bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022‒08‒28
twenty-six papers selected by
Dario Brunetti
Fondazione IRCCS Istituto Neurologico
  1. Modulating Mitochondrial DNA Heteroplasmy with Mitochondrially Targeted Endonucleases.
  2. Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation.
  3. Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes.
  4. Common methods in mitochondrial research (Review).
  5. HIGHER SYSTOLIC BLOOD PRESSURE IN FEMALE PATIENTS WITH MITOCHONDRIAL DISEASE.
  6. Mitochondrial Dysregulation and the Influence in Neurodegenerative Diseases.
  7. Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
  8. Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
  9. Retraction: Oxidized LDL causes endothelial apoptosis by inhibiting mitochondrial fusion and mitochondria autophagy.
  10. The Role of Bioenergetics in Neurodegeneration.
  11. Frataxin controls ketone body metabolism through regulation of OXCT1.
  12. Cell death: All roads lead to mitochondria.
  13. Mitochondrial behavior when things go wrong in the axon.
  14. Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System.
  15. Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.
  16. Downregulating Mitochondrial DNA Polymerase γ in the Muscle Stimulated Autophagy, Apoptosis, and Muscle Aging-Related Phenotypes in Drosophila Adults.
  17. The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.
  18. Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
  19. The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data.
  20. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women.
  21. Exercise performed during pregnancy positively modulates liver metabolism and promotes mitochondrial biogenesis of female offspring in a rat model of diet-induced gestational diabetes.
  22. Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons.
  23. Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
  24. Mitochondrial Dysfunction in Individuals with Diabetic Kidney Disease: A Systematic Review.
  25. AAV-mediated gene therapy improving mitochondrial function provides benefit in age-related macular degeneration models.
  26. Stem cell therapy for central nervous system disorders: Metabolic interactions between transplanted cells and local microenvironments.
  1. Ann Biomed Eng. 2022 Aug 24.
    Modulating Mitochondrial DNA Heteroplasmy with Mitochondrially Targeted Endonucleases.
    Nikita Mikhailov, Riikka H Hämäläinen.
      Mitochondria, mainly known as energy factories of eukaryotic cells, also exert several additional signaling and metabolic functions and are today recognized as major cellular biosynthetic and signaling hubs. Mitochondria possess their own genome (mitochondrial DNA-mtDNA), that encodes proteins essential for oxidative phosphorylation, and mutations in it are an important contributor to human disease. The mtDNA mutations often exist in heteroplasmic conditions, with both healthy and mutant versions of the mtDNA residing in patients' cells and the level of mutant mtDNA may vary between different tissues and organs and affect the clinical outcome of the disease. Thus, shifting the ratio between healthy and mutant mtDNA in patients' cells provides an intriguing therapeutic option for mtDNA diseases. In this review we describe current strategies for modulating mitochondrial heteroplasmy levels with engineered endonucleases including mitochondrially targeted TALENs and Zinc finger nucleases (ZFNs) and discuss their therapeutic potential. These gene therapy tools could in the future provide therapeutic help both for patients with mitochondrial disease as well as in preventing the transfer of pathogenic mtDNA mutations from a mother to her offspring.
    Keywords:  Gene therapy; Genetic engineering; Oxidative phosphorylation; Restriction endonuclease; Zinc finger nuclease; mitoTALEN
    DOI:  https://doi.org/10.1007/s10439-022-03051-7
  2. Nucleic Acids Res. 2022 Aug 24. pii: gkac699. [Epub ahead of print]
    Aberrant RNA processing contributes to the pathogenesis of mitochondrial diseases in trans-mitochondrial mouse model carrying mitochondrial tRNALeu(UUR) with a pathogenic A2748G mutation.
    Haruna Tani, Kaori Ishikawa, Hiroaki Tamashiro, Emi Ogasawara, Takehiro Yasukawa, Shigeru Matsuda, Akinori Shimizu, Dongchon Kang, Jun-Ichi Hayashi, Fan-Yan Wei, Kazuto Nakada.
      Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated 'mito-mice tRNALeu(UUR)2748', that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.
    DOI:  https://doi.org/10.1093/nar/gkac699
  3. Cells. 2022 Aug 19. pii: 2593. [Epub ahead of print]11(16):
    Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes.
    Sanna Ryytty, Shalem R Modi, Nikolay Naumenko, Anastasia Shakirzyanova, Muhammad Obaidur Rahman, Miia Vaara, Anu Suomalainen, Pasi Tavi, Riikka H Hämäläinen.
      The m.3243A>G mutation in mitochondrial tRNA-Leu(UUR) is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown. Approximately one third of patients suffer from cardiac disease, which often increases mortality. Why only some patients develop cardiomyopathy is unknown. Here, we studied the molecular effects of a high m.3243A>G mutation load on cardiomyocyte functionality, using cells derived from induced pluripotent stem cells (iPSC-CM) of two different m.3243A>G patients, only one of them suffering from severe cardiomyopathy. While high mutation load impaired mitochondrial respiration in both patients' iPSC-CMs, the downstream consequences varied. mtDNA mutant cells from a patient with no clinical heart disease showed increased glucose metabolism and retained cellular ATP levels, whereas cells from the cardiac disease patient showed reduced ATP levels. In this patient, the mutations also affected intracellular calcium signaling, while this was not true in the other patient's cells. Our results reflect the clinical variability in mitochondrial disease patients and show that iPSC-CMs retain tissue specific features seen in patients.
    Keywords:  cardiomyocyte; cardiomyopathy; iPS-cell; mitochondria; mtDNA; respiratory chain dysfunction
    DOI:  https://doi.org/10.3390/cells11162593
  4. Int J Mol Med. 2022 Oct;pii: 126. [Epub ahead of print]50(4):
    Common methods in mitochondrial research (Review).
    Yiyuan Yin, Haitao Shen.
      Mitochondrial abnormalities are primarily seen in morphology, structure and function. They can cause damage to organs, including the heart, brain and muscle, by various mechanisms, such as oxidative stress, abnormal energy metabolism, or genetic mutations. Identifying and detecting pathophysiological alterations in mitochondria is the principal means of studying mitochondrial abnormalities. The present study reviewed methods in mitochondrial research and focused on three aspects: Mitochondrial extraction and purification, morphology and structure and function. In addition to classical methods, such as electron microscopy and mitochondrial membrane potential monitoring, newly developed methods, such as mitochondrial ultrastructural determination, mtDNA mutation assays, metabolomics and analyses of regulatory mechanisms, have also been utilized in recent years. These approaches enable the accurate detection of mitochondrial abnormalities and provide guidance for the diagnosis and treatment of related diseases.
    Keywords:  mitochondria; mitochondrial DNA; mitochondrial diseases; mitochondrial dysfunction; mitochondrial morphology
    DOI:  https://doi.org/10.3892/ijmm.2022.5182
  5. J Hypertens. 2022 Jun 01. 40(Suppl 1): e35
    HIGHER SYSTOLIC BLOOD PRESSURE IN FEMALE PATIENTS WITH MITOCHONDRIAL DISEASE.
    Jaap Deinum, Daan Viering, Marjolein D Van Borselen, René Bindels, Jeroen De Baaij, Mirian Ch Janssen.
      OBJECTIVE: Previous research suggests that hypertension is more prevalent among patients with mitochondrial diseases. Blood pressure (BP) is linearly related to increased cardiovascular risk, and this relationship is strongest for systolic blood pressure; nevertheless, studies on systolic and diastolic blood pressure in mitochondrial diseases have not yet been performed.DESIGN AND METHOD: In a retrospective case-control study design, BP in mitochondrial disease patients was compared to BP in a population cohort. Secondly, using multiple linear regression, we examined blood pressure differences in various genetic mitochondrial diseases. Lastly, we explored additional predictors of BP in a subgroup with the m.3243A>G variant.
    RESULTS: 286 genetically confirmed mitochondrial disease patients were included. Of these patients 180 carried the m.3243A>G mitochondrial DNA variant. Systolic BP (SBP) was 9 mmHg higher in female mitochondrial disease patients than in the general female population (95% CI: 4.4 - 13.3 mmHg, p < 0.001), while male patients had similar BP compared to controls. BP was not significantly different in patients with (1) m.8344A>G and m.8363G>A, (2) a mtDNA deletion or (3) a nuclear mutation compared to m.3243A>G patients. Higher SBP was a predictor of left ventricular hypertrophy in the m.3243A>G subgroup (p = 0.04).
    CONCLUSIONS: Novel aspects of the role of mitochondrial dysfunction in blood pressure regulation are exposed in this study. Compared to the general population, female mitochondrial disease patients have a higher SBP. Left ventricular hypertrophy is more prevalent in patients with higher SBP. Clinicians should be aware of this to prevent hypertensive complications in mitochondrial disease patients.
    DOI:  https://doi.org/10.1097/01.hjh.0000835572.58453.32
  6. Adv Exp Med Biol. 2022 ;1382 109-118
    Mitochondrial Dysregulation and the Influence in Neurodegenerative Diseases.
    Giuliana S Zuccoli, Victor Corasolla Carregari.
      Mitochondrial function is essential to ensure vital cellular processes. Given the energy requirement of the brain, neuronal function, viability, and survival are closely related to proper mitochondrial function. Dysregulation of mitochondrial processes can lead to several detrimental effects in the cells and stablish the condition of mitochondrial dysfunction. This dysfunction is proposed to be greatly implicated in several neurodegenerative diseases, with evidence of compromised mitochondrial function and dynamics in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
    Keywords:  Brain metabolism; Mitochondrial dysfunction; Neurogenerative diseases; Proteomics
    DOI:  https://doi.org/10.1007/978-3-031-05460-0_8
  7. Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00304-6. [Epub ahead of print]
    Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy.
    Xiaotong Hong, Joan Isern, Silvia Campanario, Eusebio Perdiguero, Ignacio Ramírez-Pardo, Jessica Segalés, Pablo Hernansanz-Agustín, Andrea Curtabbi, Oleg Deryagin, Angela Pollán, José A González-Reyes, José M Villalba, Marco Sandri, Antonio L Serrano, José A Enríquez, Pura Muñoz-Cánoves.
      Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells-due to aging or genetic impairment-deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.
    Keywords:  Drp1; OXPHOS; aging; metabolism; mitochondria; mitochondrial dynamics; mitophagy; muscle regeneration; muscle stem cells; satellite cells
    DOI:  https://doi.org/10.1016/j.stem.2022.07.009
  8. Hum Mol Genet. 2022 Aug 22. pii: ddac201. [Epub ahead of print]
    Mitofusin 2 mutation drives cell proliferation in Charcot-Marie-Tooth 2A fibroblasts.
    Paola Zanfardino, Giovanna Longo, Alessandro Amati, Federica Morani, Ernesto Picardi, Francesco Girolamo, Mariella Pafundi, Sharon N Cox, Caterina Manzari, Apollonia Tullo, Stefano Doccini, Filippo M Santorelli, Vittoria Petruzzella.
      Dominant mutations in ubiquitously expressed Mitofusin 2 gene (MFN2) cause Charcot-Marie-Tooth type 2A (CMT2A; OMIM 609260), an inherited sensory-motor neuropathy that affects peripheral nerve axons. Mitofusin 2 protein has been found to take part in mitochondrial fusion, mitochondria-endoplasmic reticulum tethering, mitochondrial trafficking along axons, mitochondrial quality control, and various types of cancer, in which MFN2 has been indicated as a tumor suppressor gene. Discordant data on the mitochondrial altered phenotypes in patient-derived fibroblasts harboring MFN2 mutations and in animal models have been reported. We addressed some of these issues by focusing on mitochondria behavior during autophagy and mitophagy in fibroblasts derived from a CMT2AMFN2 patient with an MFN2650G > T/C217F mutation in the GTPase domain. This study investigated mitochondrial dynamics, respiratory capacity, and autophagy/mitophagy, to tackle the multifaceted MFN2 contribution to CMT2A pathogenesis. We found that MFN2 mutated fibroblasts showed impairment of mitochondrial morphology, bioenergetics capacity, and impairment of the early stages of autophagy, but not mitophagy. Unexpectedly, transcriptomic analysis of mutated fibroblasts highlighted marked differentially expressed pathways related to cell population proliferation and extracellular matrix organization. We consistently found the activation of mTORC2/AKT signaling and accelerated proliferation in the CMT2AMFN2 fibroblasts. In conclusion, our evidence indicates that MFN2 mutation can positively drive cell proliferation in CMT2AMFN2 fibroblasts.
    DOI:  https://doi.org/10.1093/hmg/ddac201
  9. Front Cell Dev Biol. 2022 ;10 1006515
    Retraction: Oxidized LDL causes endothelial apoptosis by inhibiting mitochondrial fusion and mitochondria autophagy.
    Frontiers Editorial Office
      [This retracts the article DOI: 10.3389/fcell.2020.600950.].
    DOI:  https://doi.org/10.3389/fcell.2022.1006515
  10. Int J Mol Sci. 2022 Aug 16. pii: 9212. [Epub ahead of print]23(16):
    The Role of Bioenergetics in Neurodegeneration.
    Taylor A Strope, Cole J Birky, Heather M Wilkins.
      Bioenergetic and mitochondrial dysfunction are common hallmarks of neurodegenerative diseases. Decades of research describe how genetic and environmental factors initiate changes in mitochondria and bioenergetics across Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Mitochondria control many cellular processes, including proteostasis, inflammation, and cell survival/death. These cellular processes and pathologies are common across neurodegenerative diseases. Evidence suggests that mitochondria and bioenergetic disruption may drive pathological changes, placing mitochondria as an upstream causative factor in neurodegenerative disease onset and progression. Here, we discuss evidence of mitochondrial and bioenergetic dysfunction in neurodegenerative diseases and address how mitochondria can drive common pathological features of these diseases.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; bioenergetics; mitochondria
    DOI:  https://doi.org/10.3390/ijms23169212
  11. PNAS Nexus. 2022 Jul;1(3): pgac142
    Frataxin controls ketone body metabolism through regulation of OXCT1.
    Yi Na Dong, Clementina Mesaros, Peining Xu, Elizabeth Mercado-Ayón, Sarah Halawani, Lucie Vanessa Ngaba, Nathan Warren, Patrick Sleiman, Layne N Rodden, Kimberly A Schadt, Ian A Blair, David R Lynch.
      Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of mitochondrial protein frataxin, which plays a crucial role in iron-sulphur cluster formation and ATP production. The cellular function of frataxin is not entirely known. Here, we demonstrate that frataxin controls ketone body metabolism through regulation of 3-Oxoacid CoA-Transferase 1 (OXCT1), a rate limiting enzyme catalyzing the conversion of ketone bodies to acetoacetyl-CoA that is then fed into the Krebs cycle. Biochemical studies show a physical interaction between frataxin and OXCT1 both in vivo and in vitro. Frataxin overexpression also increases OXCT1 protein levels in human skin fibroblasts while frataxin deficiency decreases OXCT1 in multiple cell types including cerebellum and skeletal muscle both acutely and chronically, suggesting that frataxin directly regulates OXCT1. This regulation is mediated by frataxin-dependent suppression of ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. Concomitantly, plasma ketone bodies are significantly elevated in frataxin deficient knock-in/knockout (KIKO) mice with no change in the levels of other enzymes involved in ketone body production. In addition, ketone bodies fail to be metabolized to acetyl-CoA accompanied by increased succinyl-CoA in vitro in frataxin deficient cells, suggesting that ketone body elevation is caused by frataxin-dependent reduction of OXCT1 leading to deficits in tissue utilization of ketone bodies. Considering the potential role of metabolic abnormalities and deficiency of ATP production in FRDA, our results suggest a new role for frataxin in ketone body metabolism and also suggest modulation of OXCT1 may be a potential therapeutic approach for FRDA.
    Keywords:  Friedreich's ataxia; OXCT1; frataxin; ketone body
    DOI:  https://doi.org/10.1093/pnasnexus/pgac142
  12. Curr Biol. 2022 Aug 22. pii: S0960-9822(22)01126-5. [Epub ahead of print]32(16): R891-R894
    Cell death: All roads lead to mitochondria.
    Alexander Poltorak.
      Mitochondria are central to apoptosis, an immunologically silent form of cell death. The mitochondrial, or 'intrinsic', apoptotic pathway is activated when the permeabilized mitochondrial membrane of stressed cells releases apoptotic effectors. A new study now characterizes how mitochondria are involved in the switch from pyroptotic to necroptotic cell death.
    DOI:  https://doi.org/10.1016/j.cub.2022.07.025
  13. Front Cell Neurosci. 2022 ;16 959598
    Mitochondrial behavior when things go wrong in the axon.
    Victorio M Pozo Devoto, Isaac G Onyango, Gorazd B Stokin.
      Axonal homeostasis is maintained by processes that include cytoskeletal regulation, cargo transport, synaptic activity, ionic balance, and energy supply. Several of these processes involve mitochondria to varying degrees. As a transportable powerplant, the mitochondria deliver ATP and Ca2+-buffering capabilities and require fusion/fission to maintain proper functioning. Taking into consideration the long distances that need to be covered by mitochondria in the axons, their transport, distribution, fusion/fission, and health are of cardinal importance. However, axonal homeostasis is disrupted in several disorders of the nervous system, or by traumatic brain injury (TBI), where the external insult is translated into physical forces that damage nervous tissue including axons. The degree of damage varies and can disconnect the axon into two segments and/or generate axonal swellings in addition to cytoskeletal changes, membrane leakage, and changes in ionic composition. Cytoskeletal changes and increased intra-axonal Ca2+ levels are the main factors that challenge mitochondrial homeostasis. On the other hand, a proper function and distribution of mitochondria can determine the recovery or regeneration of the axonal physiological state. Here, we discuss the current knowledge regarding mitochondrial transport, fusion/fission, and Ca2+ regulation under axonal physiological or pathological conditions.
    Keywords:  axonal degeneration; calcium homeostasis; mitochondria; mitochondrial dynamics; mitochondrial transport; traumatic brain injury
    DOI:  https://doi.org/10.3389/fncel.2022.959598
  14. Cells. 2022 Aug 21. pii: 2607. [Epub ahead of print]11(16):
    Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System.
    Masaru Tanaka, Ágnes Szabó, Eleonóra Spekker, Helga Polyák, Fanni Tóth, László Vécsei.
      Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently, a growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among others. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders. This review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.
    Keywords:  Alzheimer’s disease; anxiety; depression; kynurenine; mitochondria; neurodegenerative; plasticity; psychiatric; stress; stress resilience
    DOI:  https://doi.org/10.3390/cells11162607
  15. Int J Mol Sci. 2022 Aug 09. pii: 8852. [Epub ahead of print]23(16):
    Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview.
    Vlad Florian Avram, Adrian Petru Merce, Iasmina Maria Hâncu, Alina Doruța Bătrân, Gabrielle Kennedy, Mariana Georgeta Rosca, Danina Mirela Muntean.
      Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.
    Keywords:  diabetes mellitus; high-resolution respirometry; insulin resistance; mitochondrial respiration; obesity
    DOI:  https://doi.org/10.3390/ijms23168852
  16. Biomolecules. 2022 Aug 11. pii: 1105. [Epub ahead of print]12(8):
    Downregulating Mitochondrial DNA Polymerase γ in the Muscle Stimulated Autophagy, Apoptosis, and Muscle Aging-Related Phenotypes in Drosophila Adults.
    Mika Ozaki, Tuan Dat Le, Yoshihiro H Inoue.
      Reactive oxygen species, generated as by-products of mitochondrial electron transport, can induce damage to mitochondrial DNA (mtDNA) and proteins. Here, we investigated whether the moderate accumulation of mtDNA damage in adult muscles resulted in accelerated aging-related phenotypes in Drosophila. DNA polymerase γ (Polγ) is the sole mitochondrial DNA polymerase. The muscle-specific silencing of the genes encoding the polymerase subunits resulted in the partial accumulation of mtDNA with oxidative damage and a reduction in the mtDNA copy number. This subsequently resulted in the production of abnormal mitochondria with reduced membrane potential and, consequently, a partially reduced ATP quantity in the adult muscle. Immunostaining indicated a moderate increase in autophagy and mitophagy in adults with RNA interference of Polγ (PolγRNAi) muscle cells with abnormal mitochondria. In adult muscles showing continuous silencing of Polγ, malformation of both myofibrils and mitochondria was frequently observed. This was associated with the partially enhanced activation of pro-apoptotic caspases in the muscle. Adults with muscle-specific PolγRNAi exhibited a shortened lifespan, accelerated age-dependent impairment of locomotor activity, and disturbed circadian rhythms. Our findings in this Drosophila model contribute to understanding how the accumulation of mtDNA damage results in impaired mitochondrial activity and how this contributes to muscle aging.
    Keywords:  DNA polymeraseγ; Drosophila; autophagy; mitochondria; muscle aging
    DOI:  https://doi.org/10.3390/biom12081105
  17. Cell Stem Cell. 2022 Aug 19. pii: S1934-5909(22)00333-2. [Epub ahead of print]
    The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells.
    Nicole Baker, Steven Wade, Matthew Triolo, John Girgis, Damian Chwastek, Sarah Larrigan, Peter Feige, Ryo Fujita, Colin Crist, Michael A Rudnicki, Yan Burelle, Mireille Khacho.
      Quiescence regulation is essential for adult stem cell maintenance and sustained regeneration. Our studies uncovered that physiological changes in mitochondrial shape regulate the quiescent state of adult muscle stem cells (MuSCs). We show that MuSC mitochondria rapidly fragment upon an activation stimulus, via systemic HGF/mTOR, to drive the exit from deep quiescence. Deletion of the mitochondrial fusion protein OPA1 and mitochondrial fragmentation transitions MuSCs into G-alert quiescence, causing premature activation and depletion upon a stimulus. OPA1 loss activates a glutathione (GSH)-redox signaling pathway promoting cell-cycle progression, myogenic gene expression, and commitment. MuSCs with chronic OPA1 loss, leading to mitochondrial dysfunction, continue to reside in G-alert but acquire severe cell-cycle defects. Additionally, we provide evidence that OPA1 decline and impaired mitochondrial dynamics contribute to age-related MuSC dysfunction. These findings reveal a fundamental role for OPA1 and mitochondrial dynamics in establishing the quiescent state and activation potential of adult stem cells.
    Keywords:  G-alert; GSH; OPA1; ROS; adult muscle stem cells; aging; glutathione; mTOR; mitochondrial dynamics; quiescence; reactive oxygen species; stem cell activation; stem cell maintenance; systemic factors
    DOI:  https://doi.org/10.1016/j.stem.2022.07.010
  18. Aging Cell. 2022 Aug 22. e13669
    Premature aging is associated with higher levels of 8-oxoguanine and increased DNA damage in the Polg mutator mouse.
    Tenghui Yu, Jesse Slone, Wensheng Liu, Ryan Barnes, Patricia L Opresko, Landon Wark, Sabine Mai, Steve Horvath, Taosheng Huang.
      Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut ). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.
    Keywords:  8-oxoguanine; aging; mitochondria; oxidative stress; telomeres
    DOI:  https://doi.org/10.1111/acel.13669
  19. Life (Basel). 2022 Jul 29. pii: 1153. [Epub ahead of print]12(8):
    The Role of Mitochondrial Mutations in Chronification of Inflammation: Hypothesis and Overview of Own Data.
    Alexander N Orekhov, Nikita G Nikiforov, Andrey V Omelchenko, Vasily V Sinyov, Igor A Sobenin, Andrey Y Vinokurov, Varvara A Orekhova.
      Chronic human diseases, especially age-related disorders, are often associated with chronic inflammation. It is currently not entirely clear what factors are responsible for the sterile inflammatory process becoming chronic in affected tissues. This process implies impairment of the normal resolution of the inflammatory response, when pro-inflammatory cytokine production ceases and tissue repair process begins. The important role of the mitochondria in the correct functioning of innate immune cells is currently well recognized, with mitochondrial signals being an important component of the inflammatory response regulation. In this work, we propose a hypothesis according to which mitochondrial DNA (mtDNA) mutations may play a key role in rendering certain cells prone to prolonged pro-inflammatory activation, therefore contributing to chronification of inflammation. The affected cells become sites of constant pro-inflammatory stimulation. The study of the distribution of atherosclerotic lesions on the surface of the arterial wall samples obtained from deceased patients revealed a focal distribution of lesions corresponding to the distribution of cells with altered morphology that are affected by mtDNA mutations. These observations support the proposed hypothesis and encourage further studies.
    Keywords:  atherosclerosis; inflammation; mitophagy; mtDNA mutation
    DOI:  https://doi.org/10.3390/life12081153
  20. Sci Rep. 2022 Aug 24. 12(1): 14442
    Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women.
    Yuichiro Fukamizu, Yoshiaki Uchida, Akari Shigekawa, Toshiya Sato, Hisayuki Kosaka, Takanobu Sakurai.
      A decrease in the intracellular level of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for metabolic activity, causes various age-related diseases and metabolic abnormalities. Both in-vivo and in-vitro studies have shown that increasing certain NAD+ levels in cell or tissue by supplementing nicotinamide mononucleotide (NMN), a precursor of NAD+, alleviates age-related diseases and metabolic disorders. In recent years, several clinical trials have been performed to elucidate NMN efficacy in humans. However, previous clinical studies with NMN have not reported on the safety of repeated daily oral administration of ≥ 1000 mg/shot in healthy adult men and women, and human clinical trials on NMN safety are limited. Therefore, we conducted a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety of 1250 mg of β-NMN administered orally once daily for up to 4 weeks in 31 healthy adult men and women aged 20-65 years. Oral administration of β-NMN did not result in changes exceeding physiological variations in multiple clinical trials, including anthropometry, hematological, biochemical, urine, and body composition analyses. Moreover, no severe adverse events were observed during the study period. Our results indicate that β-NMN is safe and well-tolerated in healthy adult men and women an oral dose of 1250 mg once daily for up to 4 weeks.Trial registration Clinicaltrials.gov Identifier: UMIN000043084. Registered 21/01/2021. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049188 .
    DOI:  https://doi.org/10.1038/s41598-022-18272-y
  21. Biochim Biophys Acta Mol Basis Dis. 2022 Aug 20. pii: S0925-4439(22)00197-1. [Epub ahead of print]1868(11): 166526
    Exercise performed during pregnancy positively modulates liver metabolism and promotes mitochondrial biogenesis of female offspring in a rat model of diet-induced gestational diabetes.
    Jelena Stevanović-Silva, Jorge Beleza, Pedro Coxito, Hugo Rocha, Tiago Bordeira Gaspar, Fátima Gärtner, Rossana Correia, Rui Fernandes, Paulo J Oliveira, António Ascensão, José Magalhães.
      Gestational diabetes mellitus (GDM) is associated with a high-risk for metabolic complications in offspring. However, exercise is recognized as a non-pharmacological strategy against metabolic disorders and is recommended in GDM treatment. This study aimed to investigate whether gestational exercise (GE) could modulate maternal high-fat high-sucrose (HFHS) diet-related hepatic metabolic and mitochondrial outcomes in female offspring of mothers with HFHS-induced GDM. Female Sprague-Dawley rats were fed with control or HFHS diet and kept sedentary or submitted to GE. Their female offspring were fed with control diet and kept sedentary. Hepatic lipid accumulation, lipid metabolism regulators, mitochondrial biogenesis and dynamics markers, and microRNAs associated to the regulation of these markers were evaluated. Female offspring of GDM mothers showed increased body weight at early age, whereas GE prevented this effect of maternal HFHS-feeding and reduced hepatic lipid accumulation. GE stimulated hepatic mRNA transcription and protein expression of mitochondrial biogenesis markers (peroxisome proliferator-activated receptor-gamma co-activator-1alpha and mitochondrial transcription factor A) and mRNA transcription of mitochondrial dynamics markers (mitofusin-1, mitofusin-2, and dynamin-related protein-1) that were altered by maternal GDM, while mitochondrial dynamics markers protein expression was not affected by maternal diet/GE except for optic atrophy-1. MicroRNAs associated with these processes (miR-122, miR-34a, miR-130b, miR-494), and the expression of auto/mitophagy- and apoptosis-related proteins were not substantially influenced by altered intrauterine environment. Our findings suggest that GE is an important regulator of the intrauterine environment positively affecting liver metabolism and promoting liver mitochondrial biogenesis in female offspring despite eventual effects of maternal HFHS-feeding and related GDM.
    Keywords:  Fetal programming; Gestational exercise; Physical exercise; Pregnancy
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166526
  22. EMBO J. 2022 Aug 25. e110486
    Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons.
    Sumiko Kiryu-Seo, Reika Matsushita, Yoshitaka Tashiro, Takeshi Yoshimura, Yohei Iguchi, Masahisa Katsuno, Ryosuke Takahashi, Hiroshi Kiyama.
      The proteasome is essential for cellular responses to various physiological stressors. However, how proteasome function impacts the stress resilience of regenerative damaged motor neurons remains unclear. Here, we develop a unique mouse model using a regulatory element of the activating transcription factor (Atf3) gene to label mitochondria in a damage-induced manner while simultaneously genetically disrupting the proteasome. Using this model, we observed that in injury-induced proteasome-deficient mouse motor neurons, the increase of mitochondrial influx from soma into axons is inhibited because neurons fail to disassemble ankyrin G, an organizer of the axon initial segment (AIS), in a proteasome-dependent manner. Further, these motor neurons exhibit amyotrophic lateral sclerosis (ALS)-like degeneration despite having regenerative potential. Selectively vulnerable motor neurons in SOD1G93A ALS mice, which induce ATF3 in response to pathological damage, also fail to disrupt the AIS, limiting the number of axonal mitochondria at a pre-symptomatic stage. Thus, damage-induced proteasome-sensitive AIS disassembly could be a critical post-translational response for damaged motor neurons to temporarily transit to an immature state and meet energy demands for axon regeneration or preservation.
    Keywords:  axonal transport; nerve injury; neurodegenerative disease; organelle; stress response
    DOI:  https://doi.org/10.15252/embj.2021110486
  23. Cell Death Dis. 2022 Aug 25. 13(8): 735
    Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
    Kai Zhang, Huifang Zhao, Yaru Sheng, Xinyu Chen, Penghui Xu, Jinming Wang, Zhongzhong Ji, Yuman He, Wei-Qiang Gao, Helen He Zhu.
      Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin-Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41419-022-05194-w
  24. Cells. 2022 Aug 10. pii: 2481. [Epub ahead of print]11(16):
    Mitochondrial Dysfunction in Individuals with Diabetic Kidney Disease: A Systematic Review.
    Nicole Flemming, Laura Pernoud, Josephine Forbes, Linda Gallo.
      Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease (DKD). Compared to the vast body of evidence from preclinical in vitro and in vivo studies, evidence from human studies is limited. In a comprehensive search of the published literature, findings from studies that reported evidence of mitochondrial dysfunction in individuals with DKD were examined. Three electronic databases (PubMed, Embase, and Scopus) were searched in March 2022. A total of 1339 articles were identified, and 22 articles met the inclusion criteria. Compared to non-diabetic controls (NDC) and/or individuals with diabetes but without kidney disease (DC), individuals with DKD (age ~55 years; diabetes duration ~15 years) had evidence of mitochondrial dysfunction. Individuals with DKD had evidence of disrupted mitochondrial dynamics (11 of 11 articles), uncoupling (2 of 2 articles), oxidative damage (8 of 8 articles), decreased mitochondrial respiratory capacity (1 of 1 article), decreased mtDNA content (5 of 6 articles), and decreased antioxidant capacity (3 of 4 articles) compared to ND and/or DC. Neither diabetes nor glycemic control explained these findings, but rather presence and severity of DKD may better reflect degree of mitochondrial dysfunction in this population. Future clinical studies should include individuals closer to diagnosis of diabetes to ascertain whether mitochondrial dysfunction is implicated in the development of, or is a consequence of, DKD.
    Keywords:  diabetic kidney disease; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission; mitochondrial fusion; mitophagy; oxidative stress; systematic review
    DOI:  https://doi.org/10.3390/cells11162481
  25. Clin Transl Med. 2022 Aug;12(8): e952
    AAV-mediated gene therapy improving mitochondrial function provides benefit in age-related macular degeneration models.
    Sophia Millington-Ward, Naomi Chadderton, Laura K Finnegan, Iris J M Post, Matthew Carrigan, Tom Gardiner, Elisa Peixoto, Daniel Maloney, Marian M Humphries, Alan Stitt, Thierry Léveillard, Pete Humphries, Paul F Kenna, Arpad Palfi, G Jane Farrar.
      
    DOI:  https://doi.org/10.1002/ctm2.952
  26. Neurobiol Dis. 2022 Aug 18. pii: S0969-9961(22)00234-0. [Epub ahead of print] 105842
    Stem cell therapy for central nervous system disorders: Metabolic interactions between transplanted cells and local microenvironments.
    Stacey A Sakowski, Kevin S Chen.
      Stem cell therapy is a promising and rapidly advancing treatment strategy for a multitude of neurologic disorders. Yet, while early phase clinical trials are being pursued in many disorders, the mechanism of action often remains unclear. One important potential mechanism by which stem cells provide neuroprotection is through metabolic signaling with diseased neurons, glia, and other cell types in the nervous system microenvironment. Early studies exploring such interactions report normalization of glucose metabolism, induction of protective mitochondrial genes, and even interactions with supportive neurovasculature. Local metabolic conditions also impact stem cell biology, which can have a large impact on transplant viability and efficacy. Epigenetic changes that occur in the donor prior to collection of stem cells, and even during in vitro culture conditions, may have effects on stem cell biology that are carried into the host upon stem cell transplantation. Transplanted stem cells also face potentially toxic metabolic microenvironments at the targeted transplant site. Novel approaches for metabolically "preconditioning" stem cells prior to transplant harness metabolic machinery to optimize stem cell survival upon transplant. Ultimately, an improved understanding of the metabolic cross-talk between implanted stem cells and the local nervous system environment, in both disease and injury states, will increase the likelihood of success in translating stem cell therapy to early trials in neurological disease.
    Keywords:  Central nervous system; Metabolism; Stem cell; Transplantation
    DOI:  https://doi.org/10.1016/j.nbd.2022.105842
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