chain were also reduced in males. Maternal hypothyroidism reduced LZ (PTrt<0.001) and fetal plasma triglycerides (P = 0.019) while fetal free fatty acids and the expression of LZ lipid transporters was not affected.
    DISCUSSION: Overall, maternal hypothyroidism may lead to FGR through reduced maternal T4 availability, changes to placental morphology, altered nutrient transporter expression and sex-specific effects on placental metabolism. Changes to LZ glycogen and triglyceride stores as well as mitochondrial content suggest a metabolic shift from oxidative phosphorylation to anaerobic glycolysis in males. These changes also likely impact fetal substrate availability and therefore fetal growth.
    Keywords:  Asymmetrical fetal growth restriction; Hypothyroidism; Nutrient transport; Placental metabolism; Pregnancy
    DOI:  https://doi.org/10.1016/j.placenta.2023.06.010
  29. Front Pharmacol. 2023 ;14 1209890
    Natural compounds targeting mitochondrial dysfunction: emerging therapeutics for target organ damage in hypertension.
    Xiaolin Liao, Yuanshan Han, Ying He, Jianjun Liu, Yuhong Wang.
      Hypertension generally causes target organ damage (TOD) in the heart, brain, kidney, and blood vessels. This can result in atherosclerosis, plaque formation, cardiovascular and cerebrovascular events, and renal failure. Recent studies have indicated that mitochondrial dysfunction is crucial in hypertensive target organ damage. Consequently, mitochondria-targeted therapies attract increasing attention. Natural compounds are valuable resources for drug discovery and development. Many studies have demonstrated that natural compounds can ameliorate mitochondrial dysfunction in hypertensive target organ damage. This review examines the contribution of mitochondrial dysfunction to the development of target organ damage in hypertension. Moreover, it summarizes therapeutic strategies based on natural compounds that target mitochondrial dysfunction, which may be beneficial for preventing and treating hypertensive target organ damage.
    Keywords:  flavonoids; hypertension; mitochondrial dysfunction; natural compounds; target organ damage
    DOI:  https://doi.org/10.3389/fphar.2023.1209890
  30. J Alzheimers Dis. 2023 Jun 27.
    The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer's Disease.
    Neeraj Chhimpa, Neha Singh, Nikkita Puri, Hanuman Prasad Kayath.
      Citrate synthase is a key mitochondrial enzyme that utilizes acetyl-CoA and oxaloacetate to form citrate in the mitochondrial membrane, which participates in energy production in the TCA cycle and linked to the electron transport chain. Citrate transports through a citrate malate pump and synthesizes acetyl-CoA and acetylcholine (ACh) in neuronal cytoplasm. In a mature brain, acetyl-CoA is mainly utilized for ACh synthesis and is responsible for memory and cognition. Studies have shown low citrate synthase in different regions of brain in Alzheimer's disease (AD) patients, which reduces mitochondrial citrate, cellular bioenergetics, neurocytoplasmic citrate, acetyl-CoA, and ACh synthesis. Reduced citrate mediated low energy and favors amyloid-β (Aβ) aggregation. Citrate inhibits Aβ25-35 and Aβ1-40 aggregation in vitro. Hence, citrate can be a better therapeutic option for AD by improving cellular energy and ACh synthesis, and inhibiting Aβ aggregation, which prevents tau hyperphosphorylation and glycogen synthase kinase-3 beta. Therefore, we need to study if citrate reverses Aβ deposition by balancing mitochondrial energy pathway and neurocytoplasmic ACh production. Furthermore, in AD's silent phase pathophysiology, when neuronal cells are highly active, they shift ATP utilization from oxidative phosphorylation to glycolysis and prevent excessive generation of hydrogen peroxide and reactive oxygen species (oxidative stress) as neuroprotective action, which upregulates glucose transporter-3 (GLUT3) and pyruvate dehydrogenase kinase-3 (PDK3). PDK3 inhibits pyruvate dehydrogenase, which decreases mitochondrial-acetyl-CoA, citrate, and cellular bioenergetics, and decreases neurocytoplasmic citrate, acetyl-CoA, and ACh formation, thus initiating AD pathophysiology. Therefore, GLUT3 and PDK3 can be biomarkers for silent phase of AD.
    Keywords:  APOEɛ4; Acetyl-CoA; Alzheimer’s disease; GLUT3; acetylcholine; amyloid-beta; cellular bioenergetics; citrate; citrate synthase
    DOI:  https://doi.org/10.3233/JAD-220514
  31. STAR Protoc. 2023 Jul 01. pii: S2666-1667(23)00375-1. [Epub ahead of print]4(3): 102408
    Quantifying mitochondrial redox and bilirubin content in intact primary hepatocytes of obese mice using fluorescent reporters.
    Thomas Belmas, Marc Liesa, Michaël Shum.
      Assessing the physiological role of H2O2 requires sensitive techniques to quantify H2O2 and antioxidants in live cells. Here, we present a protocol to assess the mitochondrial redox state and unconjugated bilirubin levels in intact live primary hepatocytes from obese mice. We described steps to quantify H2O2, GSSG/GSH, and bilirubin content in the mitochondrial matrix and the cytosol using the fluorescent reporters roGFP2-ORP1, GRX1-roGFP2, and UnaG, respectively. We detail hepatocyte isolation, plating, and transduction and live-cell imaging using a high-content imaging reader. For complete details on the use and execution of this protocol, please refer to Shum et al.1.
    Keywords:  Cell Biology; Metabolism; Molecular Biology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102408
  32. Genes Dis. 2023 Jul;10(4): 1165-1168
    A homozygous nonsense mutation in DNAJC30 causes Leber's hereditary optic neuropathy with Leigh-like phenotypes.
    Chao Shen, Kitty Wang, Wei Li, Alvaro Serrano, Kelly Powers, Chengwan Zhang, Jianjun Chen, Miao Sun.
      
    DOI:  https://doi.org/10.1016/j.gendis.2022.09.011
  33. Front Pharmacol. 2023 ;14 1191517
    Mitochondrial homeostasis: a potential target for delaying renal aging.
    Ming Yang, Chongbin Liu, Na Jiang, Yan Liu, Shilu Luo, Chenrui Li, Hao Zhao, Yachun Han, Wei Chen, Li Li, Li Xiao, Lin Sun.
      Mitochondria, which are the energy factories of the cell, participate in many life activities, and the kidney is a high metabolic organ that contains abundant mitochondria. Renal aging is a degenerative process associated with the accumulation of harmful processes. Increasing attention has been given to the role of abnormal mitochondrial homeostasis in renal aging. However, the role of mitochondrial homeostasis in renal aging has not been reviewed in detail. Here, we summarize the current biochemical markers associated with aging and review the changes in renal structure and function during aging. Moreover, we also review in detail the role of mitochondrial homeostasis abnormalities, including mitochondrial function, mitophagy and mitochondria-mediated oxidative stress and inflammation, in renal aging. Finally, we describe some of the current antiaging compounds that target mitochondria and note that maintaining mitochondrial homeostasis is a potential strategy against renal aging.
    Keywords:  inflammation; mitochondria; mitophagy; oxidative stress; renal aging
    DOI:  https://doi.org/10.3389/fphar.2023.1191517
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