bims-mitmed 2021-11-28 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2021–11–28
38 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant.
Long-chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy.
Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.
Flow Cytometric Analysis of Multiple Mitochondrial Parameters in Human Induced Pluripotent Stem Cells and Their Neural and Glial Derivatives.
Leigh syndrome in an infant: autopsy and histopathology findings.
An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases.
Clinical Characteristics of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes.
The magnetic resonance imaging of Leigh syndrome in a child.
A new automated tool to quantify nucleoid distribution within mitochondrial networks.
Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?
Phenotypes and genotypes of mitochondrial diseases with mtDNA variations in Chinese children: a multi-center study.
Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients.
Coenzyme Q at the Hinge of Health and Metabolic Diseases.
Rewiring cell signalling pathways in pathogenic mtDNA mutations.
NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms.
Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts.
Dilated Cardiomyopathy due to the Novel MT-CYB Missense Mutation m.14757T>C.
A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool.
Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson's Disease.
The PINK1 advantage: recycling mitochondria in times of trouble?
MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes.
Mitochondrial signals regulate ER size and TNF production in rheumatoid arthritis.
The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels.
Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.
ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
Multiocular organoids from human induced pluripotent stem cells displayed retinal, corneal, and retinal pigment epithelium lineages.
Preimplantation genetic diagnosis for a carrier with m.3697G > A mitochondrial DNA mutation.
The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.
Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.
Targeting Mitochondria by Plant Secondary Metabolites: A Promising Strategy in Combating Parkinson's Disease.
Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion.
A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation.
Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.
Mild Muscle Mitochondrial Fusion Distress Extends Drosophila Lifespan through an Early and Systemic Metabolome Reorganization.
Dietary essential amino acids restore liver metabolism in ovariectomized mice via hepatic estrogen receptor α.
Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions.
A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.
Adult neurogenesis in neurological diseases.

Brain Pathol. 2021 Nov 21. e13038

Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant.

Sara Roos, Carola Hedberg-Oldfors, Kittichate Visuttijai, My Stein, Gittan Kollberg, Ólöf Elíasdóttir, Christopher Lindberg, Niklas Darin, Anders Oldfors.

  Two homoplasmic variants in tRNAGlu (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole-genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX-deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT-TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow-up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.

Keywords:  homoplasmic mt-tRNAGlu variant; mitochondrial myopathy; mtDNA; reversible infantile respiratory chain deficiency; whole genome sequencing

DOI:  https://doi.org/10.1111/bpa.13038
J Inherit Metab Dis. 2021 Nov 25.

Long-chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy.

Kathryn C Chatfield, Genevieve C Sparagna, Kalyn S Specht, Luke A Whitcomb, Asma K Omar, Shelley D Miyamoto, Lisa M Wolfe, Adam J Chicco.

Barth syndrome (BTHS) is an X-linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early-onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age- and sex-matched patients with idiopathic dilated cardiomyopathy (DCM) and non-failing (NF) controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso-) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of Complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long-chain fatty acid oxidation enzymes and the tissue acyl-CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta-oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12459
Brain Commun. 2021 ;3(4): fcab215

Lysosomal dysfunction impairs mitochondrial quality control and is associated with neurodegeneration in TBCK encephaloneuronopathy.

Jesus A Tintos-Hernández, Adrian Santana, Kierstin N Keller, Xilma R Ortiz-González.

  Biallelic variants in the TBCK gene cause intellectual disability with remarkable clinical variability, ranging from static encephalopathy to progressive neurodegeneration (TBCK-Encephaloneuronopathy). The biological factors underlying variable disease penetrance remain unknown. Since previous studies had suggested aberrant autophagy, we tested whether mitophagy and mitochondrial function are altered in TBCK -/- fibroblasts derived from patients exhibiting variable clinical severity. Our data show significant accumulation of mitophagosomes, reduced mitochondrial respiratory capacity and mitochondrial DNA content, suggesting impaired mitochondrial quality control. Furthermore, the degree of mitochondrial dysfunction correlates with a neurodegenerative clinical course. Since mitophagy ultimately depends on lysosomal degradation, we also examined lysosomal function. Our data show that lysosomal proteolytic function is significantly reduced in TBCK -/- fibroblasts. Moreover, acidifying lysosomal nanoparticles rescue the mitochondrial respiratory defects in fibroblasts, suggesting impaired mitochondrial quality control secondary to lysosomal dysfunction. Our data provide insight into the disease mechanisms of TBCK Encephaloneuronopathy and the potential relevance of mitochondrial function as a biomarker beyond primary mitochondrial disorders. It also supports the benefit of lysosomal acidification strategies for disorders of impaired lysosomal degradation affecting mitochondrial quality control.

Keywords:  intellectual disability; lysosome; mitochondria; mitophagy; neurodegeneration

DOI:  https://doi.org/10.1093/braincomms/fcab215
J Vis Exp. 2021 Nov 08.

Flow Cytometric Analysis of Multiple Mitochondrial Parameters in Human Induced Pluripotent Stem Cells and Their Neural and Glial Derivatives.

Kristina Xiao Liang, Anbin Chen, Cecilie Katrin Kristiansen, Laurence A Bindoff.

Mitochondria are important in the pathophysiology of many neurodegenerative diseases. Changes in mitochondrial volume, mitochondrial membrane potential (MMP), mitochondrial production of reactive oxygen species (ROS), and mitochondrial DNA (mtDNA) copy number are often features of these processes. This report details a novel flow cytometry-based approach to measure multiple mitochondrial parameters in different cell types, including human induced pluripotent stem cells (iPSCs) and iPSC-derived neural and glial cells. This flow-based strategy uses live cells to measure mitochondrial volume, MMP, and ROS levels, as well as fixed cells to estimate components of the mitochondrial respiratory chain (MRC) and mtDNA-associated proteins such as mitochondrial transcription factor A (TFAM). By co-staining with fluorescent reporters, including MitoTracker Green (MTG), tetramethylrhodamine ethyl ester (TMRE), and MitoSox Red, changes in mitochondrial volume, MMP, and mitochondrial ROS can be quantified and related to mitochondrial content. Double staining with antibodies against MRC complex subunits and translocase of outer mitochondrial membrane 20 (TOMM20) permits the assessment of MRC subunit expression. As the amount of TFAM is proportional to mtDNA copy number, the measurement of TFAM per TOMM20 gives an indirect measurement of mtDNA per mitochondrial volume. The entire protocol can be carried out within 2-3 h. Importantly, these protocols allow the measurement of mitochondrial parameters, both at the total level and the specific level per mitochondrial volume, using flow cytometry.

DOI: https://doi.org/10.3791/63116
Autops Case Rep. 2021 ;11 e2021334

Leigh syndrome in an infant: autopsy and histopathology findings.

Arushi Gahlot Saini, Debjyoti Chatterjee, Chandana Bhagwat, Sameer Vyas, Savita Verma Attri.

  Leigh syndrome is an inherited neurodegenerative disorder of infancy that typically manifests between 3 and 12 months of age. The common neurological manifestations are developmental delay or regression, progressive cognitive decline, dystonia, ataxia, brainstem dysfunction, epileptic seizures, and respiratory dysfunction. Although the disorder is clinically and genetically heterogeneous, the histopathological and radiological features characteristically show focal and bilaterally symmetrical, necrotic lesions in the basal ganglia and brainstem. The syndrome has a characteristic histopathological signature that helps in clinching the diagnosis. We discuss these unique findings on autopsy and radiology in a young infant who succumbed to a subacute, progressive neurological illness suggestive of Leigh syndrome. Our case highlights that Leigh syndrome should be considered in the differential diagnosis of infantile-onset, subacute neuroregression with dystonia and seizures, a high anion gap metabolic acidosis, normal ketones, elevated lactates in blood, brain, and urine, and bilateral basal ganglia involvement.

Keywords:  Basal Ganglia; Brain Damage, Chronic; Leigh Disease; Mitochondrial Diseases

DOI:  https://doi.org/10.4322/acr.2021.334
Biomolecules. 2021 Nov 04. pii: 1633. [Epub ahead of print]11(11):

An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases.

Federica Marra, Paola Lunetti, Rosita Curcio, Francesco Massimo Lasorsa, Loredana Capobianco, Vito Porcelli, Vincenza Dolce, Giuseppe Fiermonte, Pasquale Scarcia.

  Neuromuscular diseases (NMDs) are dysfunctions that involve skeletal muscle and cause incorrect communication between the nerves and muscles. The specific causes of NMDs are not well known, but most of them are caused by genetic mutations. NMDs are generally progressive and entail muscle weakness and fatigue. Muscular impairments can differ in onset, severity, prognosis, and phenotype. A multitude of possible injury sites can make diagnosis of NMDs difficult. Mitochondria are crucial for cellular homeostasis and are involved in various metabolic pathways; for this reason, their dysfunction can lead to the development of different pathologies, including NMDs. Most NMDs due to mitochondrial dysfunction have been associated with mutations of genes involved in mitochondrial biogenesis and metabolism. This review is focused on some mitochondrial routes such as the TCA cycle, OXPHOS, and β-oxidation, recently found to be altered in NMDs. Particular attention is given to the alterations found in some genes encoding mitochondrial carriers, proteins of the inner mitochondrial membrane able to exchange metabolites between mitochondria and the cytosol. Briefly, we discuss possible strategies used to diagnose NMDs and therapies able to promote patient outcome.

Keywords:  Leigh syndrome; MELAS; MERF; OXPHOS; mitochondrial carrier family; mitochondrial metabolism; myopathy; neuromuscular diseases; neuromuscular junction; therapy

DOI:  https://doi.org/10.3390/biom11111633
Life (Basel). 2021 Oct 20. pii: 1111. [Epub ahead of print]11(11):

Clinical Characteristics of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes.

Hueng-Chuen Fan, Hsiu-Fen Lee, Chen-Tang Yue, Ching-Shiang Chi.

  Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized by its genetic, biochemical and clinical complexity. The most common mutation associated with MELAS syndrome is the mtDNA A3243G mutation in the MT-TL1 gene encoding the mitochondrial tRNA-leu(UUR), which results in impaired mitochondrial translation and protein synthesis involving the mitochondrial electron transport chain complex subunits, leading to impaired mitochondrial energy production. Angiopathy, either alone or in combination with nitric oxide (NO) deficiency, further contributes to multi-organ involvement in MELAS syndrome. Management for MELAS syndrome is amostly symptomatic multidisciplinary approach. In this article, we review the clinical presentations, pathogenic mechanisms and options for management of MELAS syndrome.

Keywords:  MELAS; genetics; mitochondrial DNA

DOI:  https://doi.org/10.3390/life11111111
Clin Ter. 2021 Nov 22. 172(6): 500-503

The magnetic resonance imaging of Leigh syndrome in a child.

N Thanh Hai, V Kim Ngan, N Quynh Giang, V Huy Hoang, Le Anh Viet, N Truong Duc, T T Thu Hien, D V He, N Minh Duc.

   Abstract: Leigh syndrome is a rare progressive neurodegenerative disease with variable clinical presentations associated with mitochondrial dysfunction. However, the most common presentations are motor and intellectual developmental delays, with signs and symptoms of brainstem and basal ganglia involvement. We describe a 6-year-old boy with a history of delayed developmental milestones who presen-ted to our hospital due to unconscious status and respiratory distress syndrome. The patient underwent brain magnetic resonance imaging (MRI), and multiple subacute necrotic lesions were identified at the bilateral basal ganglia, thalamus, cerebral peduncles, brainstem, and cortical regions. DNA analysis was performed, which revealed muta-tions in SURF1. The patient experienced several relapses and died of respiratory failure and hospital-acquired infections, 3 years after the diagnosis of Leigh syndrome. Leigh syndrome should be considered in children with neurological problems and bilateral basal ganglia or brainstem abnormalities. Neurological MRI can be useful for guiding clinicians in ordering the most appropriate enzymatic and genetic analyses for further diagnosis.

Keywords:  Leigh syndrome; mitochondrial diseases; subacute necrotizing encephalopathy

DOI:  https://doi.org/10.7417/CT.2021.2364
Sci Rep. 2021 Nov 23. 11(1): 22755

A new automated tool to quantify nucleoid distribution within mitochondrial networks.

Hema Saranya Ilamathi, Mathieu Ouellet, Rasha Sabouny, Justine Desrochers-Goyette, Matthew A Lines, Gerald Pfeffer, Timothy E Shutt, Marc Germain.

Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.

DOI: https://doi.org/10.1038/s41598-021-01987-9
Genes (Basel). 2021 Oct 22. pii: 1668. [Epub ahead of print]12(11):

Gaining Insight into Mitochondrial Genetic Variation and Downstream Pathophysiology: What Can i(PSCs) Do?

Jesse D Moreira, Deepa M Gopal, Darrell N Kotton, Jessica L Fetterman.

  Mitochondria are specialized organelles involved in energy production that have retained their own genome throughout evolutionary history. The mitochondrial genome (mtDNA) is maternally inherited and requires coordinated regulation with nuclear genes to produce functional enzyme complexes that drive energy production. Each mitochondrion contains 5-10 copies of mtDNA and consequently, each cell has several hundreds to thousands of mtDNAs. Due to the presence of multiple copies of mtDNA in a mitochondrion, mtDNAs with different variants may co-exist, a condition called heteroplasmy. Heteroplasmic variants can be clonally expanded, even in post-mitotic cells, as replication of mtDNA is not tied to the cell-division cycle. Heteroplasmic variants can also segregate during germ cell formation, underlying the inheritance of some mitochondrial mutations. Moreover, the uneven segregation of heteroplasmic variants is thought to underlie the heterogeneity of mitochondrial variation across adult tissues and resultant differences in the clinical presentation of mitochondrial disease. Until recently, however, the mechanisms mediating the relation between mitochondrial genetic variation and disease remained a mystery, largely due to difficulties in modeling human mitochondrial genetic variation and diseases. The advent of induced pluripotent stem cells (iPSCs) and targeted gene editing of the nuclear, and more recently mitochondrial, genomes now provides the ability to dissect how genetic variation in mitochondrial genes alter cellular function across a variety of human tissue types. This review will examine the origins of mitochondrial heteroplasmic variation and propagation, and the tools used to model mitochondrial genetic diseases. Additionally, we discuss how iPSC technologies represent an opportunity to advance our understanding of human mitochondrial genetics in disease.

Keywords:  heteroplasmy; induced pluripotent stem cells; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/genes12111668
Mitochondrion. 2021 Nov 17. pii: S1567-7249(21)00166-5. [Epub ahead of print]

Phenotypes and genotypes of mitochondrial diseases with mtDNA variations in Chinese children: a multi-center study.

Yuqing Shi, Guohong Chen, Dan Sun, Chaoping Hu, Zhimei Liu, Danmin Shen, Junling Wang, Tianyu Song, Weihua Zhang, Jiuwei Li, Xiaotun Ren, Tongli Han, Changhong Ding, Yi Wang, Fang Fang.

Among the 262 patients of four children's hospitals in China, 96%-point mutations (30 alleles in 11 genes encoding tRNA, rRNA, Complex I and V) and 4%-deletions (seven of ten had not been reported before) were identified as the cause of 14 phenotypes. MILS had the highest genetic heterogeneity, while the m.3243A>G mutation was the only "hotspot" mutation with a wide range of phenotypes. The degrees of heteroplasmy in the leukocytes of MM were higher than MELAS. The heteroplasmy level of patients was higher than in mild and carrier group, while we found low-level heteroplasmy pathogenic mutations as well. Some homoplasmic variations (e.g., m.9176T>C mutation) are having high incomplete penetrance. For a suspected MELAS, m.3243A>G mutation was recommended first; while for a suspected LS, trios-WES and mtDNA genome sequencing by NGS were recommended first in both blood and urine.

DOI: https://doi.org/10.1016/j.mito.2021.11.006
Front Cell Dev Biol. 2021 ;9 765408

Mitochondrial Defects in Fibroblasts of Pathogenic MAPT Patients.

Vinita Bharat, Chung-Han Hsieh, Xinnan Wang.

  Mutations in MAPT gene cause multiple neurological disorders, including frontal temporal lobar degeneration and parkinsonism. Increasing evidence indicates impaired mitochondrial homeostasis and mitophagy in patients and disease models of pathogenic MAPT. Here, using MAPT patients' fibroblasts as a model, we report that disease-causing MAPT mutations compromise early events of mitophagy. By employing biochemical and mitochondrial assays we discover that upon mitochondrial depolarization, the recruitment of LRRK2 and Parkin to mitochondria and degradation of the outer mitochondrial membrane protein Miro1 are disrupted. Using high resolution electron microscopy, we reveal that the contact of mitochondrial membranes with ER and cytoskeleton tracks is dissociated following mitochondrial damage. This membrane dissociation is blocked by a pathogenic MAPT mutation. Furthermore, we provide evidence showing that tau protein, which is encoded by MAPT gene, interacts with Miro1 protein, and this interaction is abolished by pathogenic MAPT mutations. Lastly, treating fibroblasts of a MAPT patient with a small molecule promotes Miro1 degradation following depolarization. Altogether, our results show molecular defects in a peripheral tissue of patients and suggest that targeting mitochondrial quality control may have a broad application for future therapeutic intervention.

Keywords:  ER; FTLD; MAPT; Miro; mitochondria; mitophagy; parkinsonism; tau

DOI:  https://doi.org/10.3389/fcell.2021.765408
Antioxidants (Basel). 2021 Nov 08. pii: 1785. [Epub ahead of print]10(11):

Coenzyme Q at the Hinge of Health and Metabolic Diseases.

Juan Diego Hernández-Camacho, Laura García-Corzo, Daniel José Moreno Fernández-Ayala, Plácido Navas, Guillermo López-Lluch.

  Coenzyme Q is a unique lipidic molecule highly conserved in evolution and essential to maintaining aerobic metabolism. It is endogenously synthesized in all cells by a very complex pathway involving a group of nuclear genes that share high homology among species. This pathway is tightly regulated at transcription and translation, but also by environment and energy requirements. Here, we review how coenzyme Q reacts within mitochondria to promote ATP synthesis and also integrates a plethora of metabolic pathways and regulates mitochondrial oxidative stress. Coenzyme Q is also located in all cellular membranes and plasma lipoproteins in which it exerts antioxidant function, and its reaction with different extramitochondrial oxidoreductases contributes to regulate the cellular redox homeostasis and cytosolic oxidative stress, providing a key factor in controlling various apoptosis mechanisms. Coenzyme Q levels can be decreased in humans by defects in the biosynthesis pathway or by mitochondrial or cytosolic dysfunctions, leading to a highly heterogeneous group of mitochondrial diseases included in the coenzyme Q deficiency syndrome. We also review the importance of coenzyme Q levels and its reactions involved in aging and age-associated metabolic disorders, and how the strategy of its supplementation has had benefits for combating these diseases and for physical performance in aging.

Keywords:  coenzyme Q; metabolic disease; mitochondria; rare disease; ubiquinone

DOI:  https://doi.org/10.3390/antiox10111785
Trends Cell Biol. 2021 Nov 23. pii: S0962-8924(21)00207-5. [Epub ahead of print]

Rewiring cell signalling pathways in pathogenic mtDNA mutations.

Chih-Yao Chung, Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.

  Mitochondria generate the energy to sustain cell viability and serve as a hub for cell signalling. Their own genome (mtDNA) encodes genes critical for oxidative phosphorylation. Mutations of mtDNA cause major disease and disability with a wide range of presentations and severity. We review here an emerging body of data suggesting that changes in cell metabolism and signalling pathways in response to the presence of mtDNA mutations play a key role in shaping disease presentation and progression. Understanding the impact of mtDNA mutations on cellular energy homeostasis and signalling pathways seems fundamental to identify novel therapeutic interventions with the potential to improve the prognosis for patients with primary mitochondrial disease.

Keywords:  cell signalling; heteroplasmy; metabolic remodelling; mitochondrial disease; mtDNA

DOI:  https://doi.org/10.1016/j.tcb.2021.10.005
Genet Mol Biol. 2021 ;pii: S1415-47572021000600104. [Epub ahead of print]44(4): e20210149

NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms.

Vanessa Zanette, Daniel do Valle, Bruno Augusto Telles, Alan J Robinson, Vaneisse Monteiro, Mara Lucia S F Santos, Ricardo Lehtonen R Souza, Cristiane Benincá.

Mitochondrial complex I (CI) deficiency is the most common oxidative phosphorylation disorder described. It shows a wide range of phenotypes with poor correlation within genotypes. Herein we expand the clinics and genetics of CI deficiency in the brazilian population by reporting three patients with pathogenic (c.640G>A, c.1268C>T, c.1207dupG) and likely pathogenic (c.766C>T) variants in the NDUFV1 gene. We show the mutation c.766C>T associated with a childhood onset phenotype of hypotonia, muscle weakness, psychomotor regression, lethargy, dysphagia, and strabismus. Additionally, this mutation was found to be associated with headaches and exercise intolerance in adulthood. We also review reported pathogenic variants in NDUFV1 highlighting the wide phenotypic heterogeneity in CI deficiency.

DOI: https://doi.org/10.1590/1678-4685-GMB-2021-0149
Stem Cell Reports. 2021 Nov 16. pii: S2213-6711(21)00552-X. [Epub ahead of print]

Simultaneous high-efficiency base editing and reprogramming of patient fibroblasts.

Sami Jalil, Timo Keskinen, Rocío Maldonado, Joonas Sokka, Ras Trokovic, Timo Otonkoski, Kirmo Wartiovaara.

  Human induced pluripotent stem cells (hiPSCs) allow in vitro study of genetic diseases and hold potential for personalized stem cell therapy. Gene editing, precisely modifying specifically targeted loci, represents a valuable tool for different hiPSC applications. This is especially useful in monogenic diseases to dissect the function of unknown mutations or to create genetically corrected, patient-derived hiPSCs. Here we describe a highly efficient method for simultaneous base editing and reprogramming of fibroblasts employing a CRISPR-Cas9 adenine base editor. As a proof of concept, we apply this approach to generate gene-edited hiPSCs from skin biopsies of four patients carrying a Finnish-founder pathogenic point mutation in either NOTCH3 or LDLR genes. We also show LDLR activity restoration after the gene correction. Overall, this method yields tens of gene-edited hiPSC monoclonal lines with unprecedented efficiency and robustness while considerably reducing the cell culture time and thus the risk for in vitro alterations.

Keywords:  CADASIL; CRISPR-Cas9; Finnish-founder mutation; LDLR; NOTCH3; disease modeling; familial hypercholesterolemia; gene editing; induced pluripotent stem cells; reprogramming

DOI:  https://doi.org/10.1016/j.stemcr.2021.10.017
J Med Cases. 2021 Nov;12(11): 455-459

Dilated Cardiomyopathy due to the Novel MT-CYB Missense Mutation m.14757T>C.

Sinda Zarrouk, Josef Finsterer, Sounira Mehri, Fatma Ourda, Saida Ben Arab, Raafik Boussada.

  Mitochondrial DNA (mtDNA) mutations frequently manifest with multisystem disease, including cardiomyopathy (CM). Various studies described mutations in protein-encoding mtDNA genes, such as cytochrome-b, manifesting with CM. A detailed clinical, biochemical, and molecular genetic analysis was performed in a 40-year-old male with dilated CM (DCM) to detect the underlying mtDNA defect. Muscle biopsy showed complex-III deficiency, and sequencing of the cytochrome-b gene revealed the pathogenic variant m.14757T>C in MT-CYB, resulting in the replacement of the hydrophobic methionine by the polar threonine (M4T). By application of the PolyPhen algorithm the variant was predicted as pathogenic. The mutation was not found in 100 healthy controls and never reported as a neutral polymorphism despite extensive sequencing of the cytochrome-b gene in 2,704 normal healthy controls from different ethnic backgrounds. In conclusion, the novel variant m.14757T>C in MT-CYB is associated with DCM suggesting a pathophysiologic role of the variant in the development of DCM.

Keywords:  Cytochrome-b gene; Dilated cardiomyopathy; Mitochondria; Mitochondrial; Oxidative phosphorylation; Systolic dysfunction; mtDNA

DOI:  https://doi.org/10.14740/jmc3787
Int J Mol Sci. 2021 Nov 12. pii: 12223. [Epub ahead of print]22(22):

A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool.

Giulia di Punzio, Micol Gilberti, Enrico Baruffini, Tiziana Lodi, Claudia Donnini, Cristina Dallabona.

  Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.

Keywords:  MIP1; MPV17; POLG; RNR2; RRM2B; SYM1; drug repurposing; mitochondrial DNA depletion syndromes (MDS); mitochondrial dNTP pool; yeast

DOI:  https://doi.org/10.3390/ijms222212223
Cells. 2021 Nov 04. pii: 3022. [Epub ahead of print]10(11):

Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson's Disease.

Maria Vizziello, Linda Borellini, Giulia Franco, Gianluca Ardolino.

  The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson's disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.

Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.3390/cells10113022
Autophagy. 2021 Nov 23. 1-2

The PINK1 advantage: recycling mitochondria in times of trouble?

Zak Doric, Huihui Li, Ken Nakamura.

  Parkinson disease remains a debilitating neurodegenerative disorder, despite the discovery of multiple causative genes that account for familial forms. Prominent among these are PRKN/Parkin and PINK1, whose protein products participate in mitochondrial turnover, or mitophagy. But our poor understanding of the basic biological mechanisms driven by those genes in neurons limits our ability to target them therapeutically. Here, we summarize our recent findings enabled by a new platform to track individual mitochondria in neurons. Our analysis delineates the steps of PINK1- and PRKN-dependent mitochondrial turnover, including the unexplored fates of mitochondria after fusion with lysosomes. These studies reveal unexpected mechanisms of mitochondrial quality control, which may contribute to the reliance of neurons on PINK1 under conditions of stress.

Keywords:  Mitophagy; PARKIN; PINK1; Parkinson’s disease; mitochondrial turnover

DOI:  https://doi.org/10.1080/15548627.2021.1998872
Cells. 2021 Nov 13. pii: 3152. [Epub ahead of print]10(11):

MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes.

Naveen Mekala, Jacob Kurdys, Alexis Paige Vicenzi, Leana Rose Weiler, Carmen Avramut, Edwin J Vazquez, Neli Ragina, Mariana G Rosca.

  Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

Keywords:  bioenergetics; cardiomyocytes; metabolic syndrome; miR 208a; mitochondrial biogenesis

DOI:  https://doi.org/10.3390/cells10113152
Nat Immunol. 2021 Nov 22.

Mitochondrial signals regulate ER size and TNF production in rheumatoid arthritis.

DOI: https://doi.org/10.1038/s41590-021-01070-5
Cell Rep. 2021 Nov 23. pii: S2211-1247(21)01479-0. [Epub ahead of print]37(8): 110000

The TFAM-to-mtDNA ratio defines inner-cellular nucleoid populations with distinct activity levels.

Christian Brüser, Jan Keller-Findeisen, Stefan Jakobs.

  In human cells, generally a single mitochondrial DNA (mtDNA) is compacted into a nucleoprotein complex denoted the nucleoid. Each cell contains hundreds of nucleoids, which tend to cluster into small groups. It is unknown whether all nucleoids are equally involved in mtDNA replication and transcription or whether distinct nucleoid subpopulations exist. Here, we use multi-color STED super-resolution microscopy to determine the activity of individual nucleoids in primary human cells. We demonstrate that only a minority of all nucleoids are active. Active nucleoids are physically larger and tend to be involved in both replication and transcription. Inactivity correlates with a high ratio of the mitochondrial transcription factor A (TFAM) to the mtDNA of the individual nucleoid, suggesting that TFAM-induced nucleoid compaction regulates nucleoid replication and transcription activity in vivo. We propose that the stable population of highly compacted inactive nucleoids represents a storage pool of mtDNAs with a lower mutational load.

Keywords:  DNA packaging; STED nanoscopy; mitochondrial gene expression; mtDNA mutations; mtDNA replication

DOI:  https://doi.org/10.1016/j.celrep.2021.110000
Cells. 2021 Nov 03. pii: 3003. [Epub ahead of print]10(11):

Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence.

Yun Haeng Lee, Ji Yun Park, Haneur Lee, Eun Seon Song, Myeong Uk Kuk, Junghyun Joo, Sekyung Oh, Hyung Wook Kwon, Joon Tae Park, Sang Chul Park.

  Mitochondria are one of organelles that undergo significant changes associated with senescence. An increase in mitochondrial size is observed in senescent cells, and this increase is ascribed to the accumulation of dysfunctional mitochondria that generate excessive reactive oxygen species (ROS). Such dysfunctional mitochondria are prime targets for ROS-induced damage, which leads to the deterioration of oxidative phosphorylation and increased dependence on glycolysis as an energy source. Based on findings indicating that senescent cells exhibit mitochondrial metabolic alterations, a strategy to induce mitochondrial metabolic reprogramming has been proposed to treat aging and age-related diseases. In this review, we discuss senescence-related mitochondrial changes and consequent mitochondrial metabolic alterations. We assess the significance of mitochondrial metabolic reprogramming for senescence regulation and propose the appropriate control of mitochondrial metabolism to ameliorate senescence. Learning how to regulate mitochondrial metabolism will provide knowledge for the control of aging and age-related pathologies. Further research focusing on mitochondrial metabolic reprogramming will be an important guide for the development of anti-aging therapies, and will provide novel strategies for anti-aging interventions.

Keywords:  ROS; mitochondria; mitochondrial metabolic reprogramming; senescence amelioration

DOI:  https://doi.org/10.3390/cells10113003
Exp Mol Med. 2021 Nov 26.

ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.

Seong Keun Sonn, Seungwoon Seo, Jaemoon Yang, Ki Sook Oh, Hsiuchen Chen, David C Chan, Kunsoo Rhee, Kyung S Lee, Young Yang, Goo Taeg Oh.

C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER-mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.

DOI: https://doi.org/10.1038/s12276-021-00701-z
Stem Cell Res Ther. 2021 Nov 22. 12(1): 581

Multiocular organoids from human induced pluripotent stem cells displayed retinal, corneal, and retinal pigment epithelium lineages.

Helena Isla-Magrané, Anna Veiga, José García-Arumí, Anna Duarri.

   BACKGROUND: Recently, great efforts have been made to design protocols for obtaining ocular cells from human stem cells to model diseases or for regenerative purposes. Current protocols generally focus on isolating retinal cells, retinal pigment epithelium (RPE), or corneal cells and fail to recapitulate the complexity of the tissue during eye development. Here, the generation of more advanced in vitro multiocular organoids from human induced pluripotent stem cells (hiPSCs) is demonstrated.
METHODS: A 2-step method was established to first obtain self-organized multizone ocular progenitor cells (mzOPCs) from 2D hiPSC cultures within three weeks. Then, after the cells were manually isolated and grown in suspension, 3D multiocular organoids were generated to model important cellular features of developing eyes.
RESULTS: In the 2D culture, self-formed mzOPCs spanned the neuroectoderm, surface ectoderm, neural crest, and RPE, mimicking early stages of eye development. After lifting, mzOPCs developed into different 3D multiocular organoids composed of multiple cell lineages including RPE, retina, and cornea, and interactions between the different cell types and regions of the eye system were observed. Within these organoids, the retinal regions exhibited correct layering and contained all major retinal cell subtypes as well as retinal morphological cues, whereas the corneal regions closely resembled the transparent ocular-surface epithelium and contained of corneal, limbal, and conjunctival epithelial cells. The arrangement of RPE cells also formed organoids composed of polarized pigmented epithelial cells at the surface that were completely filled with collagen matrix.
CONCLUSIONS: This approach clearly demonstrated the advantages of the combined 2D-3D construction tissue model as it provided a more ocular native-like cellular environment than that of previous models. In this complex preparations, multiocular organoids may be used to model the crosstalk between different cell types in eye development and disease.

Keywords:  Cornea; Ocular organoids; Ocular precursor cells; RPE; Retina; Retinal pigment epithelium; Stem cells

DOI:  https://doi.org/10.1186/s13287-021-02651-9
J Assist Reprod Genet. 2021 Nov 21.

Preimplantation genetic diagnosis for a carrier with m.3697G > A mitochondrial DNA mutation.

Dongmei Ji, Xinyuan Li, Jianxin Pan, Kai Zong, Dawei Chen, Jordan Lee Marley, Weiwei Zou, Xiaohong Deng, Yu Cao, Zhiguo Zhang, Ping Zhou, Hongying Sha, Yunxia Cao.

   OBJECTIVE: To explore inheritance of the m.3697G > A mitochondrial DNA (mtDNA) mutation and the effectiveness of preimplantation genetic diagnosis (PGD) for the carrier.
METHODS: The study encompassed a pedigree of m.3697G > A mtDNA mutation, including one asymptomatic patient who pursued for PGD treatment. Twelve cumulus oocyte complexes (COCs) were collected in the first PGD cycle and 11 COCs in the second cycle. The efficiency of cumulus cells, polar bodies, and trophectoderm (TE) in predicting the m.3697G > A heteroplasmy of embryos was analyzed.
RESULTS: From 23 COCs, 20 oocytes were fertilized successfully. On day 5 and 6 post-fertilization, 15 blastocysts were biopsied. The m.3697G > A mutation load of TE biopsies ranged from 15.2 to 100%. In the first cycle, a blastocyst with mutation load of 31.7% and chromosomal mosaicism was transferred, but failed to yield a clinical pregnancy. In the second cycle, a euploid blastocyst with mutation load of 53.9% was transferred, which gave rise to a clinical pregnancy. However, the pregnancy was terminated due to fetal cleft lip and palate. The mutation loads of different tissues (47.7 ± 1.8%) from the induced fetus were comparable to that of the biopsied TE and amniotic fluid cell (49.7%). The mutation load of neither cumulus cells (R2 = 0.02, p = 0.58) nor polar bodies (R2 = 0.33, p = 0.13) correlated with TE mutation load which was regarded as a gold standard.
CONCLUSIONS: The m.3697G > A mutation showed a random pattern of inheritance. PGD could be used to reduce the risk of inheritance of a high mutation load. Cumulus cells are not a suitable predictor of blastocyst mutation load.

Keywords:  Cumulus cells; G3697A; Leigh’s syndrome; Mitochondrial DNA mutation; Preimplantation genetic diagnosis

DOI:  https://doi.org/10.1007/s10815-021-02354-3
Front Cell Dev Biol. 2021 ;9 767221

The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.

Evanthia Pangou, Izabela Sumara.

  Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease.

Keywords:  disease; fission; fusion; mitochondria; mitosis; transport

DOI:  https://doi.org/10.3389/fcell.2021.767221
Nat Commun. 2021 Nov 25. 12(1): 6914

Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins.

Topaz Altman, Ariel Ionescu, Amjad Ibraheem, Dominik Priesmann, Tal Gradus-Pery, Luba Farberov, Gayster Alexandra, Natalia Shelestovich, Ruxandra Dafinca, Noam Shomron, Florence Rage, Kevin Talbot, Michael E Ward, Amir Dori, Marcus Krüger, Eran Perlson.

Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of amyotrophic lateral sclerosis (ALS) patients, but the contribution of axonal TDP-43 to this neurodegenerative disease is unclear. Here, we show TDP-43 accumulation in intra-muscular nerves from ALS patients and in axons of human iPSC-derived motor neurons of ALS patient, as well as in motor neurons and neuromuscular junctions (NMJs) of a TDP-43 mislocalization mouse model. In axons, TDP-43 is hyper-phosphorylated and promotes G3BP1-positive ribonucleoprotein (RNP) condensate assembly, consequently inhibiting local protein synthesis in distal axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondrial proteins are reduced. Clearance of axonal TDP-43 or dissociation of G3BP1 condensates restored local translation and resolved TDP-43-derived toxicity in both axons and NMJs. These findings support an axonal gain of function of TDP-43 in ALS, which can be targeted for therapeutic development.

DOI: https://doi.org/10.1038/s41467-021-27221-8
Int J Mol Sci. 2021 Nov 22. pii: 12570. [Epub ahead of print]22(22):

Targeting Mitochondria by Plant Secondary Metabolites: A Promising Strategy in Combating Parkinson's Disease.

Sajad Fakhri, Sadaf Abdian, Seyede Nazanin Zarneshan, Esra Küpeli Akkol, Mohammad Hosein Farzaei, Eduardo Sobarzo-Sánchez.

  Parkinson's disease (PD) is one of the most prevalent and debilitating neurodegenerative conditions, and is currently on the rise. Several dysregulated pathways are behind the pathogenesis of PD; however, the critical targets remain unclear. Accordingly, there is an urgent need to reveal the key dysregulated pathways in PD. Prevailing reports have highlighted the importance of mitochondrial and cross-talked mediators in neurological disorders, genetic changes, and related complications of PD. Multiple pathophysiological mechanisms of PD, as well as the low efficacy and side effects of conventional neuroprotective therapies, drive the need for finding novel alternative agents. Recently, much attention has been paid to using plant secondary metabolites (e.g., flavonoids/phenolic compounds, alkaloids, and terpenoids) in the modulation of PD-associated manifestations by targeting mitochondria. In this line, plant secondary metabolites have shown promising potential for the simultaneous modulation of mitochondrial apoptosis and reactive oxygen species. This review aimed to address mitochondria and multiple dysregulated pathways in PD by plant-derived secondary metabolites.

Keywords:  Parkinson’s disease; mitochondria; neurodegenerative disease; phytochemicals; secondary metabolites; signaling pathway

DOI:  https://doi.org/10.3390/ijms222212570
J Alzheimers Dis. 2021 Nov 18.

Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion.

Heather M Wilkins, Benjamin R Troutwine, Blaise W Menta, Sharon J Manley, Taylor A Strope, Colton R Lysaker, Russell H Swerdlow.

   BACKGROUND: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer's disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists.
OBJECTIVE: We considered how mitochondrial biology may impact AβPP and Aβ biology.
METHODS: SH-SY5Y cells were transfected AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results.
RESULTS: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed.
CONCLUSION: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.

Keywords:  Amyloid; amyloid-beta protein precursor; membrane potential; mitochondria

DOI:  https://doi.org/10.3233/JAD-215280
J Neurochem. 2021 Nov 27.

A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation.

Luisa Aring, Eun-Kyung Choi, Huira Kopera, Thomas Lanigan, Shigeki Iwase, Daniel J Klionsky, Young Ah Seo.

  Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by the abnormal accumulation of brain iron and the progressive degeneration of the nervous system. One of the recently identified subtypes of NBIA is β-propeller protein-associated neurodegeneration (BPAN). BPAN is caused by de novo mutations in the WDR45/WIPI4 (WD repeat domain 45) gene. WDR45 is one of the four mammalian homologs of yeast Atg18, a regulator of autophagy. WDR45 deficiency in BPAN patients and animal models may result in defects in autophagic flux. However, how WDR45 deficiency leads to brain iron overload remains unclear. To elucidate the role of WDR45, we generated a WDR45-knockout (KO) SH-SY5Y neuroblastoma cell line using CRISPR-Cas9-mediated genome editing. Using these cells, we demonstrated that the non-TF (transferrin)-bound iron pathway dominantly mediated the accumulation of iron. Moreover, the loss of WDR45 led to defects in ferritinophagy, a form of autophagy that degrades the iron storage protein ferritin. We showed that impaired ferritinophagy contributes to iron accumulation in WDR45-KO cells. Iron accumulation was also detected in the mitochondria, which was accompanied by impaired mitochondrial respiration, elevated reactive oxygen species, and increased cell death. Thus, our study links WDR45 to specific iron acquisition pathways and ferritinophagy.

Keywords:  BPAN; NBIA; ferritinophagy; iron; neurodegeneration

DOI:  https://doi.org/10.1111/jnc.15548
Nat Immunol. 2021 Nov 22.

Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.

Bowen Wu, Tuantuan V Zhao, Ke Jin, Zhaolan Hu, Matthew P Abdel, Ken J Warrington, Jörg J Goronzy, Cornelia M Weyand.

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.

DOI: https://doi.org/10.1038/s41590-021-01065-2
Int J Mol Sci. 2021 Nov 09. pii: 12133. [Epub ahead of print]22(22):

Mild Muscle Mitochondrial Fusion Distress Extends Drosophila Lifespan through an Early and Systemic Metabolome Reorganization.

Andrea Tapia, Martina Palomino-Schätzlein, Marta Roca, Agustín Lahoz, Antonio Pineda-Lucena, Víctor López Del Amo, Máximo Ibo Galindo.

  In a global aging population, it is important to understand the factors affecting systemic aging and lifespan. Mitohormesis, an adaptive response caused by different insults affecting the mitochondrial network, triggers a response from the nuclear genome inducing several pathways that promote longevity and metabolic health. Understanding the role of mitochondrial function during the aging process could help biomarker identification and the development of novel strategies for healthy aging. Herein, we interfered the muscle expression of the Drosophila genes Marf and Opa1, two genes that encode for proteins promoting mitochondrial fusion, orthologues of human MFN2 and OPA1. Silencing of Marf and Opa1 in muscle increases lifespan, improves locomotor capacities in the long term, and maintains muscular integrity. A metabolomic analysis revealed that muscle down-regulation of Marf and Opa1 promotes a non-autonomous systemic metabolome reorganization, mainly affecting metabolites involved in the energetic homeostasis: carbohydrates, lipids and aminoacids. Interestingly, the differences are consistently more evident in younger flies, implying that there may exist an anticipative adaptation mediating the protective changes at the older age. We demonstrate that mild mitochondrial muscle disturbance plays an important role in Drosophila fitness and reveals metabolic connections between tissues. This study opens new avenues to explore the link of mitochondrial dynamics and inter-organ communication, as well as their relationship with muscle-related pathologies, or in which muscle aging is a risk factor for their appearance. Our results suggest that early intervention in muscle may prevent sarcopenia and promote healthy aging.

Keywords:  Drosophila; insulin pathway; lifespan; metabolomics; mitohormesis

DOI:  https://doi.org/10.3390/ijms222212133
Nat Commun. 2021 Nov 25. 12(1): 6883

Dietary essential amino acids restore liver metabolism in ovariectomized mice via hepatic estrogen receptor α.

Sara Della Torre, Valeria Benedusi, Giovanna Pepe, Clara Meda, Nicoletta Rizzi, Nina Henriette Uhlenhaut, Adriana Maggi.

In female mammals, the cessation of ovarian functions is associated with significant metabolic alterations, weight gain, and increased susceptibility to a number of pathologies associated with ageing. The molecular mechanisms triggering these systemic events are unknown because most tissues are responsive to lowered circulating sex steroids. As it has been demonstrated that isoform alpha of the estrogen receptor (ERα) may be activated by both estrogens and amino acids, we test the metabolic effects of a diet enriched in specific amino acids in ovariectomized (OVX) mice. This diet is able to block the OVX-induced weight gain and fat deposition in the liver. The use of liver-specific ERα KO mice demonstrates that the hepatic ERα, through the control of liver lipid metabolism, has a key role in the systemic response to OVX. The study suggests that the liver ERα might be a valuable target for dietary treatments for the post-menopause.

DOI: https://doi.org/10.1038/s41467-021-27272-x
Biomedicines. 2021 Nov 05. pii: 1625. [Epub ahead of print]9(11):

Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions.

João Duarte Magalhães, Lígia Fão, Rita Vilaça, Sandra Morais Cardoso, Ana Cristina Rego.

  Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of evidence that associate protein misfolding and mitochondrial dysfunction in the etiology of Alzheimer's, Parkinson's, and Huntington's diseases. Macroautophagy has been implicated in the degradation of different protein aggregates such as Aβ, tau, alpha-synuclein (α-syn), and mutant huntingtin (mHtt) and in the clearance of dysfunctional mitochondria. Taking these into consideration, targeting autophagy might represent an effective therapeutic strategy to eliminate protein aggregates and to improve mitochondrial function in these disorders. The present review describes our current understanding on the role of macroautophagy in neurodegenerative disorders and focuses on possible strategies for its therapeutic modulation.

Keywords:  autophagy; mitophagy mitochondrial dysfunction; mutant proteins; neurodegenerative disorders; therapeutic strategies

DOI:  https://doi.org/10.3390/biomedicines9111625
Biol Psychiatry. 2021 Sep 14. pii: S0006-3223(21)01590-0. [Epub ahead of print]

A Perspective on the Potential Involvement of Impaired Proteostasis in Neuropsychiatric Disorders.

Kelvin K Hui, Ryo Endo, Akira Sawa, Motomasa Tanaka.

  Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.

Keywords:  ER stress; mitochondria; neuropsychiatric disorders; protein aggregation; protein misfolding; proteostasis

DOI:  https://doi.org/10.1016/j.biopsych.2021.09.001
Science. 2021 Nov 26. 374(6571): 1049-1050

Adult neurogenesis in neurological diseases.

Fred H Gage.

[Figure: see text].

DOI: https://doi.org/10.1126/science.abm7468