bims-mitmed 2022-08-14 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–08–14
27 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Cooperative assembly of the mitochondrial respiratory chain.
High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.
Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.
Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function.
Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.
NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson's Disease.
Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders.
Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.
mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.
Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.
Reduced VDAC1, Maintained Mitochondrial Dynamics and Enhanced Mitochondrial Biogenesis in a Transgenic Tau Mouse Model of Alzheimer's Disease.
An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia.
Lipid droplets promote efficient mitophagy.
Come on mtDNA, light my fire.
Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints.
Different platforms for mitomiRs in mitochondria: Emerging facets in regulation of mitochondrial functions.
Impaired mitochondria promote aging-associated sebaceous gland dysfunction and pathology.
High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.
Intracerebroventricular transplantation of human iPSC-derived neural stem cells (hiPSC-NSCs) into neonatal mice.
OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.
Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease.
The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR.
Clonal hematopoiesis, inflammation, and cardiovascular disorders: a mitochondrial connection.
A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia.
Sirtuins and cognition: implications for learning and memory in neurological disorders.
The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.
Identification of two novel variants of BCS1L gene in a patient with classical GRACILE syndrome.

Trends Biochem Sci. 2022 Aug 09. pii: S0968-0004(22)00187-6. [Epub ahead of print]

Cooperative assembly of the mitochondrial respiratory chain.

Erika Fernández-Vizarra, Cristina Ugalde.

  Deep understanding of the pathophysiological role of the mitochondrial respiratory chain (MRC) relies on a well-grounded model explaining how its biogenesis is regulated. The lack of a consistent framework to clarify the modes and mechanisms governing the assembly of the MRC complexes and supercomplexes (SCs) works against progress in the field. The plasticity model was postulated as an attempt to explain the coexistence of mammalian MRC complexes as individual entities and associated in SC species. However, mounting data accumulated throughout the years question the universal validity of the plasticity model as originally proposed. Instead, as we argue here, a cooperative assembly model provides a much better explanation to the phenomena observed when studying MRC biogenesis in physiological and pathological settings.

Keywords:  assembly factors; cooperative assembly model; mitochondria; plasticity model; respiratory chain organization; supercomplexes

DOI:  https://doi.org/10.1016/j.tibs.2022.07.005
STAR Protoc. 2022 Sep 16. 3(3): 101602

High-content screening of mitochondrial polarization in neural cells derived from human pluripotent stem cells.

Annika Zink, Undine Haferkamp, Annika Wittich, Mathias Beller, Ole Pless, Alessandro Prigione.

  We present a high-content screening (HCS) protocol for quantifying mitochondrial activity in live neural cells from human induced pluripotent stem cells (iPSCs). The assessment is based on mitochondrial membrane potential, which is influenced by the efficiency of mitochondrial bioenergetics. We describe how to perform the analysis using both an HCS platform and the open-source software CellProfiler. The protocol can identify the mitochondrial fitness of human neurons and may be used to carry out high-throughput compound screenings in patient-derived neural cells. For complete details on the use and execution of this protocol, please refer to Lorenz et al. (2017) and Zink et al. (2020).

Keywords:  Cell Biology; Cell-based Assays; Metabolism; Microscopy; Neuroscience; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2022.101602
Mol Metab. 2022 Aug 06. pii: S2212-8778(22)00129-6. [Epub ahead of print] 101560

Nicotinamide riboside alleviates exercise intolerance in ANT1-deficient mice.

Patrick M Schaefer, Jessica Huang, Arrienne Butic, Caroline Perry, Tal Yardeni, Wendy Tan, Ryan Morrow, Joseph A Baur, Douglas C Wallace.

   OBJECTIVE: Mitochondrial disorders are often characterized by muscle weakness and fatigue. Null mutations in the heart-muscle adenine nucleotide translocator isoform 1 (ANT1) of both humans and mice cause cardiomyopathy and myopathy associated with exercise intolerance and muscle weakness. Here we decipher the molecular underpinnings of ANT1-deficiency-mediated exercise intolerance.
METHODS: This was achieved by correlating exercise physiology, mitochondrial function and metabolomics of mice deficient in ANT1 and comparing this to control mice.
RESULTS: We demonstrate a peripheral limitation of skeletal muscle mitochondrial respiration and a reduced complex I respiration in ANT1-deficient mice. Upon exercise, this results in a lack of NAD+ leading to a substrate limitation and stalling of the TCA cycle and mitochondrial respiration, further limiting skeletal muscle mitochondrial respiration. Treatment of ANT1-deficient mice with nicotinamide riboside increased NAD+ levels in skeletal muscle and liver, which increased the exercise capacity and the mitochondrial respiration.
CONCLUSION: Increasing NAD + levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.

Keywords:  Exercise; Mitochondrial disorder; NAD(+)/NADH; Nicotinamide riboside

DOI:  https://doi.org/10.1016/j.molmet.2022.101560
FEBS J. 2022 Aug 13.

Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function.

Harrison Burgin, Alice J Sharpe, Shuai Nie, Mark Ziemann, Jordan J Crameri, Diana Stojanovski, James Pitt, Akira Ohtake, Kei Murayama, Matthew McKenzie.

  Short chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short chain enoyl-CoA esters to short chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell 'knockout' model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 'knockout' cells showed reductions in key mitochondrial pathways, including the TCA cycle, receptor mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 'knockout' cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 'knockout' cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2 , complex IV, complex V and supercomplexes CIII2 /CIV and CI/CIII2 /CIV), which were associated with a defect in complex I assembly. Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2 , CIV, CV and the CI/CIII2 /CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.

Keywords:  ECHS1 deficiency; OXPHOS; fatty acid oxidation; mitochondria; mitochondrial disease; short chain enoyl-CoA hydratase

DOI:  https://doi.org/10.1111/febs.16595
Mol Neurobiol. 2022 Aug 13.

Mitofusin 2 Integrates Mitochondrial Network Remodelling, Mitophagy and Renewal of Respiratory Chain Proteins in Neurons after Oxygen and Glucose Deprivation.

Piotr Wojtyniak, Anna Boratynska-Jasinska, Karolina Serwach, Joanna Gruszczynska-Biegala, Barbara Zablocka, Jacek Jaworski, Maria Kawalec.

  In attempts to develop effective therapeutic strategies to limit post-ischemic injury, mitochondria emerge as a key element determining neuronal fate. Mitochondrial damage can be alleviated by various mechanisms including mitochondrial network remodelling, mitochondrial elimination and mitochondrial protein biogenesis. However, the mechanisms regulating relationships between these phenomena are poorly understood. We hypothesized that mitofusin 2 (Mfn2), a mitochondrial GTPase involved in mitochondrial fusion, mitochondria trafficking and mitochondria and endoplasmic reticulum (ER) tethering, may act as one of linking and regulatory factors in neurons following ischemic insult. To verify this assumption, we performed temporal oxygen and glucose deprivation (OGD/R) on rat cortical primary culture to determine whether Mfn2 protein reduction affected the onset of mitophagy, subsequent mitochondrial biogenesis and thus neuronal survival. We found that Mfn2 knockdown increased neuronal susceptibility to OGD/R, prevented mitochondrial network remodelling and resulted in prolonged mitophagosomes formation in response to the insult. Next, Mfn2 knockdown was observed to be accompanied by reduced Parkin protein levels and increased Parkin accumulation on mitochondria. As for wild-type neurons, OGD/R insult was followed by an elevated mtDNA content and an increase in respiratory chain proteins. Neither of these phenomena were observed for Mfn2 knockdown neurons. Collectively, our findings showed that Mfn2 in neurons affected their response to mild and transient OGD stress, balancing the extent of defective mitochondria elimination and positively influencing mitochondrial respiratory protein levels. Our study suggests that Mfn2 is one of essential elements for neuronal response to ischemic insult, necessary for neuronal survival.

Keywords:  Brain ischemia; Mitochondria; Mitochondrial DNA; Mitochondrial biogenesis; Mitofusin 2; Mitophagy; Primary neurons

DOI:  https://doi.org/10.1007/s12035-022-02981-6
Cells. 2022 Aug 04. pii: 2416. [Epub ahead of print]11(15):

NADPH and Mitochondrial Quality Control as Targets for a Circadian-Based Fasting and Exercise Therapy for the Treatment of Parkinson's Disease.

William M Curtis, William A Seeds, Mark P Mattson, Patrick C Bradshaw.

  Dysfunctional mitochondrial quality control (MQC) is implicated in the pathogenesis of Parkinson's disease (PD). The improper selection of mitochondria for mitophagy increases reactive oxygen species (ROS) levels and lowers ATP levels. The downstream effects include oxidative damage, failure to maintain proteostasis and ion gradients, and decreased NAD+ and NADPH levels, resulting in insufficient energy metabolism and neurotransmitter synthesis. A ketosis-based metabolic therapy that increases the levels of (R)-3-hydroxybutyrate (BHB) may reverse the dysfunctional MQC by partially replacing glucose as an energy source, by stimulating mitophagy, and by decreasing inflammation. Fasting can potentially raise cytoplasmic NADPH levels by increasing the mitochondrial export and cytoplasmic metabolism of ketone body-derived citrate that increases flux through isocitrate dehydrogenase 1 (IDH1). NADPH is an essential cofactor for nitric oxide synthase, and the nitric oxide synthesized can diffuse into the mitochondrial matrix and react with electron transport chain-synthesized superoxide to form peroxynitrite. Excessive superoxide and peroxynitrite production can cause the opening of the mitochondrial permeability transition pore (mPTP) to depolarize the mitochondria and activate PINK1-dependent mitophagy. Both fasting and exercise increase ketogenesis and increase the cellular NAD+/NADH ratio, both of which are beneficial for neuronal metabolism. In addition, both fasting and exercise engage the adaptive cellular stress response signaling pathways that protect neurons against the oxidative and proteotoxic stress implicated in PD. Here, we discuss how intermittent fasting from the evening meal through to the next-day lunch together with morning exercise, when circadian NAD+/NADH is most oxidized, circadian NADP+/NADPH is most reduced, and circadian mitophagy gene expression is high, may slow the progression of PD.

Keywords:  DJ-1; IDH1; NAD; NADPH; PINK1; Parkin; Parkinson’s disease; circadian; coffee; exercise; fasting; metabolic therapy; mitochondrial biogenesis; mitochondrial quality control; mitophagy; nicotinamide adenine dinucleotide; nicotinamide adenine dinucleotide phosphate

DOI:  https://doi.org/10.3390/cells11152416
Cells. 2022 Aug 01. pii: 2364. [Epub ahead of print]11(15):

Mitochondrial Damage-Associated Molecular Patterns Content in Extracellular Vesicles Promotes Early Inflammation in Neurodegenerative Disorders.

Cláudia M Deus, Henrique Tavares, Margarida Beatriz, Sandra Mota, Carla Lopes.

  Neuroinflammation is a common hallmark in different neurodegenerative conditions that share neuronal dysfunction and a progressive loss of a selectively vulnerable brain cell population. Alongside ageing and genetics, inflammation, oxidative stress and mitochondrial dysfunction are considered key risk factors. Microglia are considered immune sentinels of the central nervous system capable of initiating an innate and adaptive immune response. Nevertheless, the pathological mechanisms underlying the initiation and spread of inflammation in the brain are still poorly described. Recently, a new mechanism of intercellular signalling mediated by small extracellular vesicles (EVs) has been identified. EVs are nanosized particles (30-150 nm) with a bilipid membrane that carries cell-specific bioactive cargos that participate in physiological or pathological processes. Damage-associated molecular patterns (DAMPs) are cellular components recognised by the immune receptors of microglia, inducing or aggravating neuroinflammation in neurodegenerative disorders. Diverse evidence links mitochondrial dysfunction and inflammation mediated by mitochondrial-DAMPs (mtDAMPs) such as mitochondrial DNA, mitochondrial transcription factor A (TFAM) and cardiolipin, among others. Mitochondrial-derived vesicles (MDVs) are a subtype of EVs produced after mild damage to mitochondria and, upon fusion with multivesicular bodies are released as EVs to the extracellular space. MDVs are particularly enriched in mtDAMPs which can induce an immune response and the release of pro-inflammatory cytokines. Importantly, growing evidence supports the association between mitochondrial dysfunction, EV release and inflammation. Here, we describe the role of extracellular vesicles-associated mtDAMPS in physiological conditions and as neuroinflammation activators contributing to neurodegenerative disorders.

Keywords:  extracellular vesicles; inflammation; mitochondrial damage-associated molecular patterns; neurodegenerative disorders

DOI:  https://doi.org/10.3390/cells11152364
Hum Mol Genet. 2022 Aug 10. pii: ddac190. [Epub ahead of print]

Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.

Zhipeng Nie, Chenhui Wang, Jiarong Chen, Yanchun Ji, Hongxing Zhang, Fuxin Zhao, Xiangtian Zhou, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease that results from degeneration of retinal ganglion cells (RGC). Mitochondrial ND4 11778G > A mutation, which affects structural components of complex I, is the most prevalent LHON-associated mitochondrial DNA (mtDNA) mutation worldwide. The m.11778G > A mutation is the primary contributor underlying the development of LHON and X-linked PRICKLE3 allele (c.157C > T, p.Arg53Trp) linked to biogenesis of ATPase interacts with m.11778G > A mutation to cause LHON. However, the lack of appropriate cell and animal models of LHON has been significant obstacles for deep elucidation of disease pathophysiology, specifically the tissue specific effects. Using RGC-like cells differentiated from induced pluripotent stem cells (iPSCs) from members of one Chinese family (asymptomatic subjects carrying only m.11778G > A mutation or PRICKLE3 p.Arg53Trp mutation, symptomatic individuals bearing both m.11778G > A and PRICKLE3 p.Arg53Trp mutations and control lacking these mutations), we demonstrated the deleterious effects of mitochondrial dysfunctions on the morphology and functions of RGCs. Notably, iPSCs bearing only m.11778G > A or p.Arg53Trp mutation exhibited mild defects in differentiation to RGC-like cells. The RGC-like cells carrying only m.11778G > A or p.Arg53Trp mutation displayed mild defects in RGC morphology, including the area of soma and numbers of neurites, electrophysiological properties, ATP production and apoptosis. Strikingly, those RGC-like cells derived from symptomatic individuals harboring both m.11778G > A and p.Arg53Trp mutations displayed greater defects in the development, morphology and functions than those in cells bearing single mutation. These findings provide new insights into pathophysiology of LHON arising from RGC deficiencies caused by synergy between m.11778G > A and PRICKLE3 p.Arg53Trp mutation.

DOI: https://doi.org/10.1093/hmg/ddac190
Curr Neuropharmacol. 2022 Aug 10.

mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases.

Dehao Shang, Minghao Huang, Biyao Wang, Xu Yan, Zhou Wu, Xinwen Zhang.

  Considerable evidence indicates that the semiautonomous organelles mitochondria play key roles in the progression of many neurodegenerative disorders. Mitochondrial DNA (mtDNA) encodes components of the OXPHOS complex but mutated mtDNA accumulates in cells with aging, which mirrors the increased prevalence of neurodegenerative diseases. This accumulation stems not only from the misreplication of mtDNA and the highly oxidative environment but also from defective mitophagy after fission. In this review, we focus on several pivotal mitochondrial proteins related to mtDNA maintenance (such as ATAD3A and TFAM), mtDNA alterations including mtDNA mutations, mtDNA elimination, and mtDNA release-activated inflammation to understand the crucial role played by mtDNA in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Our work outlines novel therapeutic strategies for targeting mtDNA.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Huntington’s disease; Mitochondrial DNA (mtDNA); Mitophagy; Parkinson’s disease; Reactive oxygen species (ROS)

DOI:  https://doi.org/10.2174/1570159X20666220810114644
Front Physiol. 2022 ;13 898792

Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle.

Juan Diego Hernández-Camacho, Daniel J M Fernández-Ayala, Cristina Vicente-García, Ignacio Navas-Enamorado, Guillermo López-Lluch, Clara Oliva, Rafael Artuch, Judith Garcia-Villoria, Antonia Ribes, Rafael de Cabo, Jaime J Carvajal, Plácido Navas.

  ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.

Keywords:  coenzyme Q; fatty acids; food deprivation; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fphys.2022.898792
Int J Mol Sci. 2022 Aug 02. pii: 8561. [Epub ahead of print]23(15):

Reduced VDAC1, Maintained Mitochondrial Dynamics and Enhanced Mitochondrial Biogenesis in a Transgenic Tau Mouse Model of Alzheimer's Disease.

Murali Vijayan, P Hemachandra Reddy.

  Alzheimer's disease (AD) is one of the most common forms of neurodegeneration, defined by reduced cognitive function, which is caused by the gradual death of neurons in the brain. Recent studies have shown an age-dependent rise in the levels of voltage-dependent anion channel 1 (VDAC1) in AD. In addition, we discovered an aberrant interaction between VDAC1 and P-TAU in the brains of AD patients, which led to abnormalities in the structural and functional integrity of the mitochondria. The purpose of our study is to understand the protective effects of reduced VDAC1 against impaired mitochondrial dynamics and defective mitochondrial biogenesis in transgenic TAU mice. Recently, we crossed heterozygote VDAC1 knockout (VDAC1+/-) mice with transgenic TAU mice to obtain double-mutant VDAC1+/-/TAU mice. Our goal was to evaluate whether a partial decrease in VDAC1 lessens the amount of mitochondrial toxicity in transgenic Tau (P301L) mice. We found that mitochondrial fission proteins were significantly reduced, and mitochondrial fusion and biogenesis proteins were increased in double-mutant mice compared to TAU mice. On the basis of these discoveries, the current work may have significance for the development of reduced-VDAC1-based treatments for individuals suffering from AD as well as other tauopathies.

Keywords:  Alzheimer’s disease; biogenesis; fission and fusion; mitochondria; voltage-dependent anion channel 1

DOI:  https://doi.org/10.3390/ijms23158561
Nat Commun. 2022 Aug 09. 13(1): 4655

An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich's ataxia.

Kevin C Kemp, Anastasia Georgievskaya, Kelly Hares, Juliana Redondo, Steven Bailey, Claire M Rice, Neil J Scolding, Chris Metcalfe, Alastair Wilkins.

Friedreich's ataxia (FA) is an inherited progressive neurodegenerative disease for which there is no proven disease-modifying treatment. Here we perform an open-label, pilot study of recombinant human granulocyte-colony stimulating factor (G-CSF) administration in seven people with FA (EudraCT: 2017-003084-34); each participant receiving a single course of G-CSF (Lenograstim; 1.28 million units per kg per day for 5 days). The primary outcome is peripheral blood mononuclear cell frataxin levels over a 19-day period. The secondary outcomes include safety, haematopoietic stem cell (HSC) mobilisation, antioxidant levels and mitochondrial enzyme activity. The trial meets pre-specified endpoints. We show that administration of G-CSF to people with FA is safe. Mobilisation of HSCs in response to G-CSF is comparable to that of healthy individuals. Notably, sustained increases in cellular frataxin concentrations and raised PGC-1α and Nrf2 expression are detected. Our findings show potential for G-CSF therapy to have a clinical impact in people with FA.

DOI: https://doi.org/10.1038/s41467-022-31450-w
Autophagy. 2022 Aug 08. 1-2

Lipid droplets promote efficient mitophagy.

Maeve Long, Thomas G McWilliams.

  Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.

Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy

DOI:  https://doi.org/10.1080/15548627.2022.2089956
Immunity. 2022 Aug 09. pii: S1074-7613(22)00345-4. [Epub ahead of print]55(8): 1331-1333

Come on mtDNA, light my fire.

Grace M E P Lawrence, Caroline L Holley, Kate Schroder.

Oxidized mitochondrial DNA (ox-mtDNA) activates NLRP3 inflammasome signaling through an ill-defined mechanism. In this issue of Immunity, Xian et al. reveal FEN1 endonuclease cleaves ox-mtDNA into fragments that escape mitochondria, igniting NLRP3 and cGAS-STING signaling and inflammation.

DOI: https://doi.org/10.1016/j.immuni.2022.07.011
Mol Neurobiol. 2022 Aug 06.

Integrative Profiling of Amyotrophic Lateral Sclerosis Lymphoblasts Identifies Unique Metabolic and Mitochondrial Disease Fingerprints.

Teresa Cunha-Oliveira, Marcelo Carvalho, Vilma Sardão, Elisabete Ferreiro, Débora Mena, Francisco B Pereira, Fernanda Borges, Paulo J Oliveira, Filomena S G Silva.

  Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with a rapid progression and no effective treatment. Metabolic and mitochondrial alterations in peripheral tissues of ALS patients may present diagnostic and therapeutic interest. We aimed to identify mitochondrial fingerprints in lymphoblast from ALS patients harboring SOD1 mutations (mutSOD1) or with unidentified mutations (undSOD1), compared with age-/sex-matched controls. Three groups of lymphoblasts, from mutSOD1 or undSOD1 ALS patients and age-/sex-matched controls, were obtained from Coriell Biobank and divided into 3 age-/sex-matched cohorts. Mitochondria-associated metabolic pathways were analyzed using Seahorse MitoStress and ATP Rate assays, complemented with metabolic phenotype microarrays, metabolite levels, gene expression, and protein expression and activity. Pooled (all cohorts) and paired (intra-cohort) analyses were performed by using bioinformatic tools, and the features with higher information gain values were selected and used for principal component analysis and Naïve Bayes classification. Considering the group as a target, the features that contributed to better segregation of control, undSOD1, and mutSOD1 were found to be the protein levels of Tfam and glycolytic ATP production rate. Metabolic phenotypic profiles in lymphoblasts from ALS patients with mutSOD1 and undSOD1 revealed unique age-dependent different substrate oxidation profiles. For most parameters, different patterns of variation in experimental endpoints in lymphoblasts were found between cohorts, which may be due to the age or sex of the donor. In the present work, we investigated several metabolic and mitochondrial hallmarks in lymphoblasts from each donor, and although a high heterogeneity of results was found, we identified specific metabolic and mitochondrial fingerprints, especially protein levels of Tfam and glycolytic ATP production rate, that may have a diagnostic and therapeutic interest.

Keywords:  Amyotrophic lateral sclerosis; Bioenergetics; Cellular metabolism; Mitochondria; Superoxide dismutase 1

DOI:  https://doi.org/10.1007/s12035-022-02980-7
Mitochondrion. 2022 Aug 06. pii: S1567-7249(22)00072-1. [Epub ahead of print]

Different platforms for mitomiRs in mitochondria: Emerging facets in regulation of mitochondrial functions.

Dhruv Gohel, Rajesh Singh.

  Mitochondria are one of the central organelles involved in cellular energy metabolism and play a regulatory role in various human pathologies ranging from inborn errors of metabolism, cancer, inflammation, and infections. Mitochondrial DNA encodes limited number of genes that is not sufficient for its optimal functioning. Hence, mitochondria import ∼1500 of proteins and ncRNAs from the nucleus depending on energy requirement of cell, tissue size, complexity and diversity of functions. Mitochondrial outer membrane can serve as a platform for regulation of local translation of nuclear-encoded mRNAs for mitochondrial proteins (nmRNAmp); however, underlying molecular mechanism for translational regulation of nmRNAmp at mitochondria is unexplored. Emerging evidence now suggest that mitochondria are enriched with specific miRNAs known as mitomiRs, which may be nuclear or mitochondrial DNA encoded. MitomiRs may modulate mitochondrial function and metabolism by fine-tuning protein levels related to mitochondria. The discovery of mitomiRs raised the questions of elucidating molecular pathways for their biogenesis, translocation, action sites and mechanism of action. Here, we have reviewed the existing reports describing the role of mitomiRs in sub mitochondrial compartments and discussed possible molecular mechanisms of mitomiRs in the regulation of nmRNAmp and mito-genome encoded transcripts. Further understanding of mitomiRs will uncover their implication in various pathophysiological conditions associated with mitochondria.

Keywords:  Ago2; Mitochondria; MitomiRs; RISC; nmRNAmp

DOI:  https://doi.org/10.1016/j.mito.2022.08.003
Am J Pathol. 2022 Aug 07. pii: S0002-9440(22)00214-0. [Epub ahead of print]

Impaired mitochondria promote aging-associated sebaceous gland dysfunction and pathology.

Noha S Ahmed, Jeremy B Foote, Keshav K Singh.

  Mitochondrial dysfunction is one of the hallmarks of aging. Changes in sebaceous gland function and sebum production have been reported during aging. Here we report the direct effects of mitochondrial dysfunction on sebaceous gland morphology and function. We utilized a mitochondrial DNA depleter mouse as a model for introducing mitochondrial dysfunction in the whole animal. We characterized the effects on skin sebaceous glands and modified sebaceous glands of the eyelid, lip, clitoral and preputial glands. The mtDNA depleter mice show gross morphologic and histopathologic changes in sebaceous glands associated with increased infiltration by mast cells, neutrophils, and polarized macrophages. Consistently, there was increased expression of proinflammatory cytokines. The inflammatory changes were associated with abnormal sebocyte accumulation of lipid, defective sebum delivery at the skin surface, and the upregulation of key lipogenesis regulating genes and androgen receptor. The mitochondrial DNA depleter mice expressed aging-associated senescent marker. We also observed increased sebocyte proliferation and aberrant expression of stem cell markers. These studies provide for the first time a causal link between mitochondrial dysfunction and abnormal sebocyte function within sebaceous and modified sebaceous glands throughout the whole body of the animal. Our studies suggest that mitochondrial DNA depleter mouse may serve as a novel tool to develop targeted therapeutics to address sebaceous gland disorders in aging humans.

Keywords:  Aging; Inflammation; Mitochondrial DNA; Mitochondrial dysfunction; Modified sebaceous glands; Sebaceous glands

DOI:  https://doi.org/10.1016/j.ajpath.2022.07.006
Geroscience. 2022 Aug 10.

High-throughput sequencing analysis of nuclear-encoded mitochondrial genes reveals a genetic signature of human longevity.

Brenda Gonzalez, Archana Tare, Seungjin Ryu, Simon C Johnson, Gil Atzmon, Nir Barzilai, Matt Kaeberlein, Yousin Suh.

  Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.

Keywords:  Aging; Centenarian; Genetic variant; Longevity; Mitochondria

DOI:  https://doi.org/10.1007/s11357-022-00634-z
Methods Cell Biol. 2022 ;pii: S0091-679X(22)00054-1. [Epub ahead of print]171 127-147

Intracerebroventricular transplantation of human iPSC-derived neural stem cells (hiPSC-NSCs) into neonatal mice.

Marco Luciani, Chiara Garsia, Elisabeth Mangiameli, Vasco Meneghini, Angela Gritti.

  Human neural stem cells (hNSCs) hold great promises for the development of cell-based therapies for neurodegenerative diseases, given their capability to provide immunomodulatory and trophic support and to replace, to a limited extent, damaged, or lost cells. Human NSCs are under clinical evaluation for the treatment of several neurodegenerative diseases. Still, issues related to the large-scale production of clinical-grade fetal hNSCs and their allogeneic nature-requiring immunosuppressive regimens-have hampered their full exploitation as therapeutics. NSCs derived from human induced pluripotent stem cells (hiPSCs) provide a valuable alternative to fetal hNSCs since they can be generated from autologous or HLA-matched donors expanded for large-scale clinical-grade production, and are amenable for gene addition/gene editing strategies, thus potentially addressing CNS diseases of genetic origin. The prospective use of hiPSC-derived NSCs (hiPSC-NSCs) for CNS-directed therapies demands a careful evaluation of the efficacy and safety of these cell populations in animal models. Here, we describe a protocol for the transplantation and phenotypical characterization of hiPSC-NSCs in neonatal immunodeficient mice. This protocol is relevant to assessing the safety and the efficacy of hiPSC-NSC transplantation to target early-onset neurodegenerative or demyelinating CNS diseases.

Keywords:  Cell differentiation; Cell engraftment; Cell therapy; Human iPSCs; Intracerebral transplantation; Neonatal injection; Neural stem cells

DOI:  https://doi.org/10.1016/bs.mcb.2022.04.007
Trends Endocrinol Metab. 2022 Aug 06. pii: S1043-2760(22)00134-5. [Epub ahead of print]

OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle.

John Noone, Donal J O'Gorman, Helena C Kenny.

  The mitochondria are double-membrane organelles integral for energy metabolism. Mitochondrial dynamics is regulated by inner and outer mitochondrial membrane (IMM and OMM) proteins, which promote fission and fusion. Optic atrophy 1 (OPA1) regulates IMM fusion, prevents apoptosis, and is a key regulator of morphological change in skeletal and cardiac muscle physiology and pathophysiology. OPA1 fuses the inner membranes of adjacent mitochondria, allowing for an increase in oxidative phosphorylation (OXPHOS). Considering the importance of energy metabolism in whole-body physiology, OPA1 and its regulators have been proposed as novel targets for the treatment of skeletal muscle atrophy and heart failure. Here, we review the role and regulation of OPA1 in skeletal muscle and cardiac pathophysiology, epitomizing its critical role in the cell.

Keywords:  exercise; heart; metabolism; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2022.07.003
Cell Mol Neurobiol. 2022 Aug 11.

Targeting Mitochondria as a Therapeutic Approach for Parkinson's Disease.

Maryam Abrishamdar, Maryam Sadat Jalali, Yaghoob Farbood.

  Neurodegeneration is among the most critical challenges that involve modern societies and annually influences millions of patients worldwide. While the pathophysiology of Parkinson's disease (PD) is complicated, the role of mitochondrial is demonstrated. The in vitro and in vivo models and genome-wide association studies in human cases proved that specific genes, including PINK1, Parkin, DJ-1, SNCA, and LRRK2, linked mitochondrial dysfunction with PD. Also, mitochondrial DNA (mtDNA) plays an essential role in the pathophysiology of PD. Targeting mitochondria as a therapeutic approach to inhibit or slow down PD formation and progression seems to be an exciting issue. The current review summarized known mutations associated with both mitochondrial dysfunction and PD. The significance of mtDNA in Parkinson's disease pathogenesis and potential PD therapeutic approaches targeting mitochondrial dysfunction was then discussed.

Keywords:  Mitochondrial dysfunction; Neurodegeneration; Parkinson’s disease

DOI:  https://doi.org/10.1007/s10571-022-01265-w
Mol Metab. 2022 Aug 05. pii: S2212-8778(22)00135-1. [Epub ahead of print] 101566

The mitochondrial fission protein Drp1 in liver is required to mitigate NASH and prevents the activation of the mitochondrial ISR.

Janos Steffen, Jennifer Ngo, Sheng-Ping Wang, Kevin Williams, Henning F Kramer, George Ho, Carlos Rodriguez, Krishna Yekkala, Chidozie Amuzie, Russell Bialecki, Lisa Norquay, Andrea R Nawrocki, Mark Erion, Alessandro Pocai, Orian S Shirihai, Marc Liesa.

   OBJECTIVE: The mitochondrial fission protein Drp1 was proposed to promote NAFLD, as inhibition of hepatocyte Drp1 early in life prevents liver steatosis induced by high-fat diet in mice. However, whether Drp1-knockdown in older mice can reverse established NASH is unknown.
METHODS: N-acetylgalactosamine-siRNA conjugates, an FDA approved method to deliver siRNA selectively to hepatocytes, were used to knockdown hepatocyte-Drp1 in mice (NAG-Drp1si). NASH was induced in C57BL/6NTac mice by Gubra-Amylin-NASH diet (D09100310, 40% fat, 22% fructose and 2% cholesterol) and treatment with NAG-Drp1si was started at week 24 of diet. Circulating transaminases, liver histology, gene expression of fibrosis and inflammation markers, and hydroxyproline synthesis determined NASH severity. Liver NEFA and triglycerides were quantified by GC/MS. Mitochondrial function was determined by respirometry. Western blots of OMA1, OPA1, p-eIF2α, as well as transcriptional analyses of Atf4-regulated genes determined ISR engagement.
RESULTS: NAG-Drp1si treatment decreased body weight and induced liver inflammation in adult healthy mice. Increased hepatic Gdf15 production was the major contributor to body-weight loss caused by NAG-Drp1si treatment, as Gdf15 receptor deletion (Gfral KO) prevented the decrease in food intake and mitigated weight loss. NAG-Drp1si activated the Atf4-controlled integrated stress response (ISR) to increase hepatic Gdf15 expression. NAG-Drp1si in healthy mice caused ER stress and activated the mitochondrial protease Oma1, which are the ER and mitochondrial triggers that activate the Atf4-controlled ISR. Remarkably, induction of NASH was not sufficient to activate Oma1 in liver. However, NAG-Drp1si treatment was sufficient to activate Oma1 in adult mice with NASH, as well as exacerbating NASH-induced ER stress. Consequently, NAG-Drp1si treatment in mice with NASH led to higher ISR activation, exacerbated inflammation, fibrosis and necrosis.
CONCLUSION: Drp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation and ISR exacerbation. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to liver when mitochondria are misfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.

Keywords:  Atf4; Drp1; ISR; NASH; Oma1; mitochondria

DOI:  https://doi.org/10.1016/j.molmet.2022.101566
Trends Immunol. 2022 Aug 06. pii: S1471-4906(22)00158-2. [Epub ahead of print]

Clonal hematopoiesis, inflammation, and cardiovascular disorders: a mitochondrial connection.

Francesco Pileri, Gioacchino Natoli.

Mutations in two antagonistic regulators of DNA methylation, DNMT3A and TET2, are associated with clonal hematopoiesis and increased risk of cardiovascular disorders. Recently, Cobo et al. traced the mechanistic bases for such links to loss of mitochondrial integrity, cytoplasmic dispersion of mitochondrial DNA, and the subsequent activation of interferon-stimulated genes (ISGs) in macrophages.

DOI: https://doi.org/10.1016/j.it.2022.07.009
Neurol Genet. 2022 Oct;8(5): e200004

A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia.

Flavia Palombo, Chiara La Morgia, Claudio Fiorini, Leonardo Caporali, Maria Lucia Valentino, Vincenzo Donadio, Rocco Liguori, Valerio Carelli.

Background and Objectives: To date, approximately 20 heterozygous mainly loss-of-function variants in KCND3 have been associated with spinocerebellar ataxia (SCA) type 19 and 22, a clinically heterogeneous group of neurodegenerative disorders. We aimed at reporting the second patients with the V374A KCND3 mutation from an independent family, confirming its pathogenic role.
Methods: We describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing.
Results: This male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121T>C [p.V374A] mutation in KCND3.
Discussion: This report consolidates the pathogenicity of the V374A KCND3 mutation and suggests that the ataxic paroxysmal exacerbations are not a key phenotypic feature of this mutation.

DOI: https://doi.org/10.1212/NXG.0000000000200004
Front Physiol. 2022 ;13 908689

Sirtuins and cognition: implications for learning and memory in neurological disorders.

Eric Fagerli, Iris Escobar, Fernando J Ferrier, Charles W Jackson, Efrain J Perez-Lao, Miguel A Perez-Pinzon.

  Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD+ -dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection. More recently, sirtuins have been shown to play a role in normal physiological cognitive function, and aberrant sirtuin function is seen in pathological cellular states. Sirtuins are believed to play a role in cognition through enhancing synaptic plasticity, influencing epigenetic regulation, and playing key roles in molecular pathways involved with oxidative stress affecting mitochondrial function. This review aims to discuss recent advances in the understanding of the role of mammalian sirtuins in cognitive function and the therapeutic potential of targeting sirtuins to ameliorate cognitive deficits in neurological disorders.

Keywords:  Alzheimer’s disease; cognition; epigenetics; ischemia; memory; oxidative stress; sirtuins; synaptic plasticity

DOI:  https://doi.org/10.3389/fphys.2022.908689
Metabolism. 2022 Aug 04. pii: S0026-0495(22)00153-6. [Epub ahead of print]135 155275

The mitochondrial NAD+ transporter SLC25A51 is a fasting-induced gene affecting SIRT3 functions.

Zhiyao Fu, Hyunbae Kim, Paul T Morse, Mu-Jie Lu, Maik Hüttemann, Xiaolu A Cambronne, Kezhong Zhang, Ren Zhang.

   INTRODUCTION: Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism and energy production. NAD+-dependent deacetylase sirtuin 3 (SIRT3) regulates the acetylation levels of mitochondrial proteins that are involved in mitochondrial homeostasis. Fasting up-regulates hepatic SIRT3 activity, which requires mitochondrial NAD+. What is the mechanism, then, to transport more NAD+ into mitochondria to sustain enhanced SIRT3 activity during fasting?
OBJECTIVE: SLC25A51 is a recently discovered mitochondrial NAD+ transporter. We tested the hypothesis that, during fasting, increased expression of SLC25A51 is needed for enhanced mitochondrial NAD+ uptake to sustain SIRT3 activity. Because the fasting-fed cycle and circadian rhythm are closely linked, we further tested the hypothesis that SLC25A51 is a circadian regulated gene.
METHODS: We examined Slc25a51 expression in the liver of fasted mice, and examined its circadian rhythm in wild-type mice and those with liver-specific deletion of the clock gene BMAL1 (LKO). We suppressed Slc25a51 expression in hepatocytes and the mouse liver using shRNA-mediated knockdown, and then examined mitochondrial NAD+ levels, SIRT3 activities, and acetylation levels of SIRT3 target proteins (IDH2 and ACADL). We measured mitochondrial oxygen consumption rate using Seahorse analysis in hepatocytes with reduced Slc25a51 expression.
RESULTS: We found that fasting induced the hepatic expression of Slc25a51, and its expression showed a circadian rhythm-like pattern that was disrupted in LKO mice. Reduced expression of Slc25a51 in hepatocytes decreased mitochondrial NAD+ levels and SIRT3 activity, reflected by increased acetylation of SIRT3 targets. Slc25a51 knockdown reduced the oxygen consumption rate in intact hepatocytes. Mice with reduced Slc25a51 expression in the liver manifested reduced hepatic mitochondrial NAD+ levels, hepatic steatosis and hypertriglyceridemia.
CONCLUSIONS: Slc25a51 is a fasting-induced gene that is needed for hepatic SIRT3 functions.

Keywords:  Mitochondria; NAD; SIRT3; SLC25A51

DOI:  https://doi.org/10.1016/j.metabol.2022.155275
Nephrology (Carlton). 2022 Aug 12.

Identification of two novel variants of BCS1L gene in a patient with classical GRACILE syndrome.

Wencong Guo, Yingfei Shao, Yanhua Lang, Hong Wang, Yi Lin, Xuyan Liu, Ruixiao Zhang, Leping Shao.

  BCS1L pathogenic variants cause widely different clinical phenotypes. Disease phenotypes can be as mild as Björnstad syndrome, characterized by pili torti (abnormal flat twisted hair shafts) and sensorineural hearing loss, or as severe as GRACILE syndrome, characterized by growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. BCS1L pathogenic variants are also linked to an undefined complex III deficiency, a heterogeneous condition generally involving renal and hepatic pathologies, hypotonia, and developmental delays. So far, all patients with GRACILE syndrome carry a homozygous p.Ser78Gly variant in BCS1L gene by reviewing articles. A 24-day-old boy presented with typical clinical phenotype of GRACILE syndrome. The Whole Exome Sequencing confirmed that the patient had a missense variant (c.245C>T, p.Ser82Leu) and a small deletion (c.231_232delCA, p. Ser78Cysfs*9) in BCS1L gene inherited from his father and mother separately, he died at 5 months of age. We reported a patient with GRACILE syndrome and identified two novel variants in BCS1L gene. Our study expands the mutational spectrum of BCS1L gene associated with GRACILE syndrome and will be beneficial for genetic diagnosis. This article is protected by copyright. All rights reserved.

Keywords:  Acidosis, Lactic; BCS1L gene, Finnish lethal neonatal metabolic syndrome (GRACILE Syndrome); Fanconi syndrome; Fetal Growth Retardation

DOI:  https://doi.org/10.1111/nep.14086