bims-mitdis 2021-05-02 papers

bims-mitdis

Biomed News

on Mitochondrial Disorders

Issue of 2021‒05‒02
forty-three papers selected by
Catalina Vasilescu
University of Helsinki

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants.
Application of Genome Sequencing from Blood to Diagnose Mitochondrial Diseases.
Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations.
Human Mitoribosome Biogenesis and Its Emerging Links to Disease.
The ATP Synthase Deficiency in Human Diseases.
Mitochondrial DNA Haplogroups and Three Independent Polymorphisms have no Association with the Risk of Parkinson's Disease in East Indian Population.
Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance.
Telencephalon-specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning.
FMRP attenuates activity dependent modifications in the mitochondrial proteome.
Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism.
The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development.
A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1.
Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.
Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.
Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.
GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway.
Somatic mutation landscapes at single-molecule resolution.
Towards physiologically relevant human pluripotent stem cell (hPSC) models of Parkinson's disease.
Evolving concepts in NAD+ metabolism.
Mitochondrial nicotinamide adenine dinucleotide hydride dehydrogenase (NADH) subunit 4 (MTND4) polymorphisms and their association with male infertility.
Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.
Role of PGC-1α in the Mitochondrial NAD+ Pool in Metabolic Diseases.
Nutritional Mediators of Cellular Decline and Mitochondrial Dysfunction in Older Adults.
Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies.
Motor proteins at the mitochondria-cytoskeleton interface.
Mitophagy in Human Diseases.
Structural and Functional Remodeling of Mitochondria in Cardiac Diseases.
The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space.
Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics.
PINK1-mediated mitophagy maintains pluripotency through optineurin.
A Walk in the Memory, from the First Functional Approach up to Its Regulatory Role of Mitochondrial Bioenergetic Flow in Health and Disease: Focus on the Adenine Nucleotide Translocator.
IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations.
The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease.
Next-Generation Sequencing Technologies and Neurogenetic Diseases.
Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans.
Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process.
Molecular bases of mitochondrial disorders.
Mitochondrial K+ channels and their implications for disease mechanisms.
Energy Metabolism in the Inner Retina in Health and Glaucoma.
SAHA is neuroprotective in in vitro and in situ models of retinitis pigmentosa.
Dietary Essential Amino Acid Restriction Promotes Hyperdipsia via Hepatic FGF21.

Nat Metab. 2021 Apr 26.

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.

Hans-Georg Sprenger, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.

Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

DOI: https://doi.org/10.1038/s42255-021-00385-9
Int J Mol Sci. 2021 Apr 26. pii: 4524. [Epub ahead of print]22(9):

Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants.

Sonia Figuccia, Andrea Degiorgi, Camilla Ceccatelli Berti, Enrico Baruffini, Cristina Dallabona, Paola Goffrini.

  In most eukaryotes, mitochondrial protein synthesis is essential for oxidative phosphorylation (OXPHOS) as some subunits of the respiratory chain complexes are encoded by the mitochondrial DNA (mtDNA). Mutations affecting the mitochondrial translation apparatus have been identified as a major cause of mitochondrial diseases. These mutations include either heteroplasmic mtDNA mutations in genes encoding for the mitochondrial rRNA (mtrRNA) and tRNAs (mttRNAs) or mutations in nuclear genes encoding ribosomal proteins, initiation, elongation and termination factors, tRNA-modifying enzymes, and aminoacyl-tRNA synthetases (mtARSs). Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of specific amino acids to their cognate tRNAs. Differently from most mttRNAs, which are encoded by mitochondrial genome, mtARSs are encoded by nuclear genes and then imported into the mitochondria after translation in the cytosol. Due to the extensive use of next-generation sequencing (NGS), an increasing number of mtARSs variants associated with large clinical heterogeneity have been identified in recent years. Being most of these variants private or sporadic, it is crucial to assess their causative role in the disease by functional analysis in model systems. This review will focus on the contributions of the yeast Saccharomyces cerevisiae in the functional validation of mutations found in mtARSs genes associated with human disorders.

Keywords:  mitochondrial aminoacyl-tRNA synthetases; mitochondrial diseases; novel variants; yeast model

DOI:  https://doi.org/10.3390/ijms22094524
Genes (Basel). 2021 Apr 20. pii: 607. [Epub ahead of print]12(4):

Application of Genome Sequencing from Blood to Diagnose Mitochondrial Diseases.

Rocio Rius, Alison G Compton, Naomi L Baker, AnneMarie E Welch, David Coman, Maina P Kava, Andre E Minoche, Mark J Cowley, David R Thorburn, John Christodoulou.

  Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it has not yet been universally used as a first-line approach to diagnosing mitochondrial diseases due to related costs and challenges in data analysis. In this article, we report three patients with mitochondrial disease molecularly diagnosed through GS performed on DNA extracted from blood to demonstrate different diagnostic advantages of this technology, including the detection of a low-level heteroplasmic pathogenic variant, an intragenic nuclear DNA deletion, and a large mtDNA deletion. Current technical improvements and cost reductions are likely to lead to an expanded routine diagnostic usage of GS and of the complementary "Omic" technologies in mitochondrial diseases.

Keywords:  genome sequencing; heteroplasmy; mitochondria; mutation; respiratory chain

DOI:  https://doi.org/10.3390/genes12040607
J Clin Med. 2021 Apr 20. pii: 1796. [Epub ahead of print]10(8):

Exercise Testing, Physical Training and Fatigue in Patients with Mitochondrial Myopathy Related to mtDNA Mutations.

Tina D Jeppesen, Karen L Madsen, Nanna S Poulsen, Nicoline Løkken, John Vissing.

  Mutations in mitochondrial DNA (mtDNA) cause disruption of the oxidative phosphorylation chain and impair energy production in cells throughout the human body. Primary mitochondrial disorders due to mtDNA mutations can present with symptoms from adult-onset mono-organ affection to death in infancy due to multi-organ involvement. The heterogeneous phenotypes that patients with a mutation of mtDNA can present with are thought, at least to some extent, to be a result of differences in mtDNA mutation load among patients and even among tissues in the individual. The most common symptom in patients with mitochondrial myopathy (MM) is exercise intolerance. Since mitochondrial function can be assessed directly in skeletal muscle, exercise studies can be used to elucidate the physiological consequences of defective mitochondria due to mtDNA mutations. Moreover, exercise tests have been developed for diagnostic purposes for mitochondrial myopathy. In this review, we present the rationale for exercise testing of patients with MM due to mutations in mtDNA, evaluate the diagnostic yield of exercise tests for MM and touch upon how exercise tests can be used as tools for follow-up to assess disease course or effects of treatment interventions.

Keywords:  exercise testing; fatigue; mitochondrial myopathy; mtDNA mutation

DOI:  https://doi.org/10.3390/jcm10081796
Int J Mol Sci. 2021 Apr 07. pii: 3827. [Epub ahead of print]22(8):

Human Mitoribosome Biogenesis and Its Emerging Links to Disease.

Maria Isabel G Lopez Sanchez, Annika Krüger, Dmitrii I Shiriaev, Yong Liu, Joanna Rorbach.

  Mammalian mitochondrial ribosomes (mitoribosomes) synthesize a small subset of proteins, which are essential components of the oxidative phosphorylation machinery. Therefore, their function is of fundamental importance to cellular metabolism. The assembly of mitoribosomes is a complex process that progresses through numerous maturation and protein-binding events coordinated by the actions of several assembly factors. Dysregulation of mitoribosome production is increasingly recognized as a contributor to metabolic and neurodegenerative diseases. In recent years, mutations in multiple components of the mitoribosome assembly machinery have been associated with a range of human pathologies, highlighting their importance to cell function and health. Here, we provide a review of our current understanding of mitoribosome biogenesis, highlighting the key factors involved in this process and the growing number of mutations in genes encoding mitoribosomal RNAs, proteins, and assembly factors that lead to human disease.

Keywords:  assembly factors; mitochondria; mitochondrial disease; mitoribosome; rRNA

DOI:  https://doi.org/10.3390/ijms22083827
Life (Basel). 2021 Apr 08. pii: 325. [Epub ahead of print]11(4):

The ATP Synthase Deficiency in Human Diseases.

Chiara Galber, Stefania Carissimi, Alessandra Baracca, Valentina Giorgio.

  Human diseases range from gene-associated to gene-non-associated disorders, including age-related diseases, neurodegenerative, neuromuscular, cardiovascular, diabetic diseases, neurocognitive disorders and cancer. Mitochondria participate to the cascades of pathogenic events leading to the onset and progression of these diseases independently of their association to mutations of genes encoding mitochondrial protein. Under physiological conditions, the mitochondrial ATP synthase provides the most energy of the cell via the oxidative phosphorylation. Alterations of oxidative phosphorylation mainly affect the tissues characterized by a high-energy metabolism, such as nervous, cardiac and skeletal muscle tissues. In this review, we focus on human diseases caused by altered expressions of ATP synthase genes of both mitochondrial and nuclear origin. Moreover, we describe the contribution of ATP synthase to the pathophysiological mechanisms of other human diseases such as cardiovascular, neurodegenerative diseases or neurocognitive disorders.

Keywords:  ATP synthase; human disease; mitochondria

DOI:  https://doi.org/10.3390/life11040325
Neurol India. 2021 Mar-Apr;69(2):69(2): 461-465

Mitochondrial DNA Haplogroups and Three Independent Polymorphisms have no Association with the Risk of Parkinson's Disease in East Indian Population.

Tania Saha, Somrita Roy, Rajashree Chakraborty, Arindam Biswas, Shyamal K Das, Kunal Ray, Jharna Ray, Mainak Sengupta.

  Background: Parkinson's disease (PD) is a multifaceted illness affecting ~ 0.3% of the world population. The genetic complexity of PD has not been, fully elucidated. Several studies suggest that mitochondrial DNA variants are associated with PD.Objective: Here, we have explored the possibility of genetic association between mitochondrial haplogroups as well as three independent SNPs with PD in a representative east Indian population.
Methods and Material: The Asian mtDNA haplogroups: M, N, R, B, D, M7, and 3 other SNPs: 4336 T/C, 9055 G/A, 13708 G/A were genotyped in 100 sporadic PD patients and 100 matched controls via conventional PCR-RFLP-sequencing approach.
Results: The distribution of mtDNA haplogroups, as well as 3 single polymorphisms, did not show any significant differences (P > 0.05) between patients and controls.
Conclusion: This is the first of its kind of study from India that suggests no association of selected mitochondrial DNA variations with PD.

Keywords:  Genetic Association; Haplogroups; Mitochondrial DNA; Parkinson's disease; SNP

DOI:  https://doi.org/10.4103/0028-3886.314553
Sci Adv. 2021 Apr;pii: eabe7359. [Epub ahead of print]7(18):

Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance.

Wanshu Ma, Hyea Jin Gil, Xiaolei Liu, Lauren P Diebold, Marc A Morgan, Michael J Oxendine-Burns, Peng Gao, Navdeep S Chandel, Guillermo Oliver.

Recent findings indicate that mitochondrial respiration regulates blood endothelial cell proliferation; however, its role in differentiating lymphatic endothelial cells (LECs) is unknown. We hypothesized that mitochondria could work as a sensor of LECs' metabolic specific needs by determining their functional requirements according to their differentiation status and local tissue microenvironment. Accordingly, we conditionally deleted the QPC subunit of mitochondrial complex III in differentiating LECs of mouse embryos. Unexpectedly, mutant mice were devoid of a lymphatic vasculature by mid-gestation, a consequence of the specific down-regulation of main LEC fate regulators, particularly Vegfr3, leading to the loss of LEC fate. Mechanistically, this is a result of reduced H3K4me3 and H3K27ac in the genomic locus of key LEC fate controllers (e.g., Vegfr3 and Prox1). Our findings indicate that by sensing the LEC differentiation status and microenvironmental metabolic conditions, mitochondrial complex III regulates the critical Prox1-Vegfr3 feedback loop and, therefore, LEC fate specification and maintenance.

DOI: https://doi.org/10.1126/sciadv.abe7359
FEBS Lett. 2021 Apr 30.

Telencephalon-specific Alkbh1 conditional knockout mice display hippocampal atrophy and impaired learning.

Layla Kawarada, Masahiro Fukaya, Ryo Saito, Hidetoshi Kassai, Hiroyuki Sakagami, Atsu Aiba.

  AlkB homolog 1 (ALKBH1) is responsible for the biogenesis of 5-formylcytidine (f5 C) on mitochondrial tRNAMet and essential for mitochondrial protein synthesis. The brain, especially the hippocampus, is highly susceptible to mitochondrial dysfunction; hence, the maintenance of mitochondrial activity is strongly required to prevent disorders associated with hippocampal malfunction. To study the role of ALKBH1 in the hippocampus, we generated dorsal telencephalon-specific Alkbh1 conditional KO (cKO) mice in inbred C57BL/6 background. These mice showed reduced activity of the respiratory chain complex, hippocampal atrophy and CA1 pyramidal neuron abnormalities. Furthermore, performances in the fear-conditioning and Morris water maze tests in cKO mice indicated that the hippocampal abnormalities led to impaired hippocampus-dependent learning. These findings indicate critical roles of ALKBH1 in the hippocampus.

Keywords:  Alkbh1; hippocampus; knockout mice; learning and memory; mitochondria

DOI:  https://doi.org/10.1002/1873-3468.14098
Mol Brain. 2021 Apr 30. 14(1): 75

FMRP attenuates activity dependent modifications in the mitochondrial proteome.

Pernille Bülow, Stephanie A Zlatic, Peter A Wenner, Gary J Bassell, Victor Faundez.

  Homeostatic plasticity is necessary for the construction and maintenance of functional neuronal networks, but principal molecular mechanisms required for or modified by homeostatic plasticity are not well understood. We recently reported that homeostatic plasticity induced by activity deprivation is dysregulated in cortical neurons from Fragile X Mental Retardation protein (FMRP) knockout mice (Bulow et al. in Cell Rep 26: 1378-1388 e1373, 2019). These findings led us to hypothesize that identifying proteins sensitive to activity deprivation and/or FMRP expression could reveal pathways required for or modified by homeostatic plasticity. Here, we report an unbiased quantitative mass spectrometry used to quantify steady-state proteome changes following chronic activity deprivation in wild type and Fmr1-/y cortical neurons. Proteome hits responsive to both activity deprivation and the Fmr1-/y genotype were significantly annotated to mitochondria. We found an increased number of mitochondria annotated proteins whose expression was sensitive to activity deprivation in Fmr1-/y cortical neurons as compared to wild type neurons. These findings support a novel role of FMRP in attenuating mitochondrial proteome modifications induced by activity deprivation.

Keywords:  Autism; FMRP; Homeostatic plasticity; Mitochondria; Neurodevelopmental disorder; Proteomics

DOI:  https://doi.org/10.1186/s13041-021-00783-w
Int J Mol Sci. 2021 Apr 06. pii: 3799. [Epub ahead of print]22(7):

Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism.

Sara Tucci, Khaled Ibrahim Alatibi, Zeinab Wehbe.

  In general, metabolic flexibility refers to an organism's capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. On the one hand, in a mouse model of VLCAD-deficient (VLCAD-/-) mice, the white skeletal muscle undergoes metabolic and morphologic transdifferentiation towards glycolytic muscle fiber types via the up-regulation of mitochondrial fatty acid biosynthesis (mtFAS). On the other hand, in ACSF3-deficient patients, fibroblasts show impaired mitochondrial respiration, reduced lipoylation, and reduced glycolytic flux, which are compensated for by an increased β-oxidation rate and the use of anaplerotic amino acids to address the energy needs. Here, we discuss a possible co-regulation by mtFAS and β-oxidation in the maintenance of energy homeostasis.

Keywords:  VLCADD; inherited metabolic disorders; metabolic flexibility; mitochondrial fatty acid metabolism; mtFAS

DOI:  https://doi.org/10.3390/ijms22073799
Development. 2021 Apr 15. pii: dev199026. [Epub ahead of print]148(8):

The SRCAP chromatin remodeling complex promotes oxidative metabolism during prenatal heart development.

Mingjie Xu, Jie Yao, Yingchao Shi, Huijuan Yi, Wukui Zhao, Xinhua Lin, Zhongzhou Yang.

  Mammalian heart development relies on cardiomyocyte mitochondrial maturation and metabolism. Embryonic cardiomyocytes make a metabolic shift from anaerobic glycolysis to oxidative metabolism by mid-gestation. VHL-HIF signaling favors anaerobic glycolysis but this process subsides by E14.5. Meanwhile, oxidative metabolism becomes activated but its regulation is largely elusive. Here, we first pinpointed a crucial temporal window for mitochondrial maturation and metabolic shift, and uncovered the pivotal role of the SRCAP chromatin remodeling complex in these processes in mouse. Disruption of this complex massively suppressed the transcription of key genes required for the tricarboxylic acid cycle, fatty acid β-oxidation and ubiquinone biosynthesis, and destroyed respirasome stability. Furthermore, we found that the SRCAP complex functioned through H2A.Z deposition to activate transcription of metabolic genes. These findings have unveiled the important physiological functions of the SRCAP complex in regulating mitochondrial maturation and promoting oxidative metabolism during heart development, and shed new light on the transcriptional regulation of ubiquinone biosynthesis.

Keywords:  H2A.Z; Heart development; Metabolism; Mitochondria; Mouse; SRCAP chromatin remodeling complex; Znhit1

DOI:  https://doi.org/10.1242/dev.199026
Front Neurol. 2021 ;12 641259

A Perspective on Accelerated Aging Caused by the Genetic Deficiency of the Metabolic Protein, OPA1.

Irina Erchova, Shanshan Sun, Marcela Votruba.

  Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the OPA1 gene. It has variable onset, sometimes juvenile, but in other patients, the disease does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered healthy before the onset of clinical symptoms. Our research, nonetheless, indicates that on the cellular level pathology is evident from birth and mutant cells are different from controls. We argue that the adaptation and early recruitment of cytoprotective responses allows normal development and functioning but leads to an exhaustion of cellular reserves, leading to premature cellular aging, especially in neurons and skeletal muscle cells. The appearance of clinical symptoms, thus, indicates the overwhelming of natural cellular defenses and break-down of native protective mechanisms.

Keywords:  OPA1; aging; cellular adaptation; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3389/fneur.2021.641259
Annu Rev Immunol. 2021 Apr 26. 39 395-416

Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.

Elizabeth M Steinert, Karthik Vasan, Navdeep S Chandel.

  Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.

Keywords:  ROS; TCA cycle; acetyl-CoA; epigenetics; inflammation; l-2-hydroxyglutarate; l-2HG

DOI:  https://doi.org/10.1146/annurev-immunol-101819-082015
Biomedicines. 2021 Apr 02. pii: 376. [Epub ahead of print]9(4):

Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies.

Chantal B Lucini, Ralf J Braun.

  In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

Keywords:  TDP-43; apoptosis; cell death; mitochondria; mitochondrial permeabilization; mtDNA; proteinopathy

DOI:  https://doi.org/10.3390/biomedicines9040376
Mitochondrion. 2021 Apr 21. pii: S1567-7249(21)00056-8. [Epub ahead of print]

Homoplasmy of the m. 8993 T>G variant in a patient without MRI findings of Leigh syndrome, ataxia or retinal abnormalities.

Russell P Saneto, Kristina E Patrick, Francisco A Perez.

  Leigh syndrome is a progressive neurodegenerative syndrome caused by multiple mitochondrial DNA and nuclear DNA pathological variants. Patients with Leigh syndrome consistently have distinct brain lesions found on MRI scanning involving abnormal signal in the basal ganglia, brainstem and/or cerebellum. Other clinical findings vary depending on the genetic etiology and epigenetic factors. Mitochondrial DNA-derived Leigh syndrome phenotype is thought to be modulated by heteroplasmy level. The classic example is the clinical expression of the pathological variant, m. 8993 T>G. At heteroplasmy levels above 90%, the resulting phenotype is Leigh syndrome, but at levels 70 - 90% patients present with a syndrome of neuropathy, ataxia and retinitis pigmentosa. We describe a 15-year old girl with homoplasmic variant in m.8993 T>G and clinical and biochemical findings consistent with Leigh syndrome but with normal brain MRI findings and without retinal abnormalities or ataxia.

Keywords:  Leigh syndrome; MRI brain; basal ganglia; homoplasmy; m. 8993 T>G; mitochondrial disease

DOI:  https://doi.org/10.1016/j.mito.2021.04.010
Biochem Pharmacol. 2021 Apr 22. pii: S0006-2952(21)00184-2. [Epub ahead of print]188 114578

GLP-1 improves the neuronal supportive ability of astrocytes in Alzheimer's disease by regulating mitochondrial dysfunction via the cAMP/PKA pathway.

Yunzhen Xie, Jiaping Zheng, Shiqi Li, Huiying Li, Yu Zhou, Wenrong Zheng, Meilian Zhang, Libin Liu, Zhou Chen.

  The glucagon-like peptide-1 (GLP-1) was shown to have neuroprotective effects in Alzheimer's disease (AD). However, the underlying mechanism remains elusive. Astrocytic mitochondrial abnormalities have been revealed to constitute important pathologies. In the present study, we investigated the role of astrocytic mitochondria in the neuroprotective effect of GLP-1 in AD. To this end, 6-month-old 5 × FAD mice were subcutaneously treated with liraglutide, a GLP-1 analogue (25 nmol/kg/qd) for 8 weeks. Liraglutide ameliorated mitochondrial dysfunction and prevented neuronal loss with activation of the cyclic adenosine 3',5'-monophosphate (cAMP)/phosphorylate protein kinase A (PKA) pathway in the brain of 5 × FAD mice. Next, we exposed astrocytes to β-amyloid (Aβ) in vitro and treated them with GLP-1. By activating the cAMP/PKA pathway, GLP-1 increased the phosphorylation of DRP-1 at the s637 site and mitigated mitochondrial fragmentation in Aβ-treated astrocytes. GLP-1 further improved the Aβ-induced energy failure, mitochondrial reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (MMP) collapse, and cell toxicity in astrocytes. Moreover, GLP-1 also promoted the neuronal supportive ability of Aβ-treated astrocytes via the cAMP/PKA pathway. This study revealed a new mechanism behind the neuroprotective effect of GLP-1 in AD.

Keywords:  Alzheimer’s disease; Astrocyte; Glucagon-like peptide-1; Mitochondrial dysfunction; cAMP/PKA pathway

DOI:  https://doi.org/10.1016/j.bcp.2021.114578
Nature. 2021 Apr 28.

Somatic mutation landscapes at single-molecule resolution.

Federico Abascal, Luke M R Harvey, Emily Mitchell, Andrew R J Lawson, Stefanie V Lensing, Peter Ellis, Andrew J C Russell, Raul E Alcantara, Adrian Baez-Ortega, Yichen Wang, Eugene Jing Kwa, Henry Lee-Six, Alex Cagan, Tim H H Coorens, Michael Spencer Chapman, Sigurgeir Olafsson, Steven Leonard, David Jones, Heather E Machado, Megan Davies, Nina F Øbro, Krishnaa T Mahubani, Kieren Allinson, Moritz Gerstung, Kourosh Saeb-Parsy, David G Kent, Elisa Laurenti, Michael R Stratton, Raheleh Rahbari, Peter J Campbell, Robert J Osborne, Iñigo Martincorena.

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.

DOI: https://doi.org/10.1038/s41586-021-03477-4
Stem Cell Res Ther. 2021 Apr 29. 12(1): 253

Towards physiologically relevant human pluripotent stem cell (hPSC) models of Parkinson's disease.

Elena Coccia, Tim Ahfeldt.

  The derivation of human embryonic stem cells followed by the discovery of induced pluripotent stem cells and leaps in genome editing approaches have continuously fueled enthusiasm for the development of new models of neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the relative selective loss of dopaminergic neurons (DNs) in specific areas of substantia nigra pars compacta (SNpc). While degeneration in late stages can be widespread, there is stereotypic early degeneration of these uniquely vulnerable neurons. Various causes of selective vulnerability have been investigated but much remains unclear. Most studies have sought to identify cell autonomous properties of the most vulnerable neurons. However, recent findings from genetic studies and model systems have added to our understanding of non-cell autonomous contributions including regional-specific neuro-immune interactions with astrocytes, resident or damage-activated microglia, neuro-glia cell metabolic interactions, involvement of endothelial cells, and damage to the vascular system. All of these contribute to specific vulnerability and, along with aging and environmental factors, might be integrated in a complex stressor-threshold model of neurodegeneration. In this forward-looking review, we synthesize recent advances in the field of PD modeling using human pluripotent stem cells, with an emphasis on organoid and complex co-culture models of the nigrostriatal niche, with emerging CRISPR applications to edit or perturb expression of causal PD genes and associated risk factors, such as GBA, to understand the impact of these genes on relevant phenotypes.

Keywords:  CRISPR; GBA; Human pluripotent stem cells (hPSCs); Neurodegenerative disease modeling; Parkinson’s disease

DOI:  https://doi.org/10.1186/s13287-021-02326-5
Cell Metab. 2021 Apr 22. pii: S1550-4131(21)00169-8. [Epub ahead of print]

Evolving concepts in NAD+ metabolism.

Claudia C S Chini, Julianna D Zeidler, Sonu Kashyap, Gina Warner, Eduardo Nunes Chini.

  NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.

Keywords:  NAD pathway metabolites; NAD(+); aging; disease; humans; mitochondria; transport; vitamin B3

DOI:  https://doi.org/10.1016/j.cmet.2021.04.003
J Assist Reprod Genet. 2021 Apr 24.

Mitochondrial nicotinamide adenine dinucleotide hydride dehydrogenase (NADH) subunit 4 (MTND4) polymorphisms and their association with male infertility.

Fatina W Dahadhah, Mayyas Saleh Jaweesh, Mazhar Salim Al Zoubi, Manal Issam Abu Alarjah, Mohamad Eid Hammadeh, Houda Amor.

  PURPOSE: The purpose of the present study was to determine the relationship between infertility and the polymorphisms of mitochondrial NADH dehydrogenase subunit 4 (MTND4) by spermatozoa analysis in fertile and subfertile men.METHODS: Samples were divided into 68 subfertile men (case group) and 44 fertile men (control group). After semen analysis, samples were purified. The whole genome was extracted using a QIAamp DNA Mini Kit and the mitochondrial DNA was amplified by using the REPLI-g Mitochondrial DNA Kit. Polymerase chain reaction (PCR) was used to amplify the MT-ND4 gene. Then, samples were purified and sequenced using the Sanger method.
RESULTS: Twenty-five single-nucleotide polymorphisms (SNPs) were identified in the MTND4 gene. The genotype frequencies of the study population showed a statistically significant association between rs2853495 G>A (Gly320Gly) and male infertility (P = 0.0351). Similarly, the allele frequency test showed that rs2853495 G>A (Gly320Gly) and rs869096886 A>G (Leu164Leu) were significantly associated with male infertility (adjusted OR = 2.616, 95% CI = 1.374-4.983, P = 0.002; adjusted OR = 2.237, 95% CI = 1.245-4.017, P = 0.007, respectively).
CONCLUSION: In conclusion, our findings suggested that male infertility was correlated with rs2853495 and rs869096886 SNPs in MTND4.

Keywords:  MTND4; Male infertility; SNP; mtDNA

DOI:  https://doi.org/10.1007/s10815-021-02199-w
Circulation. 2021 Apr 28.

Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.

Sabrina Geisberger, Hendrik Bartolomaeus, Patrick Neubert, Ralf Willebrand, Christin Zasada, Thomas Bartolomaeus, Victoria McParland, Dries Swinnen, Anneleen Geuzens, András Maifeld, Luka Krampert, Marion Vogl, Anja Mähler, Nicola Wilck, Lajos Marko, Ekin Tilic, Sofia K Forslund, Katrina J Binger, Johannes Stegbauer, Ralf Dechend, Markus Kleinewietfeld, Jonathan Jantsch, Stefan Kempa, Dominik N Müller.

  Background: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially, but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional and functional adaption of human and murine mononuclear phagocytes (MNP). Methods: Using Seahorse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays we characterize the central carbon metabolism and mitochondrial function of human and murine MNP under HS in vitro. HS as well as pharmacologic uncoupling of the electron transport chain (ETC) under normal salt (NS) is used to analyze mitochondrial function on immune cell activation and function (as determined by E.coli killing and CD4+ T cell migration capacity). In two independent clinical studies we analyze the impact of a HS diet over two weeks (NCT02509962) and short-term salt challenge by a single meal (NCT04175249) on mitochondrial function of human monocytes in vivo. Results: Extracellular sodium was taken up into the intracellular compartment followed by the inhibition of mitochondrial respiration in murine and human macrophages (MΦ). Mechanistically, HS reduces mitochondrial membrane potential, ETC complex II activity, oxygen consumption, and ATP production independently of the polarization status of MΦ. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like MΦ and diminished CD4+ T cell migration in HS-treated M2-like MΦ. Pharmacologic uncoupling of the ETC under NS phenocopies HS-induced transcriptional changes and bactericidal function of human and murine MNP. Clinically, also in vivo rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both, a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of ̃x = 2mM and ̃x = 2.3mM, respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. Conclusions: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. While these functional changes might help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory CVD.

Keywords:  bacterial killing; complex II; mitochondrial respiration; salt

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.052788
Int J Mol Sci. 2021 Apr 27. pii: 4558. [Epub ahead of print]22(9):

Role of PGC-1α in the Mitochondrial NAD+ Pool in Metabolic Diseases.

Jin-Ho Koh, Jong-Yeon Kim.

  Mitochondria play vital roles, including ATP generation, regulation of cellular metabolism, and cell survival. Mitochondria contain the majority of cellular nicotinamide adenine dinucleotide (NAD+), which an essential cofactor that regulates metabolic function. A decrease in both mitochondria biogenesis and NAD+ is a characteristic of metabolic diseases, and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) orchestrates mitochondrial biogenesis and is involved in mitochondrial NAD+ pool. Here we discuss how PGC-1α is involved in the NAD+ synthesis pathway and metabolism, as well as the strategy for increasing the NAD+ pool in the metabolic disease state.

Keywords:  NAD+, SIRTs; PGC-1α; metabolic disease; mitochondria

DOI:  https://doi.org/10.3390/ijms22094558
Geriatrics (Basel). 2021 Apr 06. pii: 37. [Epub ahead of print]6(2):

Nutritional Mediators of Cellular Decline and Mitochondrial Dysfunction in Older Adults.

Jack M Guralnik, Jerome N Feige, Anurag Singh, Roger A Fielding.

  Aging is a primary risk factor for the progressive loss of function, disease onset, and increased vulnerability to negative health-related outcomes. These clinical manifestations arise in part from declines in mitochondrial, metabolic, and other processes considered to be hallmarks of aging. Collectively, these changes can be defined as age-associated cellular decline (AACD) and are often associated with fatigue, reduced strength, and low physical activity. This manuscript summarizes a recent Gerontological Society of America Annual Scientific Meeting symposium that explored mechanisms, clinical signs, and emerging cellular nutrition interventions for AACD. The session opened by highlighting results of an expert consensus that developed an initial framework to identify self-reported symptoms and observable signs of AACD in adults aged >50 years. Next, findings from the multi-ethnic molecular determinants of sarcopenia study were discussed, showing impaired mitochondrial bioenergetic capacity and NAD+ metabolism in skeletal muscle of older adults with sarcopenia. Lastly, recent clinical evidence was presented linking urolithin A, a natural mitophagy activator, to improved mitochondrial and cellular health. The virtual panel discussed how stimulation of mitochondrial function via biological pathways, such as mitophagy and NAD+ augmentation, could improve cellular function and muscle health, potentially impacting clinical signs of AACD and overall healthy aging.

Keywords:  AACD; accelerated aging and cellular decline; age-associated cellular decline; cellular nutrition; mitochondria; muscle; nicotinamide riboside; sarcopenia; urolithin A

DOI:  https://doi.org/10.3390/geriatrics6020037
Front Cell Dev Biol. 2021 ;9 653322

Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies.

Marina O Gomzikova, Victoria James, Albert A Rizvanov.

  The phenomenon of mitochondria donation is found in various tissues of humans and animals and is attracting increasing attention. To date, numerous studies have described the transfer of mitochondria from stem cells to injured cells, leading to increased ATP production, restoration of mitochondria function, and rescue of recipient cells from apoptosis. Mitochondria transplantation is considered as a novel therapeutic approach for the treatment of mitochondrial diseases and mitochondrial function deficiency. Mitochondrial dysfunction affects cells with high energy needs such as neural, skeletal muscle, heart, and liver cells and plays a crucial role in type 2 diabetes, as well as Parkinson's, Alzheimer's diseases, ischemia, stroke, cancer, and age-related disorders. In this review, we summarize recent findings in the field of mitochondria donation and mechanism of mitochondria transfer between cells. We review the existing clinical trials and discuss advantages and disadvantages of mitochondrial transplantation strategies based on the injection of stem cells, isolated functional mitochondria, or EVs containing mitochondria.

Keywords:  cell fusion; extracellular vesicles; isolated mitochondria; mitochondria donation; mitochondria transplantation; tunneling nanotubes

DOI:  https://doi.org/10.3389/fcell.2021.653322
J Cell Sci. 2021 Apr 01. pii: jcs226084. [Epub ahead of print]134(7):

Motor proteins at the mitochondria-cytoskeleton interface.

Antonina J Kruppa, Folma Buss.

  Mitochondria are multifunctional organelles that not only produce energy for the cell, but are also important for cell signalling, apoptosis and many biosynthetic pathways. In most cell types, they form highly dynamic networks that are constantly remodelled through fission and fusion events, repositioned by motor-dependent transport and degraded when they become dysfunctional. Motor proteins and their tracks are key regulators of mitochondrial homeostasis, and in this Review, we discuss the diverse functions of the three classes of motor proteins associated with mitochondria - the actin-based myosins, as well as the microtubule-based kinesins and dynein. In addition, Miro and TRAK proteins act as adaptors that link kinesin-1 and dynein, as well as myosin of class XIX (MYO19), to mitochondria and coordinate microtubule- and actin-based motor activities. Here, we highlight the roles of motor proteins and motor-linked track dynamics in the transporting and docking of mitochondria, and emphasize their adaptations in specialized cells. Finally, we discuss how motor-cargo complexes mediate changes in mitochondrial morphology through fission and fusion, and how they modulate the turnover of damaged organelles via quality control pathways, such as mitophagy. Understanding the importance of motor proteins for mitochondrial homeostasis will help to elucidate the molecular basis of a number of human diseases.

Keywords:  Actin; Dynein; Kinesin; Microtubules; Mitochondria; Myosin

DOI:  https://doi.org/10.1242/jcs.226084
Int J Mol Sci. 2021 Apr 09. pii: 3903. [Epub ahead of print]22(8):

Mitophagy in Human Diseases.

Laura Doblado, Claudia Lueck, Claudia Rey, Alejandro K Samhan-Arias, Ignacio Prieto, Alessandra Stacchiotti, Maria Monsalve.

  Mitophagy is a selective autophagic process, essential for cellular homeostasis, that eliminates dysfunctional mitochondria. Activated by inner membrane depolarization, it plays an important role during development and is fundamental in highly differentiated post-mitotic cells that are highly dependent on aerobic metabolism, such as neurons, muscle cells, and hepatocytes. Both defective and excessive mitophagy have been proposed to contribute to age-related neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, metabolic diseases, vascular complications of diabetes, myocardial injury, muscle dystrophy, and liver disease, among others. Pharmacological or dietary interventions that restore mitophagy homeostasis and facilitate the elimination of irreversibly damaged mitochondria, thus, could serve as potential therapies in several chronic diseases. However, despite extraordinary advances in this field, mainly derived from in vitro and preclinical animal models, human applications based on the regulation of mitochondrial quality in patients have not yet been approved. In this review, we summarize the key selective mitochondrial autophagy pathways and their role in prevalent chronic human diseases and highlight the potential use of specific interventions.

Keywords:  Alzheimer’s; Huntington’s; PINK1; Parkin; Parkinson’s; aging; atherosclerosis; dementia; diabetes; exercise; heart failure; mice; mitophagy; muscle wasting; rats

DOI:  https://doi.org/10.3390/ijms22083903
Int J Mol Sci. 2021 Apr 17. pii: 4167. [Epub ahead of print]22(8):

Structural and Functional Remodeling of Mitochondria in Cardiac Diseases.

Xiaonan Sun, Jalen Alford, Hongyu Qiu.

  Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases' pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.

Keywords:  heart disease; heart failure; metabolism; mitochondria remodeling

DOI:  https://doi.org/10.3390/ijms22084167
Antioxidants (Basel). 2021 Apr 12. pii: 592. [Epub ahead of print]10(4):

The Mia40/CHCHD4 Oxidative Folding System: Redox Regulation and Signaling in the Mitochondrial Intermembrane Space.

Eleanor Dickson-Murray, Kenza Nedara, Nazanine Modjtahedi, Kostas Tokatlidis.

  Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron-sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.

Keywords:  Mia40; intermembrane space; mitochondria; oxidative folding; redox signaling

DOI:  https://doi.org/10.3390/antiox10040592
Metabolites. 2021 Apr 10. pii: 233. [Epub ahead of print]11(4):

Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics.

Haorong Li, Martine Uittenbogaard, Ling Hao, Anne Chiaramello.

  Mitochondria are dynamic multitask organelles that function as hubs for many metabolic pathways. They produce most ATP via the oxidative phosphorylation pathway, a critical pathway that the brain relies on its energy need associated with its numerous functions, such as synaptic homeostasis and plasticity. Therefore, mitochondrial dysfunction is a prevalent pathological hallmark of many neurodevelopmental and neurodegenerative disorders resulting in altered neurometabolic coupling. With the advent of mass spectrometry (MS) technology, MS-based metabolomics provides an emerging mechanistic understanding of their global and dynamic metabolic signatures. In this review, we discuss the pathogenetic causes of mitochondrial metabolic disorders and the recent MS-based metabolomic advances on their metabolomic remodeling. We conclude by exploring the MS-based metabolomic functional insights into their biosignatures to improve diagnostic platforms, stratify patients, and design novel targeted therapeutic strategies.

Keywords:  mass spectrometry; metabolomics; mitochondrial genetics; mitochondrial neurodevelopmental disorders; neurometabolic coupling; secondary mitochondrial neurodegenerative diseases

DOI:  https://doi.org/10.3390/metabo11040233
Cell Prolif. 2021 May 01. e13034

PINK1-mediated mitophagy maintains pluripotency through optineurin.

Chaoqun Wang, Kun Liu, Jiani Cao, Liang Wang, Qian Zhao, Zheng Li, Honghai Zhang, Quan Chen, Tongbiao Zhao.

  OBJECTIVES: Dysfunction of autophagy results in accumulation of depolarized mitochondria and breakdown of self-renewal and pluripotency in ESCs. However, the regulators that control how mitochondria are degraded by autophagy for pluripotency regulation remains largely unknown. This study aims to dissect the molecular mechanisms that regulate mitochondrial homeostasis for pluripotency regulation in mouse ESCs.MATERIALS AND METHODS: Parkin+/+ and parkin-/- ESCs were established from E3.5 blastocysts of parkin+/- x parkin+/- mating mice. The pink1-/- , optn-/- and ndp52-/- ESCs were generated by CRISPR-Cas9. shRNAs were used for function loss assay of target genes. Mito-Keima, ROS and ATP detection were used to investigate the mitophagy and mitochondrial function. Western blot, Q-PCR, AP staining and teratoma formation assay were performed to evaluate the PSC stemness.
RESULTS: PINK1 or OPTN depletion impairs the degradation of dysfunctional mitochondria during reprogramming, and reduces the reprogramming efficiency and quality. In ESCs, PINK1 or OPTN deficiency leads to accumulation of dysfunctional mitochondria and compromised pluripotency. The defective mitochondrial homeostasis and pluripotency in pink1-/- ESCs can be compensated by gain expression of phosphomimetic Ubiquitin (Ub-S65D) together with WT or a constitutively active phosphomimetic OPTN mutant (S187D, S476D, S517D), rather than constitutively inactive OPTN (S187A, S476A, S517A) or a Ub-binding dead OPTN mutant (D477N).
CONCLUSIONS: The mitophagy receptor OPTN guards ESC mitochondrial homeostasis and pluripotency by scavenging damaged mitochondria through TBK1-activated OPTN binding of PINK1-phosphorylated Ubiquitin.

Keywords:  OPTN; PINK1; embryonic stem cells; mitochondria; mitophagy; reprogramming

DOI:  https://doi.org/10.1111/cpr.13034
Int J Mol Sci. 2021 Apr 17. pii: 4164. [Epub ahead of print]22(8):

A Walk in the Memory, from the First Functional Approach up to Its Regulatory Role of Mitochondrial Bioenergetic Flow in Health and Disease: Focus on the Adenine Nucleotide Translocator.

Anna Atlante, Daniela Valenti.

  The mitochondrial adenine nucleotide translocator (ANT) plays the fundamental role of gatekeeper of cellular energy flow, carrying out the reversible exchange of ADP for ATP across the inner mitochondrial membrane. ADP enters the mitochondria where, through the oxidative phosphorylation process, it is the substrate of Fo-F1 ATP synthase, producing ATP that is dispatched from the mitochondrion to the cytoplasm of the host cell, where it can be used as energy currency for the metabolic needs of the cell that require energy. Long ago, we performed a method that allowed us to monitor the activity of ANT by continuously detecting the ATP gradually produced inside the mitochondria and exported in the extramitochondrial phase in exchange with externally added ADP, under conditions quite close to a physiological state, i.e., when oxidative phosphorylation takes place. More than 30 years after the development of the method, here we aim to put the spotlight on it and to emphasize its versatile applicability in the most varied pathophysiological conditions, reviewing all the studies, in which we were able to observe what really happened in the cell thanks to the use of the "ATP detecting system" allowing the functional activity of the ANT-mediated ADP/ATP exchange to be measured.

Keywords:  ATP detecting system; adenine nucleotide translocator; disease; mitochondria; physiological role; transport

DOI:  https://doi.org/10.3390/ijms22084164
EMBO J. 2021 Apr 29. e106868

IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.

Emilie Tresse, Lluís Riera-Ponsati, Elham Jaberi, Wei Qi Guinevere Sew, Karsten Ruscher, Shohreh Issazadeh-Navikas.

  Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria-endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-β in the Ifnb-/- model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-β rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-β activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.

Keywords:  ATP; Parkinson disease; ROS; hydroxydopamine; mitochondrial metabolism

DOI:  https://doi.org/10.15252/embj.2020106868
Int J Mol Sci. 2021 Apr 24. pii: 4461. [Epub ahead of print]22(9):

A Yeast-Based Screening Unravels Potential Therapeutic Molecules for Mitochondrial Diseases Associated with Dominant ANT1 Mutations.

Giulia di Punzio, Maria Antonietta Di Noia, Agnès Delahodde, Carole Sellem, Claudia Donnini, Luigi Palmieri, Tiziana Lodi, Cristina Dallabona.

  Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations.

Keywords:  ANT1 mutations; mitochondrial diseases; yeast model

DOI:  https://doi.org/10.3390/ijms22094461
J Neurochem. 2021 Apr 27.

The human brain acetylome reveals that decreased acetylation of mitochondrial proteins associates with Alzheimer's disease.

Lidan Sun, Ruchika Bhawal, Hui Xu, Huanlian Chen, Elizabeth T Anderson, Vahrum Haroutunian, Abigail C Cross, Sheng Zhang, Gary E Gibson.

  Metabolic changes that correlate to cognitive changes are well known in AD. Metabolism is often linked to functional changes in proteins by post-translational modifications. The importance of the regulation of transcription by acetylation is well documented. Advanced mass spectrometry reveals hundreds of acetylated proteins in multiple tissues, but the acetylome of human brain, its functional significance and the changes with disease are unknown. Filling this gap is critical for understanding the pathophysiology and development of therapies. To fill this gap, we assessed the human brain acetylome in human brain and its changes with Alzheimer's Disease (AD). More than 5% of the 4,442 proteins from the human brain global proteome were acetylated. Acetylated proteins were primarily found in the cytosol (148), mitochondria (100), nucleus (91) and plasma membrane (58). The comparison of the brain acetylome in controls to that of patients with AD revealed striking and selective differences in terms of its abundances of acetylated peptides/sites. Acetylation of 18 mitochondrial proteins decreased, while acetylation of two cytosolic proteins, tau and GFAP, increased. Our experiments demonstrate that acetylation at some specific lysine sites alters enzyme function. The results indicate that general activation of de-acetylases (i.e., sirtuins) is not an appropriate therapeutic approach for AD.

Keywords:  Alzheimer’s disease; acetylation; human brain; ketoglutarate dehydrogenase complex; pyruvate dehydrogenase complex

DOI:  https://doi.org/10.1111/jnc.15377
Life (Basel). 2021 Apr 19. pii: 361. [Epub ahead of print]11(4):

Next-Generation Sequencing Technologies and Neurogenetic Diseases.

Hui Sun, Xiao-Rong Shen, Zi-Bing Fang, Zong-Zhi Jiang, Xiao-Jing Wei, Zi-Yi Wang, Xue-Fan Yu.

  Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot-Marie-Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.

Keywords:  Charcot–Marie–Tooth disease; epilepsy; neurogenetics; next generation sequencing; rare disorders; spinocerebellar ataxias

DOI:  https://doi.org/10.3390/life11040361
Int J Mol Sci. 2021 Apr 22. pii: 4363. [Epub ahead of print]22(9):

Common Principles and Specific Mechanisms of Mitophagy from Yeast to Humans.

Rajesh Kumar, Andreas S Reichert.

  Mitochondria are double membrane-bound organelles in eukaryotic cells essential to a variety of cellular functions including energy conversion and ATP production, iron-sulfur biogenesis, lipid and amino acid metabolism, and regulating apoptosis and stress responses. Mitochondrial dysfunction is mechanistically linked to several neurodegenerative diseases, cancer, and ageing. Excessive and dysfunctional/damaged mitochondria are degraded by selective autophagic pathways known as mitophagy. Both budding yeast and mammals use the well-conserved machinery of core autophagy-related genes (ATGs) to execute and regulate mitophagy. In mammalian cells, the PINK1-PARKIN mitophagy pathway is a well-studied pathway that senses dysfunctional mitochondria and marks them for degradation in the lysosome. PINK1-PARKIN mediated mitophagy relies on ubiquitin-binding mitophagy adaptors that are non-ATG proteins. Loss-of-function mutations in PINK1 and PARKIN are linked to Parkinson´s disease (PD) in humans, and defective mitophagy is proposed to be a main pathomechanism. Despite the common view that yeast cells lack PINK1- and PARKIN-homologs and that mitophagy in yeast is solely regulated by receptor-mediated mitophagy, some studies suggest that a ubiquitination-dependent mitophagy pathway also exists. Here, we will discuss shared mechanisms between mammals and yeast, how mitophagy in the latter is regulated in a ubiquitin-dependent and -independent manner, and why these pathways are essential for yeast cell survival and fitness under various physiological stress conditions.

Keywords:  PARKIN; PINK1; autophagy; cancer; mitophagy; quality control; ubiquitin

DOI:  https://doi.org/10.3390/ijms22094363
Int J Mol Sci. 2021 Apr 02. pii: 3709. [Epub ahead of print]22(7):

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process.

Fiqri D Khaidizar, Yasumasa Bessho, Yasukazu Nakahata.

  Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD+, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD+ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD+ production through the NAD+ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD+ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD+ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD+ biosynthesis pathways in mammals, the NAD+ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD+, have been developed so far. In this review, we will focus on the importance of NAD+ and the possible application of an activator of NAMPT to promote successive aging.

Keywords:  IRW; NAD+; NAMPT; NMN; NMNH; NR; P7C3; PNGL; SBI-797812; aging/senescence

DOI:  https://doi.org/10.3390/ijms22073709
FEBS Lett. 2021 Apr;595(8): 973-975

Molecular bases of mitochondrial disorders.

Agnieszka Chacinska, Peter Rehling.

DOI: https://doi.org/10.1002/1873-3468.14086
Pharmacol Ther. 2021 Apr 27. pii: S0163-7258(21)00076-0. [Epub ahead of print] 107874

Mitochondrial K+ channels and their implications for disease mechanisms.

Vanessa Checchetto, Luigi Leanza, Diego De Stefani, Rosario Rizzuto, Erich Gulbins, Ildiko Szabo.

  The field of mitochondrial ion channels underwent a rapid development during the last decade, thanks to the molecular identification of some of the nuclear-encoded organelle channels and to advances in strategies allowing specific pharmacological targeting of these proteins. Thereby, genetic tools and specific drugs aided definition of the relevance of several mitochondrial channels both in physiological as well as pathological conditions. Unfortunately, in the case of mitochondrial K+ channels, efforts of genetic manipulation provided only limited results, due to their dual localization to mitochondria and to plasma membrane in most cases. Although the impact of mitochondrial K+ channels on human diseases is still far from being genuinely understood, pre-clinical data strongly argue for their substantial role in the context of several pathologies, including cardiovascular and neurodegenerative diseases as well as cancer. Importantly, these channels are druggable targets, and their in-depth investigation could thus pave the way to the development of innovative small molecules with huge therapeutic potential. In the present review we summarize the available experimental evidences that mechanistically link mitochondrial potassium channels to the above pathologies and underline the possibility of exploiting them for therapy.

Keywords:  Bioenergetics; Cancer; Cardiovascular diseases; Mitochondria; Potassium channels

DOI:  https://doi.org/10.1016/j.pharmthera.2021.107874
Int J Mol Sci. 2021 Apr 01. pii: 3689. [Epub ahead of print]22(7):

Energy Metabolism in the Inner Retina in Health and Glaucoma.

Hanhan Liu, Verena Prokosch.

  Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma's pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them.

Keywords:  energy metabolism; glaucoma; mitochondrial function; retinal blood flow; retinal ganglion cell

DOI:  https://doi.org/10.3390/ijms22073689
Mol Vis. 2021 ;27 151-160

SAHA is neuroprotective in in vitro and in situ models of retinitis pigmentosa.

Nathan R Perron, Cécile Nasarre, Mausumi Bandyopadhyay, Craig C Beeson, Baerbel Rohrer.

PURPOSE: Recent reports linking HDAC6 to mitochondrial turnover and neurodegeneration led us to hypothesize that an inhibitor such as Vorinostat (suberoylanilide hydroxamic acid, SAHA) may reduce mitochondrial damage found in retinitis pigmentosa (RP), a progressive neurodegenerative disease of the eye. Here we tested the efficacy of SAHA for its ability to protect photoreceptors in in-vitro and in-situ models of RP. As the stressor, we focused on calcium overload. Calcium is one of the main drivers of cell death, and is associated with rod loss in the rd1 mouse retina, which harbors a mutation in the Pde6b gene similar to that found in human patients suffering from autosomal recessive RP.METHOD: Murine photoreceptor cell line (661W) were exposed to agents that led to calcium stress. Cell survival and redox capacity were measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, real-time changes in cellular metabolism were assessed using the Seahorse Biosciences XF24 analyzer, and mitochondrial fission-fusion using imaging. In-situ, neuroprotection was assessed in RPE/retina organ cultures of the rd1 mouse. SAHA effects on cell survival were compared in 661W cells with those of the specific HDAC6 inhibitor tubastatin A, and those on protein acetylation by Western blotting.
RESULTS: In stressed 661W cells, SAHA was found to increase cell survival that was associated with improved mitochondrial respiration and reduced mitochondrial fission. The protective effects of SAHA were also observed on photoreceptor cell survival in whole retinal organ explants of the rd1 mouse. Even though tubastatin A was ineffective in increasing cell survival in 661W cells, HDAC6 activity was confirmed in 661W cells after SAHA treatment with protein acetylation specific for HDAC6, defined by an increase in tubulin, but not histone acetylation.
CONCLUSIONS: SAHA was found to protect mitochondria from damage, and concomitantly reduced photoreceptor cell death in cell and organ cultures. The lack of activity of tubastatin A suggests that there must be an additional mechanism of action involved in the protective mechanism of SAHA that is responsible for its neuroprotection. Overall, SAHA may be a useful treatment for the prevention of photoreceptor degeneration associated with human RP. The results are discussed in the context of the effects of inhibitors that target different classes and members of the HDAC family and their effects on rod versus cone survival.
Nutrients. 2021 Apr 26. pii: 1469. [Epub ahead of print]13(5):

Dietary Essential Amino Acid Restriction Promotes Hyperdipsia via Hepatic FGF21.

Patricia M Rusu, Andrea Y Chan, Mathias Heikenwalder, Oliver J Müller, Adam J Rose.

  Prior studies have reported that dietary protein dilution (DPD) or amino acid dilution promotes heightened water intake (i.e., hyperdipsia) however, the exact dietary requirements and the mechanism responsible for this effect are still unknown. Here, we show that dietary amino acid (AA) restriction is sufficient and required to drive hyperdipsia during DPD. Our studies demonstrate that particularly dietary essential AA (EAA) restriction, but not non-EAA, is responsible for the hyperdipsic effect of total dietary AA restriction (DAR). Additionally, by using diets with varying amounts of individual EAA under constant total AA supply, we demonstrate that restriction of threonine (Thr) or tryptophan (Trp) is mandatory and sufficient for the effects of DAR on hyperdipsia and that liver-derived fibroblast growth factor 21 (FGF21) is required for this hyperdipsic effect. Strikingly, artificially introducing Thr de novo biosynthesis in hepatocytes reversed hyperdipsia during DAR. In summary, our results show that the DPD effects on hyperdipsia are induced by the deprivation of Thr and Trp, and in turn, via liver/hepatocyte-derived FGF21.

Keywords:  amino acids; dietary protein; restriction; water intake

DOI:  https://doi.org/10.3390/nu13051469