bims-mitmed 2021-10-17 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2021–10–17
34 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.
Endocrine manifestations and new developments in mitochondrial disease.
Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity.
Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.
Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations.
p107 mediated mitochondrial function controls muscle stem cell proliferative fates.
Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism.
Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management.
An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T).
A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.
Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases.
A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss.
Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.
In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.
Interplay Between Cardiolipin and Plasmalogens in Barth Syndrome.
Cellular Models for Primary CoQ Deficiency Pathogenesis Study.
New therapeutic approaches to Parkinson's disease targeting GBA, LRRK2 and Parkin.
Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia.
Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington's Disease.
Resveratrol and its derivative pterostilbene attenuate oxidative stress-induced intestinal injury by improving mitochondrial redox homeostasis and function via SIRT1 signaling.
Resveratrol enhanced mitochondrial recovery from cryopreservation-induced damages in oocytes and embryos.
Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling.
Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene.
Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms.
Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson's disease: comparison of mice strains and dose regimens.
Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder.
Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities.
Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
Folding Mitochondrial-Mediated Cytosolic Proteostasis Into the Mitochondrial Unfolded Protein Response.
Miro1 provides neuroprotection via the mitochondrial trafficking pathway in a rat model of traumatic brain injury.
Lactate and Pyruvate Activate Autophagy and Mitophagy that Protect Cells in Toxic Model of Parkinson's Disease.
Antioxidant properties of flavonoid metal complexes and their potential inclusion in the development of novel strategies for the treatment against neurodegenerative diseases.
Molecular mechanism of interactions between ACAD9 and binding partners in mitochondrial respiratory complex I assembly.
Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Orphanet J Rare Dis. 2021 Oct 09. 16(1): 413

Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.

Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, Isabella Moroni.

   BACKGROUND: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.
RESULTS: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.
CONCLUSION: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.

Keywords:  Basal ganglia; Childhood; Leigh syndrome; Mitochondrial disease

DOI:  https://doi.org/10.1186/s13023-021-02029-3
Endocr Rev. 2021 Oct 13. pii: bnab036. [Epub ahead of print]

Endocrine manifestations and new developments in mitochondrial disease.

Yi Shiau Ng, Albert Zishen Lim, Grigorios Panagiotou, Doug M Turnbull, Mark Walker.

  Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes being predominant but also include hypogonadism, hypoadrenalism and hypoparathyroidism. There have been major developments in mitochondrial disease over the last decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important since it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial since there are important reproductive options have been developed which will prevent the transmission of mitochondrial disease due to mitochondrial DNA variants to the next generation.

Keywords:  MIDD; clinical management; diabetes mellitus; genomic testing; mitochondrial DNA; reproductive options

DOI:  https://doi.org/10.1210/endrev/bnab036
Int J Mol Sci. 2021 Sep 26. pii: 10344. [Epub ahead of print]22(19):

Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity.

Ajibola B Bakare, Joseph Dean, Qun Chen, Vedant Thorat, Yimin Huang, Thomas LaFramboise, Edward J Lesnefsky, Shilpa Iyer.

  Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (>90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (<39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS.

Keywords:  bioenergetics health index; glycolysis; leigh syndrome; mitochondrial disorders; mitochondrial respiration

DOI:  https://doi.org/10.3390/ijms221910344
J Biomed Sci. 2021 Oct 11. 28(1): 70

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.

Ching-Pang Chang, Kuo-Chen Wu, Chien-Yu Lin, Yijuang Chern.

  In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.

Keywords:  ATP; Adenosine; Alzheimer’s disease; Amyotrophic lateral sclerosis; ENTs; Huntington’s disease; Mitochondria; Neuroinflammation; Parkinson’s disease; Therapeutic treatment

DOI:  https://doi.org/10.1186/s12929-021-00766-y
Front Cell Dev Biol. 2021 ;9 737304

Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations.

Anbin Chen, Cecilie Katrin Kristiansen, Yu Hong, Atefeh Kianian, Evandro Fei Fang, Gareth John Sullivan, Jian Wang, Xingang Li, Laurence A Bindoff, Kristina Xiao Liang.

  Mitophagy specifically recognizes and removes damaged or superfluous mitochondria to maintain mitochondrial homeostasis and proper neuronal function. Defective mitophagy and the resulting accumulation of damaged mitochondria occur in several neurodegenerative diseases. Previously, we showed mitochondrial dysfunction in astrocytes with POLG mutations, and here, we examined how POLG mutations affect mitophagy in astrocytes and how this can be ameliorated pharmacologically. Using induced pluripotent stem cell (iPSC)-derived astrocytes carrying POLG mutations, we found downregulation of mitophagy/autophagy-related genes using RNA sequencing-based KEGG metabolic pathway analysis. We confirmed a deficit in mitochondrial autophagosome formation under exogenous stress conditions and downregulation of the mitophagy receptor p62, reduced lipidation of LC3B-II, and decreased expression of lysosome protein lysosomal-associated membrane protein 2A (LAMP2A). These changes were regulated by the PINK1/Parkin pathway and AKT/mTOR/AMPK/ULK1 signaling pathways. Importantly, we found that double treatment with nicotinamide riboside (NR) and metformin rescued mitophagy defects and mitochondrial dysfunction in POLG-mutant astrocytes. Our findings reveal that impaired mitophagy is involved in the observed mitochondrial dysfunction caused by POLG mutations in astrocytes, potentially contributing to the phenotype in POLG-related diseases. This study also demonstrates the therapeutic potential of NR and metformin in these incurable mitochondrial diseases.

Keywords:  IPSC (induced pluripotent stem cells); POLG; astrocytes; metformin; mitochondria; mitophagy; nicotinamide riboside (NR)

DOI:  https://doi.org/10.3389/fcell.2021.737304
Nat Commun. 2021 Oct 13. 12(1): 5977

p107 mediated mitochondrial function controls muscle stem cell proliferative fates.

Debasmita Bhattacharya, Vicky Shah, Oreoluwa Oresajo, Anthony Scimè.

Muscle diseases and aging are associated with impaired myogenic stem cell self-renewal and fewer proliferating progenitors (MPs). Importantly, distinct metabolic states induced by glycolysis or oxidative phosphorylation have been connected to MP proliferation and differentiation. However, how these energy-provisioning mechanisms cooperate remain obscure. Herein, we describe a mechanism by which mitochondrial-localized transcriptional co-repressor p107 regulates MP proliferation. We show p107 directly interacts with the mitochondrial DNA, repressing mitochondrial-encoded gene transcription. This reduces ATP production by limiting electron transport chain complex formation. ATP output, controlled by the mitochondrial function of p107, is directly associated with the cell cycle rate. Sirt1 activity, dependent on the cytoplasmic glycolysis product NAD+, directly interacts with p107, impeding its mitochondrial localization. The metabolic control of MP proliferation, driven by p107 mitochondrial function, establishes a cell cycle paradigm that might extend to other dividing cell types.

DOI: https://doi.org/10.1038/s41467-021-26176-0
Hum Mol Genet. 2021 Oct 12. pii: ddab299. [Epub ahead of print]

Threshold of heteroplasmic truncating MT-ATP6 mutation in reprogramming, Notch hyperactivation and motor neuron metabolism.

Sebastian Kenvin, Ruben Torregrosa-Muñumer, Marco Reidelbach, Jana Pennonen, Jeremi J Turkia, Erika Rannila, Jouni Kvist, Markus T Sainio, Nadine Huber, Sanna-Kaisa Herukka, Annakaisa Haapasalo, Mari Auranen, Ras Trokovic, Vivek Sharma, Emil Ylikallio, Henna Tyynismaa.

Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. Here we investigated the functional consequences of an unusual heteroplasmic truncating mutation m.9154C>T in MT-ATP6, which caused peripheral neuropathy, ataxia and IgA nephropathy. ATP synthase not only generates cellular ATP, but its dimerization is required for mitochondrial cristae formation. Accordingly, the MT-ATP6 truncating mutation impaired the assembly of ATP synthase and disrupted cristae morphology, supporting our molecular dynamics simulations that predicted destabilized a/c subunit subcomplex. Next, we modeled the effects of the truncating mutation using patient-specific induced pluripotent stem cells. Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). Interestingly, MN differentiation beyond progenitor stage was impaired by Notch hyperactivation in the MT-ATP6 mutant, but not by rotenone-induced inhibition of mitochondrial respiration, suggesting that altered mitochondrial morphology contributed to Notch hyperactivation. Finally, we also identified a lower mutation threshold for a metabolic shift in mature MN, affecting lactate utilization, which may be relevant for understanding the mechanisms of mitochondrial involvement in peripheral motor neuropathies. These results establish a critical and disease-relevant role for ATP synthase in human cell fate decisions and neuronal metabolism.

DOI: https://doi.org/10.1093/hmg/ddab299
Cell Death Discov. 2021 Oct 14. 7(1): 293

Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management.

Qin Yang, Ling Wang, Jiaye Liu, Wanlu Cao, Qiuwei Pan, Meng Li.

Liver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.

DOI: https://doi.org/10.1038/s41420-021-00675-x
Mol Metab. 2021 Oct 09. pii: S2212-8778(21)00201-5. [Epub ahead of print] 101354

An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T).

A J Yeo, G N Subramanian, K L Chong, M Gatei, R G Parton, D Coman, M F Lavin.

   OBJECTIVE: ATM, the protein defective in the human genetic disorder, ataxia telangiectasia (A-T) plays a central role in the response to DNA double strand breaks (DSBs) and in protecting the cell against oxidative stress. We recently showed that A-T cells are hypersensitive to metabolic stress which can be accounted for by a failure to exhibit efficient endoplasmic reticulum (ER)-mitochondrial signalling and Ca2+ transfer in response to nutrient deprivation resulting in mitochondrial dysfunction. The objective of the current study is to use an anaplerotic approach using the fatty acid, heptanoate (C7), a metabolic product of the triglyceride, triheptanoin to correct the defect in ER-mitochondrial signalling and enhance cell survival of A-T cells in response to metabolic stress.
METHODS: We treated control cells and A-T cells with the anaplerotic agent, heptanoate to determine their sensitivity to metabolic stress induced by inhibition of glycolysis with 2 deoxyglucose (2DG) using live-cell imaging to monitor cell survival for 72 hours using the Incucyte system. We examined ER-mitochondrial signalling in A-T cells exposed to metabolic stress using a suite of techniques including immunofluorescence staining of Grp75, ER-mitochondrial Ca2+ channel, the VAPB-PTPIP51 ER-mitochondrial tether complexes as well as proximity ligation assays between Grp75-IP3R1 and VAPB1-PTPIP51 to establish a functional interaction between ER and mitochondria. Finally, we also performed metabolomic analysis using LC-MS/MS to determine altered levels of TCA intermediates A-T cells compared to healthy control cells.
RESULTS: We demonstrate here that heptanoate corrects all aspects of the defective ER-mitochondrial signalling observed in A-T cells. Heptanoate enhances ER-mitochondrial contacts; increases the flow of calcium from the ER to the mitochondrion; restores normal mitochondrial function and mitophagy and increases resistance of ATM-deficient cells and cells from A-T patients to metabolic stress-induced killing. The defect in mitochondrial function in ATM-deficient cells was accompanied by more reliance on aerobic glycolysis as shown by increased lactate dehydrogenase A (LDHA), accumulation of lactate and reduced levels of both acetyl CoA and ATP which are all restored by heptanoate.
CONCLUSIONS: These data together show that heptanoate corrects metabolic stress in A-T cells by restoring ER-mitochondria signalling and mitochondrial function and suggest that the parent compound, triheptanoin, has great potential as a novel therapeutic agent for patients with A-T.

Keywords:  ATM; Ataxia-telangiectasia; endoplasmic reticulum; heptanoate (C7); mitochondrial dysfunction; mitochondrial interaction; nutrient deprivation

DOI:  https://doi.org/10.1016/j.molmet.2021.101354
Mov Disord. 2021 Oct 11.

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia.

Derek E Neilson, Michael Zech, Robert B Hufnagel, Jesse Slone, Xinjian Wang, Shelli Homan, Lisa M Gutzwiller, Elizabeth J Leslie, Nancy D Leslie, Jianfeng Xiao, Peter Hedera, Mark S LeDoux, Brian Gebelein, Friederike Wilbert, Matthias Eckenweiler, Juliane Winkelmann, Donald L Gilbert, Taosheng Huang.

BACKGROUND: In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31.
OBJECTIVE: The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia.
METHODS: Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function.
RESULTS: Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility.
CONCLUSION: A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

DOI: https://doi.org/10.1002/mds.28821
Front Mol Neurosci. 2021 ;14 730604

Mitochondrial Protein PGAM5 Emerges as a New Regulator in Neurological Diseases.

Min-Zong Liang, Ting-Ling Ke, Linyi Chen.

  As mitochondrial dysfunction has increasingly been implicated in neurological diseases, much of the investigation focuses on the response of the mitochondria. It appears that mitochondria can respond to external stimuli speedy fast, in seconds. Understanding how mitochondria sense the signal and communicate with cytosolic pathways are keys to understand mitochondrial regulation in diseases or in response to trauma. It was not until recently that a novel mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5) has emerged to be a new regulator of mitochondrial homeostasis. Although controversial results reveal beneficial as well as detrimental roles of PGAM5 in cancers, these findings also suggest PGAM5 may have diverse regulation on cellular physiology. Roles of PGAM5 in neuronal tissues remain to be uncovered. This review discusses current knowledge of PGAM5 in neurological diseases and provides future perspectives.

Keywords:  PGAM5; mitochondrial dynamics; mitochondrial homeostasis; mitophagy; neurological diseases

DOI:  https://doi.org/10.3389/fnmol.2021.730604
Hum Genet. 2021 Oct 13.

A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss.

Farid Ullah, Waqar Rauf, Kamal Khan, Sheraz Khan, Katrina M Bell, Vanessa Cristina de Oliveira, Muhammad Tariq, Shabnam Bakhshalizadeh, Philippe Touraine, Nicholas Katsanis, Andrew Sinclair, Sijie He, Elena J Tucker, Shahid M Baig, Erica E Davis.

Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C > T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.

DOI: https://doi.org/10.1007/s00439-021-02380-2
NPJ Aging Mech Dis. 2021 Oct 14. 7(1): 26

Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.

Kristina Bečanović, Asghar Muhammad, Izabella Gadawska, Shiny Sachdeva, David Walker, Eduardo R Lazarowski, Sonia Franciosi, Kevin H J Park, Hélène C F Côté, Blair R Leavitt.

Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.

DOI: https://doi.org/10.1038/s41514-021-00079-2
J Neurol. 2021 Oct 15.

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich's ataxia.

Gayatri Maria Schur, Julia Dunn, Sara Nguyen, Anna Dedio, Kristin Wade, Jaclyn Tamaroff, Nithya Mitta, Neil Wilson, Ravinder Reddy, David R Lynch, Shana E McCormack.

   BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by decreased expression of frataxin, a protein involved in many cellular metabolic processes, including mitochondrial oxidative phosphorylation (OXPHOS). Our objective was to assess skeletal muscle oxidative metabolism in vivo in adults with FRDA as compared to adults without FRDA using chemical exchange saturation transfer (CrCEST) MRI, which measures free creatine (Cr) over time following an in-magnet plantar flexion exercise.
METHODS: Participants included adults with FRDA (n = 11) and healthy adults (n = 25). All underwent 3-Tesla CrCEST MRI of the calf before and after in-scanner plantar flexion exercise. Participants also underwent whole-body dual-energy X-ray absorptiometry (DXA) scans to measure body composition and completed questionnaires to assess physical activity.
RESULTS: We found prolonged post-exercise exponential decline in CrCEST (τCr) in the lateral gastrocnemius (LG, 274 s vs. 138 s, p = 0.01) in adults with FRDA (vs. healthy adults), likely reflecting decreased OXPHOS capacity. Adults with FRDA (vs. healthy adults) also engaged different muscle groups during exercise, as indicated by muscle group-specific changes in creatine with exercise (∆CrCEST), possibly reflecting decreased coordination. Across all participants, increased adiposity and decreased usual physical activity were associated with smaller ∆CrCEST.
CONCLUSION: In FRDA, CrCEST MRI may be a useful biomarker of muscle-group-specific decline in OXPHOS capacity that can be leveraged to track within-participant changes over time. Appropriate participant selection and further optimization of the exercise stimulus will enhance the utility of this technique.

Keywords:  Exercise; Friedreich’s ataxia; Magnetic resonance imaging; Mitochondrial disorders; OXPHOS; Oxidative metabolism; Skeletal muscle

DOI:  https://doi.org/10.1007/s00415-021-10821-1
J Inherit Metab Dis. 2021 Oct 16.

Interplay Between Cardiolipin and Plasmalogens in Barth Syndrome.

José Carlos Bozelli, Richard M Epand.

  Barth Syndrome (BTHS) is a rare inherited metabolic disease resulting from mutations in the gene of the enzyme tafazzin, which catalyzes the acyl chain remodeling of the mitochondrial-specific lipid cardiolipin (CL). Tissue samples of individuals with BTHS present abnormalities in the level and the molecular species of CL. In addition, in tissues of a tafazzin knockdown mouse as well as in cells derived from BTHS patients it has been shown that plasmalogens, a subclass of glycerophospholipids, also have abnormal levels. Likewise, administration of a plasmalogen precursor to cells derived from BTHS patients led to an increase in plasmalogen and to some extent CL levels. These results indicate an interplay between CL and plasmalogens in BTHS. This interdependence is supported by the concomitant loss in these lipids in different pathological conditions. However, currently the molecular mechanism linking CL and plasmalogens is not fully understood. Here, a review of the evidence showing the linkage between the levels of CL and plasmalogens is presented. In addition, putative mechanisms that might play a role in this interplay are proposed. Finally, the opportunity of therapeutic approaches based on the regulation of plasmalogens as new therapies for the treatment of BTHS is discussed. This article is protected by copyright. All rights reserved.

Keywords:  Barth Syndrome; cardiolipin; lipid disorders; lipid metabolism; plasmalogen replacement therapy; plasmalogens

DOI:  https://doi.org/10.1002/jimd.12449
Int J Mol Sci. 2021 Sep 22. pii: 10211. [Epub ahead of print]22(19):

Cellular Models for Primary CoQ Deficiency Pathogenesis Study.

Carlos Santos-Ocaña, María V Cascajo, María Alcázar-Fabra, Carmine Staiano, Guillermo López-Lluch, Gloria Brea-Calvo, Plácido Navas.

  Primary coenzyme Q10 (CoQ) deficiency includes a heterogeneous group of mitochondrial diseases characterized by low mitochondrial levels of CoQ due to decreased endogenous biosynthesis rate. These diseases respond to CoQ treatment mainly at the early stages of the disease. The advances in the next generation sequencing (NGS) as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have increased the discoveries of mutations in either gene already described to participate in CoQ biosynthesis or new genes also involved in this pathway. However, these technologies usually provide many mutations in genes whose pathogenic effect must be validated. To functionally validate the impact of gene variations in the disease's onset and progression, different cell models are commonly used. We review here the use of yeast strains for functional complementation of human genes, dermal skin fibroblasts from patients as an excellent tool to demonstrate the biochemical and genetic mechanisms of these diseases and the development of human-induced pluripotent stem cells (hiPSCs) and iPSC-derived organoids for the study of the pathogenesis and treatment approaches.

Keywords:  cell models; coenzyme Q; coenzyme Q deficiency; human fibroblasts; iPSC; mitochondrial diseases; yeast

DOI:  https://doi.org/10.3390/ijms221910211
Neuropharmacology. 2021 Oct 06. pii: S0028-3908(21)00377-4. [Epub ahead of print] 108822

New therapeutic approaches to Parkinson's disease targeting GBA, LRRK2 and Parkin.

Konstantin Senkevich, Uladzislau Rudakou, Ziv Gan-Or.

  Parkinson's disease (PD) is defined as a complex disorder with multifactorial pathogenesis, yet a more accurate definition could be that PD is not a single entity, but rather a mixture of different diseases with similar phenotypes. Attempts to classify subtypes of PD have been made based on clinical phenotypes or biomarkers. However, the most practical approach, at least for a portion of the patients, could be to classify patients based on genes involved in PD. GBA and LRRK2 mutations are the most common genetic causes or risk factors of PD, and PRKN is the most common cause of autosomal recessive form of PD. Patients carrying variants in GBA, LRRK2 or PRKN differ in some of their clinical characteristics, pathology and biochemical parameters. Thus, these three PD-associated genes are of special interest for drug development. Existing therapeutic approaches in PD are strictly symptomatic, as numerous clinical trials aimed at modifying PD progression or providing neuroprotection have failed over the last few decades. The lack of precision medicine approach in most of these trials could be one of the reasons why they were not successful. In the current review we discuss novel therapeutic approaches targeting GBA, LRRK2 and PRKN and discuss different aspects related to these genes and clinical trials.

Keywords:  Clinical trials; GBA; Genetic targets; LRRK2; PRKN; Parkinson's disease

DOI:  https://doi.org/10.1016/j.neuropharm.2021.108822
Int J Mol Sci. 2021 Oct 04. pii: 10735. [Epub ahead of print]22(19):

Deletion of Neuronal CuZnSOD Accelerates Age-Associated Muscle Mitochondria and Calcium Handling Dysfunction That Is Independent of Denervation and Precedes Sarcopenia.

Yu Su, Dennis R Claflin, Meixiang Huang, Carol S Davis, Peter C D Macpherson, Arlan Richardson, Holly Van Remmen, Susan V Brooks.

  Skeletal muscle suffers atrophy and weakness with aging. Denervation, oxidative stress, and mitochondrial dysfunction are all proposed as contributors to age-associated muscle loss, but connections between these factors have not been established. We examined contractility, mitochondrial function, and intracellular calcium transients (ICTs) in muscles of mice throughout the life span to define their sequential relationships. We performed these same measures and analyzed neuromuscular junction (NMJ) morphology in mice with postnatal deletion of neuronal Sod1 (i-mn-Sod1-/- mice), previously shown to display accelerated age-associated muscle loss and exacerbation of denervation in old age, to test relationships between neuronal redox homeostasis, NMJ degeneration and mitochondrial function. In control mice, the amount and rate of the decrease in mitochondrial NADH during contraction was greater in middle than young age although force was not reduced, suggesting decreased efficiency of NADH utilization prior to the onset of weakness. Declines in both the peak of the ICT and force were observed in old age. Muscles of i-mn-Sod1-/- mice showed degeneration of mitochondrial and calcium handling functions in middle-age and a decline in force generation to a level not different from the old control mice, with maintenance of NMJ morphology. Together, the findings support the conclusion that muscle mitochondrial function decreases during aging and in response to altered neuronal redox status prior to NMJ deterioration or loss of mass and force suggesting mitochondrial defects contribute to sarcopenia independent of denervation.

Keywords:  NADH; calcium; denervation; oxidative stress; sarcopenia

DOI:  https://doi.org/10.3390/ijms221910735
Aging Dis. 2021 Oct;12(7): 1753-1772

Targeting Mitochondrial Network Disorganization is Protective in C. elegans Models of Huntington's Disease.

Emily Machiela, Paige D Rudich, Annika Traa, Ulrich Anglas, Sonja K Soo, Megan M Senchuk, Jeremy M Van Raamsdonk.

  Huntington's disease (HD) is an adult-onset neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the HTT gene. While the pathogenesis of HD is incompletely understood, mitochondrial dysfunction is thought to be a key contributor. In this work, we used C. elegans models to elucidate the role of mitochondrial dynamics in HD. We found that expression of a disease-length polyglutamine tract in body wall muscle, either with or without exon 1 of huntingtin, results in mitochondrial fragmentation and mitochondrial network disorganization. While mitochondria in young HD worms form elongated tubular networks as in wild-type worms, mitochondrial fragmentation occurs with age as expanded polyglutamine protein forms aggregates. To correct the deficit in mitochondrial morphology, we reduced levels of DRP-1, the GTPase responsible for mitochondrial fission. Surprisingly, we found that disrupting drp-1 can have detrimental effects, which are dependent on how much expression is decreased. To avoid potential negative side effects of disrupting drp-1, we examined whether decreasing mitochondrial fragmentation by targeting other genes could be beneficial. Through this approach, we identified multiple genetic targets that rescue movement deficits in worm models of HD. Three of these genetic targets, pgp-3, F25B5.6 and alh-12, increased movement in the HD worm model and restored mitochondrial morphology to wild-type morphology. This work demonstrates that disrupting the mitochondrial fission gene drp-1 can be detrimental in animal models of HD, but that decreasing mitochondrial fragmentation by targeting other genes can be protective. Overall, this study identifies novel therapeutic targets for HD aimed at improving mitochondrial health.

Keywords:  C. elegans; DRP1; Huntington’s disease; aggregation; animal model; genetics; mitochondria; mitochondrial dynamics; neurodegeneration; neuroprotection

DOI:  https://doi.org/10.14336/AD.2021.0404
Free Radic Biol Med. 2021 Oct 11. pii: S0891-5849(21)00759-0. [Epub ahead of print]

Resveratrol and its derivative pterostilbene attenuate oxidative stress-induced intestinal injury by improving mitochondrial redox homeostasis and function via SIRT1 signaling.

Yanan Chen, Hao Zhang, Shuli Ji, Peilu Jia, Yueping Chen, Yue Li, Tian Wang.

  Oxidative stress inflicts mitochondrial dysfunction, which has been recognized as a key driver of intestinal diseases. Resveratrol (RSV) and its derivative pterostilbene (PTS) are natural antioxidants and exert a protective influence on intestinal health. However, the therapeutic effects and mechanisms of RSV and PTS on oxidative stress-induced mitochondrial dysfunction and intestinal injury remain unclear. The present study used porcine and cellular settings to compare the effects of RSV and PTS on mitochondrial redox homeostasis and function to alleviate oxidative stress-induced intestinal injury. Our results indicated that PTS was more potent than RSV in reducing oxidative stress, maintaining intestinal integrity, and preserving the mitochondrial function of diquat-challenged piglets. In the in vitro study, RSV and PTS protected against hydrogen peroxide (H2O2)-induced mitochondrial dysfunction in intestinal porcine enterocyte cell line (IPEC-J2) by facilitating mitochondrial biogenesis and increasing the activities of mitochondrial complexes. In addition, both RSV and PTS efficiently mitigated mitochondrial oxidative stress by increasing sirtuin 3 protein expression and the deacetylation of superoxide dismutase 2 and peroxiredoxin 3 in H2O2-exposed IPEC-J2 cells. Furthermore, RSV and PTS preserved mitochondrial membrane potential, which restrained the release of cytochrome C from mitochondria to the cytoplasm and caspase-3 activation and further reduced apoptotic rates in H2O2-exposed IPEC-J2 cells. Mechanistically, depletion of sirtuin 1 (SIRT1) abrogated RSV's and PTS's benefits against mitochondrial reactive oxygen species (mtROS) overproduction, mitochondrial dysfunction, and apoptosis in H2O2-exposed IPEC-J2 cells, suggesting that SIRT1 was required for RSV and PTS to protect against oxidative stress-induced intestinal injury. In conclusion, RSV and PTS improve oxidative stress-induced intestinal injury by regulating mitochondrial redox homeostasis and function via SIRT1 signaling pathway. In offering this protection, PTS is superior to RSV.

Keywords:  Intestinal oxidative injury; Mitochondrial function; Mitochondrial redox homeostasis; Pterostilbene; Resveratrol; Sirtuin 1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.011
Reprod Med Biol. 2021 Oct;20(4): 419-426

Resveratrol enhanced mitochondrial recovery from cryopreservation-induced damages in oocytes and embryos.

Hisataka Iwata.

   Background: Mitochondria play a crucial role in nuclear maturation, fertilization, and subsequent embryo development. Cryopreservation is an important assisted reproductive technology that is used worldwide for humans and domestic animals. Although mitochondrial quantity and quality are decisive factors for successful development of oocytes and embryos, cryopreservation induces mitochondrial dysfunction. Upon thawing, the damaged mitochondria are removed, and de novo synthesis occurs to restore the function of mitochondria. Resveratrol, 3,5,4'-trihydroxystilbene, is a polyphenolic antioxidant that has versatile target proteins, among which sirtuin-1 (SIRT1) is a key regulator of in mitochondrial biogenesis and degradation.
Methods: The present study is a literature review focusing on experiments involving the hypothesis that the activation of mitochondrial biogenesis and degradation following cryopreservation and warming by resveratrol may help mitochondrial recovery and improve oocyte and embryo development.
Main findings and conclusion: Resveratrol improves oocyte maturation and development and upregulates mitochondrial biogenesis and degradation. When vitrified-warmed embryos are treated with resveratrol, it helps in mitochondrial regulation and recovery of embryos from cryopreservation-induced damage.
Conclusion: Resveratrol treatment is a possible countermeasure against cryopreservation-induced mitochondrial damage.

Keywords:  SIRT1; cryopreservation; mitochondria; resveratrol

DOI:  https://doi.org/10.1002/rmb2.12401
Int J Mol Sci. 2021 Oct 01. pii: 10657. [Epub ahead of print]22(19):

Environmental Enrichment Induces Meningeal Niche Remodeling through TrkB-Mediated Signaling.

Stefania Zorzin, Andrea Corsi, Francesca Ciarpella, Emanuela Bottani, Sissi Dolci, Giorgio Malpeli, Annachiara Pino, Alessia Amenta, Guido Franceso Fumagalli, Cristiano Chiamulera, Francesco Bifari, Ilaria Decimo.

  Neural precursors (NPs) present in the hippocampus can be modulated by several neurogenic stimuli, including environmental enrichment (EE) acting through BDNF-TrkB signaling. We have recently identified NPs in meninges; however, the meningeal niche response to pro-neurogenic stimuli has never been investigated. To this aim, we analyzed the effects of EE exposure on NP distribution in mouse brain meninges. Following neurogenic stimuli, although we did not detect modification of the meningeal cell number and proliferation, we observed an increased number of neural precursors in the meninges. A lineage tracing experiment suggested that EE-induced β3-Tubulin+ immature neuronal cells present in the meninges originated, at least in part, from GLAST+ radial glia cells. To investigate the molecular mechanism responsible for meningeal reaction to EE exposure, we studied the BDNF-TrkB interaction. Treatment with ANA-12, a TrkB non-competitive inhibitor, abolished the EE-induced meningeal niche changes. Overall, these data showed, for the first time, that EE exposure induced meningeal niche remodeling through TrkB-mediated signaling. Fluoxetine treatment further confirmed the meningeal niche response, suggesting it may also respond to other pharmacological neurogenic stimuli. A better understanding of the neurogenic stimuli modulation for meninges may be useful to improve the effectiveness of neurodegenerative and neuropsychiatric treatments.

Keywords:  ANA-12; BDNF; EE; ENR; TrkB; enriched environment; meningeal niche; meninges; neural precursor; neurogenesis; radial glia cell

DOI:  https://doi.org/10.3390/ijms221910657
Int J Mol Sci. 2021 Sep 27. pii: 10393. [Epub ahead of print]22(19):

Relationships between Mitochondrial Function, AMPK, and TORC1 Signaling in Lymphoblasts with Premutation Alleles of the FMR1 Gene.

Paul R Fisher, Claire Y Allan, Oana Sanislav, Anna Atkinson, Kevin R W Ngoei, Bruce E Kemp, Elsdon Storey, Danuta Z Loesch, Sarah J Annesley.

  The X-linked FMR1 gene contains a non-coding trinucleotide repeat in its 5' region that, in normal, healthy individuals contains 20-44 copies. Large expansions of this region (>200 copies) cause fragile X syndrome (FXS), but expansions of 55-199 copies (referred to as premutation alleles) predispose carriers to a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS). The cytopathological mechanisms underlying FXTAS are poorly understood, but abnormalities in mitochondrial function are believed to play a role. We previously reported that lymphoblastoid cell lines (LCLs, or lymphoblasts) of premutation carriers have elevated mitochondrial respiratory activities. In the carriers, especially those not clinically affected with FXTAS, AMP-activated protein kinase (AMPK) activity was shown to be elevated. In the FXTAS patients, however, it was negatively correlated with brain white matter lesions, suggesting a protective role in the molecular mechanisms. Here, we report an enlarged and extended study of mitochondrial function and associated cellular stress-signaling pathways in lymphoblasts isolated from male and female premutation carriers, regardless of their clinical status, and healthy controls. The results confirmed the elevation of AMPK and mitochondrial respiratory activities and reduction in reactive O2 species (ROS) levels in premutation cells and revealed for the first time that target of rapamycin complex I (TORC1) activities are reduced. Extensive correlation, multiple regression, and principal components analysis revealed the best fitting statistical explanations of these changes in terms of the other variables measured. These suggested which variables might be the most "proximal" regulators of the others in the extensive network of known causal interactions amongst the measured parameters of mitochondrial function and cellular stress signaling. In the resulting model, the premutation alleles activate AMPK and inhibit both TORC1 and ROS production, the reduced TORC1 activity contributes to activation of AMPK and of nonmitochondrial metabolism, and the higher AMPK activity results in elevated catabolic metabolism, mitochondrial respiration, and ATP steady state levels. In addition, the results suggest a separate CGG repeat number-dependent elevation of TORC1 activity that is insufficient to overcome the inhibition of TORC1 in premutation cells but may presage the previously reported activation of TORC1 in FXS cells.

Keywords:  AMPK; CGG repeat; FMR1; TOR complex I; fragile X-associated tremor/ataxia syndrome (FXTAS); mitochondria

DOI:  https://doi.org/10.3390/ijms221910393
Front Cell Dev Biol. 2021 ;9 750382

Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms.

Haoxiao Zheng, Hailan Zhu, Xinyue Liu, Xiaohui Huang, Anqing Huang, Yuli Huang.

  Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.

Keywords:  diabetic cardiomyopathy; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.3389/fcell.2021.750382
Metab Brain Dis. 2021 Oct 14.

Impaired mitochondrial functions and energy metabolism in MPTP-induced Parkinson's disease: comparison of mice strains and dose regimens.

Anjana Pathania, Priyanka Garg, Rajat Sandhir.

  Heterogenous diseases such as Parkinson's disease (PD) needs an efficient animal model to enhance understanding of the underlying mechanisms and to develop therapeutics. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin, has been widely used to replicate the pathophysiology of PD in rodents, however, the knowledge about its effects on energy metabolism is limited. Moreover, susceptibility to different dose regimens of MPTP also varies among mice strains. Thus, the present study compares the effect of acute and sub-acute MPTP administration on mitochondrial functions in C57BL/6 and BALB/c mice. In addition, activity of enzymes involved in energy metabolism was also studied along with behavioural alterations. The findings show that acute dose of MPTP in C57BL/6 mice had more profound effect on the activity of electron transport chain complexes. Further, the activity of MAO-B was increased following acute and sub-acute MPTP administration in C57BL/6 mice. However, no significant change was observed in BALB/c mice. Acute MPTP treatment resulted in decreased mitochondrial membrane potential along with increased swelling of mitochondria in C57BL/6 mice. In addition, perturbations were observed in hexokinase, the rate limiting enzyme of glycolysis and pyruvate dehydrogenase, the enzymes that connects glycolysis and TCA cycle. The activity of TCA cycle enzymes; citrate synthase, aconitase, isocitrate dehydrogenase and fumarase were also altered following MPTP intoxication. Furthermore, acute MPTP administration led to drastic reduction in dopamine levels in striatum of C57BL/6 as compared to BALB/c mice. Behavioral tests such as open field, narrow beam walk and footprint analysis revealed severe impairment in locomotor activity in C57BL/6 mice. These results clearly demonstrate that C57BL/6 strain is more vulnerable to MPTP-induced mitochondrial dysfunctions, perturbations in energy metabolism and motor defects as compared to BALB/c strain. Thus, the findings suggest that the dose and strain of mice need to be considered for pre-clinical studies using MPTP-induced model of Parkinson's disease.

Keywords:  BALB/c; Behaviour; C57BL/6; Cytochrome c oxidase; Dopamine; F1–F0 ATPase Synthase; MPTP; Mitochondria; NADH Dehydrogenase; Neurotransmitter; Parkinson’s disease; Succinate Dehydrogenase

DOI:  https://doi.org/10.1007/s11011-021-00840-2
Transl Psychiatry. 2021 Oct 13. 11(1): 527

Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder.

Richard E Frye, Loïc Lionnard, Indrapal Singh, Mohammad A Karim, Hanane Chajra, Mathilde Frechet, Karima Kissa, Victor Racine, Amrit Ammanamanchi, Patrick John McCarty, Leanna Delhey, Marie Tippett, Shannon Rose, Abdel Aouacheria.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.

DOI: https://doi.org/10.1038/s41398-021-01647-6
Front Physiol. 2021 ;12 725866

Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities.

Paulo H C Mesquita, Christopher G Vann, Stuart M Phillips, James McKendry, Kaelin C Young, Andreas N Kavazis, Michael D Roberts.

  Skeletal muscle adaptations to resistance and endurance training include increased ribosome and mitochondrial biogenesis, respectively. Such adaptations are believed to contribute to the notable increases in hypertrophy and aerobic capacity observed with each exercise mode. Data from multiple studies suggest the existence of a competition between ribosome and mitochondrial biogenesis, in which the first adaptation is prioritized with resistance training while the latter is prioritized with endurance training. In addition, reports have shown an interference effect when both exercise modes are performed concurrently. This prioritization/interference may be due to the interplay between the 5' AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) signaling cascades and/or the high skeletal muscle energy requirements for the synthesis and maintenance of cellular organelles. Negative associations between ribosomal DNA and mitochondrial DNA copy number in human blood cells also provide evidence of potential competition in skeletal muscle. However, several lines of evidence suggest that ribosome and mitochondrial biogenesis can occur simultaneously in response to different types of exercise and that the AMPK-mTORC1 interaction is more complex than initially thought. The purpose of this review is to provide in-depth discussions of these topics. We discuss whether a curious competition between mitochondrial and ribosome biogenesis exists and show the available evidence both in favor and against it. Finally, we provide future research avenues in this area of exercise physiology.

Keywords:  AMP-activated protein kinase; concurrent training; exercise training; mechanistic target of rapamycin; mitochondria; ribosomes; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2021.725866
PLoS Pathog. 2021 Oct;17(10): e1009841

Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.

Hiroki Sato, Miho Hoshi, Fusako Ikeda, Tomoko Fujiyuki, Misako Yoneda, Chieko Kai.

In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.

DOI: https://doi.org/10.1371/journal.ppat.1009841
Front Cell Dev Biol. 2021 ;9 715923

Folding Mitochondrial-Mediated Cytosolic Proteostasis Into the Mitochondrial Unfolded Protein Response.

Edmund Charles Jenkins, Mrittika Chattopadhyay, Doris Germain.

  Several studies reported that mitochondrial stress induces cytosolic proteostasis. How mitochondrial stress activates proteostasis in the cytosol remains unclear. However, the cross-talk between the mitochondria and cytosolic proteostasis has far reaching implications for treatment of proteopathies including neurodegenerative diseases. This possibility appears within reach since selected drugs have begun to emerge as being able to stimulate mitochondrial-mediated cytosolic proteostasis. In this review, we focus on studies describing how mitochondrial stress activates proteostasis in the cytosol across multiple model organisms. A model is proposed linking mitochondrial-mediated regulation of cytosolic translation, folding capacity, ubiquitination, and proteasome degradation and autophagy as a multi layered control of cytosolic proteostasis that overlaps with the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). By analogy to the conductor in an orchestra managing multiple instrumental sections into a dynamically integrated musical piece, the cross-talk between these signaling cascades places the mitochondria as a major conductor of cellular integrity.

Keywords:  estrogen receptor alpha; heat shock; mitochondria; mitochondrial UPR; mitochondrial integrated stress response; proteasome; translation

DOI:  https://doi.org/10.3389/fcell.2021.715923
Brain Res. 2021 Oct 09. pii: S0006-8993(21)00542-4. [Epub ahead of print] 147685

Miro1 provides neuroprotection via the mitochondrial trafficking pathway in a rat model of traumatic brain injury.

Chen Chen, Lina Lu, Jie Zhu, XiaoYu Gu, BoFei Liu, Di Li, Gang Chen.

  The outer mitochondrial membrane protein mitochondrial Rho-GTPase 1 (Miro1) is known to be involved in the regulation of mitochondrial transport required for neuronal protection. Previous reports established that disruption of Miro1-dependent mitochondrial movement could result in nervous system diseases such as Parkinson's disease and Alzheimer's disease. This study was designed to explore the expression and mechanisms of Miro1 in secondary brain injury after traumatic brain injury (TBI). A total of 115 male Sprague Dawley rats were used in the weight-drop TBI rat model, and Miro1 in vivo knockdown was performed 24 h before TBI modeling by treatment with Miro1 short-interfering RNA. Real-time polymerase chain reaction, western blot, immunofluorescence, adenosine triphosphate (ATP) level assay, neuronal apoptosis, brain water content measurement, and neurological score analyses were carried out. Our results showed that the mRNA and protein levels of Miro1 were increased after TBI and co-localized with neurons and astrocytes in the peri-injury cortex. Moreover, Miro1 knockdown further exacerbated neuronal apoptosis, brain edema, and neurological deficits at 48 h after TBI, accompanied by impaired mitochondrial transport, reduction of mitochondria number and energy deficiency. Additionally, the apoptosis-related factors Bax upregulation and Bcl-2 downregulation as Miro1 knockdown after TBI implied that antiapoptotic effects on neuroprotection of Miro1, which were verified by the Fluoro-Jade C (FJC) staining and TUNEL staining. In conclusion, these findings suggest that Miro1 probably plays a neuroprotective role against secondary brain injury through the mitochondria trafficking pathway, suggesting that enhancing Miro1 might be a new strategy for the treatment of TBI.

Keywords:  Miro1; apoptosis; mitochondrial trafficking; neuroprotection; traumatic brain injury

DOI:  https://doi.org/10.1016/j.brainres.2021.147685
Mol Neurobiol. 2021 Oct 13.

Lactate and Pyruvate Activate Autophagy and Mitophagy that Protect Cells in Toxic Model of Parkinson's Disease.

Evgeniya I Fedotova, Ludmila P Dolgacheva, Andrey Y Abramov, Alexey V Berezhnov.

  Intracellular quality control regulated by autophagy process is important for maintenance of cellular homeostasis. Deregulation of autophagy and more specifically mitophagy leads to accumulation of the misfolded proteins and damaged mitochondria that in turn leads to the cell loss. Alteration of autophagy and mitophagy has shown to be involved in the number of disorders including neurodegenerative diseases. Autophagy and mitophagy could be activated by short-time acidification of the cytosol; however, most of the compounds which can induce it are toxic. Here, we tested several organic compounds which are involved in cellular metabolism on their ability to change intracellular pH and induce mitophagy/autophagy. We have found that lactate and pyruvate are able to reduce intracellular pH in non-toxic concentrations. Short-term (2 h) and long-term (24 h) incubation of the cells with lactate and pyruvateinduced mitophagy and autophagy. Incubation of the SH-SY5Y cells or primary neurons and astrocytes with lactate or pyruvate also activated mitophagy and autophagy after MPP + treatment that led to recovery of mitochondrial function and protection of these cells against apoptotic and necrotic death. Thus, pyruvate- or lactate-induced acidification of cytosol activates cell protective mitophagy and autophagy.

Keywords:  Autophagy; Intracellular pH; MPP + ; Mitophagy; Parkinson’s model; Pyruvate

DOI:  https://doi.org/10.1007/s12035-021-02583-8
Biomed Pharmacother. 2021 Nov;pii: S0753-3322(21)01020-9. [Epub ahead of print]143 112236

Antioxidant properties of flavonoid metal complexes and their potential inclusion in the development of novel strategies for the treatment against neurodegenerative diseases.

Esteban Rodríguez-Arce, Marianela Saldías.

  The increased oxidative stress in the acceleration of the aging process and development of the neuronal disorder are the common feature detected in neurodegenerative illness, such as Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Searching for new treatment against these diseases, the inclusion of exogenous antioxidant agents has shown good results. Flavonoids are polyphenols compounds present in plants, fruits and vegetables that exhibit potent antioxidant and biological properties, which are related to their chemical structure that to confer an excellent radical scavenging ability. The design of metal-flavonoid complexes allows to obtain compounds with improved biological and physicochemical properties, generating important increase of the flavonoid antioxidant properties. This evidence we motive to propose that antioxidant properties of the metal flavonoids compounds can play an important role in the design of potential novel therapeutic strategies. This review presents the structure-activity relationship on the antioxidant properties of three series of metal-flavonoid complexes: M-(quercetin), M-(morin), and M-(rutin). In general, we observed that the coordination sites, the metal ion type used, and the molar ratio metal:flavonoid present in the complexes, are important factors for to increase the antioxidant activity. On these evidences we motive to propose that the development of metal-flavonoid compounds is a potentially viable approach for combating neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Antioxidant; Flavonoid metal complexes; Flavonoids; Neurodegenerative disease; Oxidative stress; Parkinson’s disease; Radical scavenging

DOI:  https://doi.org/10.1016/j.biopha.2021.112236
iScience. 2021 Oct 22. 24(10): 103153

Molecular mechanism of interactions between ACAD9 and binding partners in mitochondrial respiratory complex I assembly.

Chuanwu Xia, Baoying Lou, Zhuji Fu, Al-Walid Mohsen, Anna L Shen, Jerry Vockley, Jung-Ja P Kim.

  The dual function protein ACAD9 catalyzes α,β-dehydrogenation of fatty acyl-CoA thioesters in fatty acid β-oxidation and is an essential chaperone for mitochondrial respiratory complex I (CI) assembly. ACAD9, ECSIT, and NDUFAF1 interact to form the core mitochondrial CI assembly complex. Current studies examine the molecular mechanism of ACAD9/ECSIT/NDUFAF1interactions. ACAD9 binds to the carboxy-terminal half and NDUFAF1 to the amino-terminal half of ECSIT. Binary complexes are unstable and aggregate easily, while the ACAD9/ECSIT/NDUFAF1 ternary complex is soluble and highly stable. Molecular modeling and small-angle X-ray scattering studies identified intra-complex interaction sites and binding sites for other assembly factors. Binding of ECSIT at the ETF binding site in the amino-terminal domain of ACAD9 is consistent with observed loss of FAD and enzymatic activity and demonstrates that the two functions of ACAD9 are mutually exclusive. Mapping of 42 known pathogenic mutations onto the homology-modeled ACAD9 structure provides structural insights into pathomechanisms of CI deficiency.

Keywords:  Biological sciences; Molecular biology; Structural biology

DOI:  https://doi.org/10.1016/j.isci.2021.103153
Circulation. 2021 Oct 14.

Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Edoardo Bertero, Alexander Nickel, Michael Kohlhaas, Mathias Hohl, Vasco Sequeira, Carolin Brune, Julia Schwemmlein, Marco Abeßer, Kai Schuh, Ilona Kutschka, Christopher Carlein, Kai Münker, Sarah Atighetchi, Andreas Müller, Andrey Kazakov, Reinhard Kappl, Karina von der Malsburg, Martin van der Laan, Anna-Florentine Schiuma, Michael Böhm, Ulrich Laufs, Markus Hoth, Peter Rehling, Michaela Kuhn, Jan Dudek, Alexander von der Malsburg, Leticia Prates Roma, Christoph Maack.

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Since mitochondrial function and ROS formation are regulated by excitation-contraction (EC) coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared to wild-type (WT) littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. EC coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. Results: Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, partly compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+ ATPase (SERCA). Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter (MCU) protein that prevented Ca2+-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export via the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Conclusions: Downregulation of MCU, increased myofilament Ca2+ affinity, and preactivated SERCA provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.053755