bims-mitmed 2022-09-25 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2022–09–25
thirty papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.
Mitochondrial quality control mechanisms as molecular targets in diabetic heart.
RNA-based generation of iPSCs from a boy carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 and from his healthy mother.
Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.
Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.
Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders.
ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.
Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study.
The phenotypic spectrum of COX20-associated mitochondrial disorder.
Oocyte mitophagy is critical for extended reproductive longevity.
Sleep and Breathing Disturbances in Children With Leigh Syndrome: A Comparative Study.
Binding of Natural Inhibitors to Respiratory Complex I.
Could Amyloid-β 1-42 or α-Synuclein Interact Directly with Mitochondrial DNA? A Hypothesis.
Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.
Modeling Human Organ Development and Diseases With Fetal Tissue-Derived Organoids.
Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.
Endurance Training Increases the Running Performance of Untrained Men without Changing the Mitochondrial Volume Density in the Gastrocnemius Muscle.
Protocol to detect in vitro and in cell ubiquitylation of mitochondrial DNA polymerase gamma by mitochondrial E3 ligase MITOL.
Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis.
A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.
The inherited cerebellar ataxias: an update.
Mitochondria as the memory of preconditioning.
A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia.
Enhancing oxidative phosphorylation over glycolysis for energy production in cultured mesenchymal stem cells.
Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies.
Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders.
Maternal and Fetal PI3K-p110α Deficiency Induces Sex-Specific Changes in Conceptus Growth and Placental Mitochondrial Bioenergetic Reserve in Mice.
Enhancement of liver mitochondrial complex I and energy metabolism induced by enteritis: The key role of gut microbiota derived endotoxins.
Metabolic Profile Variations along the Differentiation of Human-Induced Pluripotent Stem Cells to Dopaminergic Neurons.
A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.

Mol Psychiatry. 2022 Sep 21.

Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.

Brendan Miller, Su-Jeong Kim, Hemal H Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Joan Vaughan, Jolene Diedrich, Alan Saghatelian, Thalida E Arpawong, Eileen M Crimmins, Nilüfer Ertekin-Taner, Meral A Tubi, Evan T Hare, Meredith N Braskie, Léa Décarie-Spain, Scott E Kanoski, Francine Grodstein, David A Bennett, Lu Zhao, Arthur W Toga, Junxiang Wan, Kelvin Yen, Pinchas Cohen.

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins.

DOI: https://doi.org/10.1038/s41380-022-01769-3
Metabolism. 2022 Sep 17. pii: S0026-0495(22)00191-3. [Epub ahead of print] 155313

Mitochondrial quality control mechanisms as molecular targets in diabetic heart.

Xing Chang, Yukun Li, Chen Cai, Feng Wu, Jing He, Yaoyuan Zhang, Jiankai Zhong, Ying Tan, Ruxiu Liu, Hang Zhu, Hao Zhou.

  Mitochondrial dysfunction has been regarded as a hallmark of diabetic cardiomyopathy. In addition to their canonical metabolic actions, mitochondria influence various other aspects of cardiomyocyte function, including oxidative stress, iron regulation, metabolic reprogramming, intracellular signaling transduction and cell death. These effects depend on the mitochondrial quality control (MQC) system, which includes mitochondrial dynamics, mitophagy and mitochondrial biogenesis. Mitochondria are not static entities, but dynamic units that undergo fission and fusion cycles to maintain their structural integrity. Increased mitochondrial fission elevates the number of mitochondria within cardiomyocytes, a necessary step for cardiomyocyte metabolism. Enhanced mitochondrial fusion promotes communication and cooperation between pairs of mitochondria, thus facilitating mitochondrial genomic repair and maintenance. On the contrary, erroneous fission or reduced fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA and exhibit impaired oxidative phosphorylation. Under normal/physiological conditions, injured mitochondria can undergo mitophagy, a degradative process that delivers poorly structured mitochondria to lysosomes. However, defective mitophagy promotes the accumulation of nonfunctional mitochondria, which may induce cardiomyocyte death. A decline in the mitochondrial population due to mitophagy can stimulate mitochondrial biogenesis), which generates new mitochondrial offspring to maintain an adequate mitochondrial number. Energy crises or ATP deficiency also increase mitochondrial biogenesis, because mitochondrial DNA encodes 13 subunits of the electron transport chain (ETC) complexes. Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence and promotes mitochondrial dysfunction. In this review, we describe the involvement of MQC in the pathogenesis of diabetic cardiomyopathy. Besides, the potential targeted therapies that could be applied to improve MQC during diabetic cardiomyopathy are also discussed and accelerate the development of cardioprotective drugs for diabetic patients.

Keywords:  Diabetic cardiomyopathy; Mitochondrial biogenesis; Mitochondrial fission; Mitochondrial fusion; Mitochondrial quality control; Mitophagy

DOI:  https://doi.org/10.1016/j.metabol.2022.155313
Stem Cell Res. 2022 Sep 15. pii: S1873-5061(22)00269-0. [Epub ahead of print]64 102920

RNA-based generation of iPSCs from a boy carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 and from his healthy mother.

Tabea Steiner, Annika Zink, Marie-Therese Henke, Giulia Cecchetto, Miriam Buenning, Andrea Rossi, Markus Schuelke, Alessandro Prigione.

We used a non-integrative self-replicating RNA vector to establish four iPSC lines: two iPSC lines from a young male carrying the mutation m.9185 T>C in the mitochondrial gene MT-ATP6 (present at virtual homoplasmic level), and two iPSC lines from his healthy mother (carrying the mutation in only about 4 % of mtDNA copies). All iPSC lines exhibited pluripotency characteristics, were capable to give rise to cells of the three germ layers in vitro, and presented a normal karyotype. The derived iPSC lines retained the MT-ATP6 mutation at levels similar to those observed in the parental fibroblasts.

DOI: https://doi.org/10.1016/j.scr.2022.102920
Cells. 2022 Sep 11. pii: 2835. [Epub ahead of print]11(18):

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.

Teresa Campbell, Jesse Slone, Taosheng Huang.

  Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Keywords:  calcium; dilated cardiomyopathy; ferroptosis; hypertrophic cardiomyopathy; iron overload; mitochondrial cardiomyopathy; mitochondrial genome; mtDNA; reactive oxygen species

DOI:  https://doi.org/10.3390/cells11182835
Trials. 2022 Sep 20. 23(1): 789

Acipimox in Mitochondrial Myopathy (AIMM): study protocol for a randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in adult patients with mitochondrial myopathy.

AIMM Trial Group:

   BACKGROUND: Mitochondrial disease is a heterogenous group of rare, complex neurometabolic disorders. Despite their individual rarity, collectively mitochondrial diseases represent the most common cause of inherited metabolic disorders in the UK; they affect 1 in every 4300 individuals, up to 15,000 adults (and a similar number of children) in the UK. Mitochondrial disease manifests multisystem and isolated organ involvement, commonly affecting those tissues with high energy demands, such as skeletal muscle. Myopathy manifesting as fatigue, muscle weakness and exercise intolerance is common and debilitating in patients with mitochondrial disease. Currently, there are no effective licensed treatments and consequently, there is an urgent clinical need to find an effective drug therapy.
AIM: To investigate the efficacy of 12-week treatment with acipimox on the adenosine triphosphate (ATP) content of skeletal muscle in patients with mitochondrial disease and myopathy.
METHODS: AIMM is a single-centre, double blind, placebo-controlled, adaptive designed trial, evaluating the efficacy of 12 weeks' administration of acipimox on skeletal muscle ATP content in patients with mitochondrial myopathy. Eligible patients will receive the trial investigational medicinal product (IMP), either acipimox or matched placebo. Participants will also be prescribed low dose aspirin as a non-investigational medical product (nIMP) in order to protect the blinding of the treatment assignment. Eighty to 120 participants will be recruited as required, with an interim analysis for sample size re-estimation and futility assessment being undertaken once the primary outcome for 50 participants has been obtained. Randomisation will be on a 1:1 basis, stratified by Fatigue Impact Scale (FIS) (dichotomised as < 40, ≥ 40). Participants will take part in the trial for up to 20 weeks, from screening visits through to follow-up at 16 weeks post randomisation. The primary outcome of change in ATP content in skeletal muscle and secondary outcomes relating to quality of life, perceived fatigue, disease burden, limb function, balance and walking, skeletal muscle analysis and symptom-limited cardiopulmonary fitness (optional) will be assessed between baseline and 12 weeks.
DISCUSSION: The AIMM trial will investigate the effect of acipimox on modulating muscle ATP content and whether it can be repurposed as a new treatment for mitochondrial disease with myopathy.
TRIAL REGISTRATION: EudraCT2018-002721-29 . Registered on 24 December 2018, ISRCTN 12895613. Registered on 03 January 2019, https://www.isrctn.com/search?q=aimm.

Keywords:  Acipimox; Adenosine triphosphate; Mitochondria; Mitochondrial disease; Myopathy; Randomised controlled trial

DOI:  https://doi.org/10.1186/s13063-022-06544-x
Membranes (Basel). 2022 Sep 16. pii: 893. [Epub ahead of print]12(9):

Mitochondrial Fission and Fusion: Molecular Mechanisms, Biological Functions, and Related Disorders.

Mode Al Ojaimi, Azza Salah, Ayman W El-Hattab.

  Mitochondria are dynamic organelles that undergo fusion and fission. These active processes occur continuously and simultaneously and are mediated by nuclear-DNA-encoded proteins that act on mitochondrial membranes. The balance between fusion and fission determines the mitochondrial morphology and adapts it to the metabolic needs of the cells. Therefore, these two processes are crucial to optimize mitochondrial function and its bioenergetics abilities. Defects in mitochondrial proteins involved in fission and fusion due to pathogenic variants in the genes encoding them result in disruption of the equilibrium between fission and fusion, leading to a group of mitochondrial diseases termed disorders of mitochondrial dynamics. In this review, the molecular mechanisms and biological functions of mitochondrial fusion and fission are first discussed. Then, mitochondrial disorders caused by defects in fission and fusion are summarized, including disorders related to MFN2, MSTO1, OPA1, YME1L1, FBXL4, DNM1L, and MFF genes.

Keywords:  mitochondrial diseases; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.3390/membranes12090893
Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01196-2. [Epub ahead of print]40(12): 111364

ORP5/8 and MIB/MICOS link ER-mitochondria and intra-mitochondrial contacts for non-vesicular transport of phosphatidylserine.

Vera F Monteiro-Cardoso, Leila Rochin, Amita Arora, Audrey Houcine, Eeva Jääskeläinen, Annukka M Kivelä, Cécile Sauvanet, Romain Le Bars, Eyra Marien, Jonas Dehairs, Julie Neveu, Naima El Khallouki, Elena Santonico, Johannes V Swinnen, David Tareste, Vesa M Olkkonen, Francesca Giordano.

  Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membrane (MAM) subdomains, physically linked to the mitochondrial intermembrane space bridging (MIB)/mitochondrial contact sites and cristae junction organizing system (MICOS) complexes that bridge the two mitochondrial membranes. We also show that ORP5/ORP8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membrane contacts maintained by the MIB/MICOS complexes.

Keywords:  CP: Cell biology; MAM; MICOS; Mic60; ORP; SAM50; cristae junctions; membrane contact sites; mitochondria; phosphatidylserine

DOI:  https://doi.org/10.1016/j.celrep.2022.111364
Int J Numer Method Biomed Eng. 2022 Sep 20. e3648

Effects of axon branching and asymmetry between the branches on transport, mean age, and age density distributions of mitochondria in neurons: a computational study.

Ivan A Kuznetsov, Andrey V Kuznetsov.

  We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities. This article is protected by copyright. All rights reserved.

Keywords:  Parkinson's disease; axonal transport; large axonal arbors; mathematical modeling; mitochondrial health

DOI:  https://doi.org/10.1002/cnm.3648
Brain. 2022 Sep 22. pii: awac344. [Epub ahead of print]

The phenotypic spectrum of COX20-associated mitochondrial disorder.

Rui Ban, Robert Kopajtich, Junlan Lv, Sarah L Stenton, Masaru Shimura, Zhaoxia Wang, Yun Yuan, Junling Wang, Xiaodi Han, Zhimei Liu, Qiang Shi, Chuanqiang Pu, Holger Prokisch, Fang Fang, Matthias Elstner.

DOI: https://doi.org/10.1093/brain/awac344
PLoS Genet. 2022 Sep 20. 18(9): e1010400

Oocyte mitophagy is critical for extended reproductive longevity.

Vanessa Cota, Salman Sohrabi, Rachel Kaletsky, Coleen T Murphy.

Women's reproductive cessation is the earliest sign of human aging and is caused by decreasing oocyte quality. Similarly, C. elegans' reproduction declines in mid-adulthood and is caused by oocyte quality decline. Aberrant mitochondrial morphology is a hallmark of age-related dysfunction, but the role of mitochondrial morphology and dynamics in reproductive aging is unclear. We examined the requirements for mitochondrial fusion and fission in oocytes of both wild-type worms and the long-lived, long-reproducing insulin-like receptor mutant daf-2. We find that normal reproduction requires both fusion and fission, but that daf-2 mutants utilize a shift towards fission, but not fusion, to extend their reproductive span and oocyte health. daf-2 mutant oocytes' mitochondria are punctate (fissioned) and this morphology is primed for mitophagy, as loss of the mitophagy regulator PINK-1 shortens daf-2's reproductive span. daf-2 mutants maintain oocyte mitochondria quality with age at least in part through a shift toward punctate mitochondrial morphology and subsequent mitophagy. Supporting this model, Urolithin A, a metabolite that promotes mitophagy, extends reproductive span in wild-type mothers-even in mid-reproduction-by maintaining youthful oocytes with age. Our data suggest that promotion of mitophagy may be an effective strategy to maintain oocyte health with age.

DOI: https://doi.org/10.1371/journal.pgen.1010400
Pediatr Neurol. 2022 Aug 29. pii: S0887-8994(22)00171-0. [Epub ahead of print]136 56-63

Sleep and Breathing Disturbances in Children With Leigh Syndrome: A Comparative Study.

Jia-Der Ju Wang, Maida Chen, Cristian Zhang, Jessica Parker, Russell Saneto, Jan-Marino Ramirez.

   BACKGROUND: Leigh syndrome (LS) is a progressive neurodegenerative mitochondrial disease characterized by necrotizing lesions affecting different parts of the central nervous system, especially in the brainstem and basal ganglia. Lesions in this area may involve respiratory and sleep centers, resulting in the clinically significant disturbances seen-but poorly characterized-in LS. The purpose of the present study is to characterize and compare the physiologic responses to respiratory disturbances quantified by polysomnography metrics of children with LS with age-sex- and apnea-hypopnea index (AHI)-matched patients with obstructive sleep apnea (OSA), a common clinical population with similar burden of sleep-disordered breathing.
METHODS: Retrospective comparative study of polysomnographic data from six patients with LS were reviewed and compared with 18 age-sex-AHI-matched patients with OSA, with particular attention to cardiorespiratory and sleep architecture metrics.
RESULTS: Sleep architecture and stage duration were conserved in LS and OSA groups, but increased wake after sleep onset was seen among the first group. The LS group exhibited both obstructive and central sleep apnea. The group also had significantly greater values of heart rate, ≥3% oxygen desaturation index, and lower values of sleep efficiency, respiratory arousal index, and total sleep time when compared with the OSA group.
CONCLUSIONS: Patients with LS exhibited significantly more sleep-related cardiorespiratory disturbances and sleep fragmentation when compared with neurotypical children with OSA. Given that these findings are plausibly detrimental to health and development, sleep evaluation in patients with similar conditions should be encouraged for early management.

Keywords:  Central sleep apnea; Leigh syndrome; Obstructive sleep apnea; Polysomnography; Sleep

DOI:  https://doi.org/10.1016/j.pediatrneurol.2022.08.006
Pharmaceuticals (Basel). 2022 Aug 31. pii: 1088. [Epub ahead of print]15(9):

Binding of Natural Inhibitors to Respiratory Complex I.

Jonathan Schiller, Volker Zickermann.

  NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a tunnel. A variety of chemically diverse compounds are known to inhibit ubiquinone reduction by complex I. Rotenone, piericidin A, and annonaceous acetogenins are representatives of complex I inhibitors from biological sources. The structure of complex I is determined at high resolution, and inhibitor binding sites are described in detail. In this review, we summarize the state of knowledge of how natural inhibitors bind in the Q reduction site and the Q access pathway and how their inhibitory mechanisms compare with that of a synthetic anti-cancer agent.

Keywords:  NADH dehydrogenase; Parkinson’s disease; acetogenin; mitochondria; piericidin; respiratory chain; rotenone

DOI:  https://doi.org/10.3390/ph15091088
ACS Chem Neurosci. 2022 Sep 20.

Could Amyloid-β 1-42 or α-Synuclein Interact Directly with Mitochondrial DNA? A Hypothesis.

Duygu Gezen-Ak, Zuhal Yurttaş, Tugay Çamoǧlu, Erdinç Dursun.

  The amyloid β (Aβ) and the α-synuclein (α-syn) are shown to be translocated into mitochondria. Even though their roles are widely investigated in pathological conditions, information on the presence and functions of Aβ and α-syn in mitochondria in endogenous levels is somewhat limited. We hypothesized that endogenous Aβ fragments or α-syn could interact with mitochondrial DNA (mtDNA) directly or influence RNAs or transcription factors in mitochondria and change the mtDNA transcription profile. In this review, we summarized clues of these possible interactions.

Keywords:  Alzheimer’s disease; Mitochondrial DNA; Parkinson disease; amyloid β; mitochondrial dysfunction; mtDNA transcription; neurodegeneration; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.2c00512
PLoS One. 2022 ;17(9): e0274774

Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.

Shengwen Zhang, Amy Bastille, Susana Gordo, Nikhil Ramesh, Jenisha Vora, Elizabeth McCarthy, Xiaohan Zhang, Dylan Frank, Chih-Wei Ko, Carmen Wu, Noel Walsh, Shreya Amarwani, Jing Liao, Qiang Xiong, Lauren Drouin, Matthias Hebben, Kyle Chiang, B Nelson Chau.

Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination. A single intravenous administration of mLB-001 to neonatal or adult MMA mice prevented body weight loss and mortality when challenged with a high protein diet. The edited hepatocytes expressed functional MMUT protein and expanded over time in the Mmut deficient mice, suggesting a selective growth advantage over the diseased cells. In mice with a humanized liver, treatment with a human homolog of mLB-001 resulted in site-specific genome editing and transgene expression in the transplanted human hepatocytes. Taken together, these findings support the development of hLB-001 that is currently in clinical trials in pediatric patients with severe forms of MMA.

DOI: https://doi.org/10.1371/journal.pone.0274774
Cell Transplant. 2022 Jan-Dec;31:31 9636897221124481

Modeling Human Organ Development and Diseases With Fetal Tissue-Derived Organoids.

Jianqing Liang, Xinyang Li, Yateng Dong, Bing Zhao.

  Recent advances in human organoid technology have greatly facilitated the study of organ development and pathology. In most cases, these organoids are derived from either pluripotent stem cells or adult stem cells for the modeling of developmental events and tissue homeostasis. However, due to the lack of human fetal tissue references and research model, it is still challenging to capture early developmental changes and underlying mechanisms in human embryonic development. The establishment of fetal tissue-derived organoids in rigorous time points is necessary. Here we provide an overview of the strategies and applications of fetal tissue-derived organoids, mainly focusing on fetal organ development research, developmental defect disease modeling, and organ-organ interaction study. Discussion of the importance of fetal tissue research also highlights the prospects and challenges in this field.

Keywords:  developmental defect diseases; human fetal tissues; organ development; organoids

DOI:  https://doi.org/10.1177/09636897221124481
Biomed Res Int. 2022 ;2022 5250254

Effects of CoQ10 Replacement Therapy on the Audiological Characteristics of Pediatric Patients with COQ6 Variants.

Dong Woo Nam, Sang Soo Park, So Min Lee, Myung-Whan Suh, Moo Kyun Park, Jae-Jin Song, Byung Yoon Choi, Jun Ho Lee, Seung Ha Oh, Kyung Chul Moon, Yo Han Ahn, Hee Gyung Kang, Hae Il Cheong, Ji Hyun Kim, Sang-Yeon Lee.

Primary coenzyme Q10 (CoQ10) deficiency refers to a group of mitochondrial cytopathies caused by genetic defects in CoQ10 biosynthesis. Primary coenzyme Q10 deficiency-6 (COQ10D6) is an autosomal recessive disorder attributable to biallelic COQ6 variants; the cardinal phenotypes are steroid-resistant nephrotic syndrome (SRNS), which inevitably progresses to kidney failure, and sensorineural hearing loss (SNHL). Here, we describe the phenotypes and genotypes of 12 children with COQ10D6 from 11 unrelated Korean families and quantitatively explore the beneficial effects of CoQ10 replacement therapy on SNHL. A diagnosis of SRNS generally precedes SNHL documentation. COQ10D6 is associated with progressive SNHL. Four causative COQ6 variants were identified in either homozygotes or compound heterozygotes: c.189_191delGAA, c.484C>T, c.686A>C, and c.782C>T. The response rate (no further hearing loss or improvement) was 42.9%; CoQ10 replacement therapy may thus limit and even improve hearing loss. Notably, the audiological benefit appeared to be genotype-specific, suggesting a genotype-phenotype correlation. The results of cochlear implantation were generally favorable, and the effects were sustained over time. Our results thus propose the beneficial effects of CoQ10 replacement therapy on hearing loss. Our work with COQ10D6 patients is a good example of personalized, genetically tailored, audiological rehabilitation of patients with syndromic deafness.

DOI: https://doi.org/10.1155/2022/5250254
Int J Mol Sci. 2022 Sep 16. pii: 10843. [Epub ahead of print]23(18):

Endurance Training Increases the Running Performance of Untrained Men without Changing the Mitochondrial Volume Density in the Gastrocnemius Muscle.

Jerzy A Zoladz, Joanna Majerczak, Lukasz Galganski, Marcin Grandys, Justyna Zapart-Bukowska, Piotr Kuczek, Leszek Kołodziejski, Lucyna Walkowicz, Dorota Szymoniak-Chochół, Wincenty Kilarski, Wieslawa Jarmuszkiewicz.

  The activity and quantity of mitochondrial proteins and the mitochondrial volume density (MitoVD) are higher in trained muscles; however, the underlying mechanisms remain unclear. Our goal was to determine if 20 weeks' endurance training simultaneously increases running performance, the amount and activity of mitochondrial proteins, and MitoVD in the gastrocnemius muscle in humans. Eight healthy, untrained young men completed a 20-week moderate-intensity running training program. The training increased the mean speed of a 1500 m run by 14.0% (p = 0.008) and the running speed at 85% of maximal heart rate by 9.6% (p = 0.008). In the gastrocnemius muscle, training significantly increased mitochondrial dynamics markers, i.e., peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) by 23%, mitochondrial transcription factor A (TFAM) by 29%, optic artrophy-1 (OPA1) by 31% and mitochondrial fission factor (MFF) by 44%, and voltage-dependent anion channel 1 (VDAC1) by 30%. Furthermore, training increased the amount and maximal activity of citrate synthase (CS) by 10% and 65%, respectively, and the amount and maximal activity of cytochrome c oxidase (COX) by 57% and 42%, respectively, but had no effect on the total MitoVD in the gastrocnemius muscle. We concluded that not MitoVD per se, but mitochondrial COX activity (reflecting oxidative phosphorylation activity), should be regarded as a biomarker of muscle adaptation to endurance training in beginner runners.

Keywords:  critical power; heart rate; muscle fatigue; oxygen uptake; running

DOI:  https://doi.org/10.3390/ijms231810843
STAR Protoc. 2022 Sep 21. pii: S2666-1667(22)00590-1. [Epub ahead of print]3(4): 101710

Protocol to detect in vitro and in cell ubiquitylation of mitochondrial DNA polymerase gamma by mitochondrial E3 ligase MITOL.

Mansoor Hussain, Shabnam Saifi, Aftab Mohammed, Sagar Sengupta.

  Mitochondrial polymerase gamma (PolγA) is the only replicative polymerase in mitochondria. To determine PolγA ubiquitylation in cells, Flag-PolγA and MITOL are overexpressed, and subsequently the immunoprecipitated Flag-PolγA is checked for ubiquitylation. Alternately, in vitro synthesized PolγA and MITOL are used to determine whether PolγA is ubiquitylated. Either anti-ubiquitin or anti-Flag antibody is used to detect the ubiquitylated product. Thus, we provide a detailed, reliable, highly reproducible protocol for detecting ubiquitylation of PolγA by MITOL, both in cells and in vitro. For complete details on the use and execution of this protocol, please refer to Hussain et al. (2021).

Keywords:  Cell biology; Genetics; Molecular biology; Protein biochemistry; Protein expression and purification

DOI:  https://doi.org/10.1016/j.xpro.2022.101710
Ren Fail. 2022 Dec;44(1): 1545-1557

Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis.

Jun Wu, Jushuang Li, Baohong Feng, Zhimin Bi, Geli Zhu, Yanxia Zhang, Xiangyou Li.

   BACKGROUND: The pathogenesis of peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is not clearly understood, and current treatment options are limited.
METHODS: In this study, the effect of PD-related PF on mitochondrial biogenesis was investigated, and the effect of activation of the adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway on PF was evaluated in mice.
RESULTS: In a mouse model of PD-related PF, AMPK-PGC-1α signaling (phospho-AMPK, PGC-1α, NRF-1, NRF-2 and TFAM expression) was downregulated, mitochondrial DNA (mtDNA) levels were reduced, and mitochondrial structure was damaged in the peritoneum. In addition, TdT-mediated dUTP nick-end labeling (TUNEL) staining showed typical apoptosis characteristics in peritoneal mesothelial cells (PMCs). Activation of the AMPK-PGC-1α pathway (PGC-1α overexpression or metformin, which is an agonist of AMPK) upregulated phospho-AMPK, PGC-1α, nuclear respiratory factors 1 (NRF-1) and 2 (NRF-2), and mitochondrial transcription factor A (TFAM) expression and mtDNA content, improved mitochondrial morphological manifestations, inhibited apoptosis of PMCs and alleviated PF.
CONCLUSION: Our study may suggest that activation of the AMPK-PGC-1α pathway ameliorates PD-related PF by enhancing mitochondrial biogenesis.

Keywords:  AMPK; PGC-1α; Peritoneal dialysis; mitochondrial biogenesis; peritoneal fibrosis

DOI:  https://doi.org/10.1080/0886022X.2022.2126789
Cells. 2022 Sep 13. pii: 2849. [Epub ahead of print]11(18):

A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.

Jia Wang, Wen-Jun Liu, Hou-Zhen Shi, Hong-Ru Zhai, Jin-Jun Qian, Wei-Ning Zhang.

  Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer's disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer's disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission-fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.

Keywords:  Alzheimer’s disease; PGC-1a; mitochondrial distribution; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/cells11182849
J Neurol. 2022 Sep 24.

The inherited cerebellar ataxias: an update.

Giulia Coarelli, Thomas Wirth, Christine Tranchant, Michel Koenig, Alexandra Durr, Mathieu Anheim.

  This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.

Keywords:  Cerebellar ataxia; Genetics; Next generation sequencing; Phenotype

DOI:  https://doi.org/10.1007/s00415-022-11383-6
Cond Med. 2021 Jun;4(3): 151-160

Mitochondria as the memory of preconditioning.

Sarah Zerimech, Hung Nguyen, Selva Baltan.

Preconditioning is such a paradigm that a stimulus below the threshold of causing harm makes the brain stronger and resilient to subsequent injury. Preconditioning affords a vigorous tolerance to the brain against neurodegeneration. Numerous efforts have tried to identify the molecular targets involved in preconditioning-induced protective responses and interestingly many of those diverse mechanisms posit mitochondria as a master regulator of preconditioning. Therefore, in this review, we will critically discuss recent and emerging evidence for the involvement of mitochondria within the preconditioning paradigm. We will introduce the crucial targets and signaling cascades by which mitochondria exert preconditioning with a focus on white matter mitochondria and whether and how mechanisms for preconditioning differ in neurons and glial cells. In this aspect, we will evaluate the role of mitochondrial shaping proteins to establish structure-function interdependence for fusion-fission balance, motility, ATP production, Ca+2, and ROS scavenging. We will also discuss how aging impacts mitochondria and the consequences of mitochondrial aging on preconditioning mechanisms. We will concentrate on the regulation of mitochondrial DNA content and quantification specifically for its value as a biomarker to monitor disease conditions. The identification of these mitochondrial preconditioning mechanisms can be translated to potential pharmacological interventions to increase intrinsic resilience of the brain to injury and to develop novel approaches to neurodegenerative diseases. Moreover, mitochondria dynamics can be used as a memory or biomarker of preconditioning.

Keywords: Aging; Biomarker; Mitochondria; Preconditioning; White matter
Front Mol Biosci. 2022 ;9 933788

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia.

Layne N Rodden, Christian Rummey, Yi Na Dong, Sarah Lagedrost, Sean Regner, Alicia Brocht, Khalaf Bushara, Martin B Delatycki, Christopher M Gomez, Katherine Mathews, Sarah Murray, Susan Perlman, Bernard Ravina, S H Subramony, George Wilmot, Theresa Zesiewicz, Alessandra Bolotta, Alain Domissy, Christine Jespersen, Baohu Ji, Elisabetta Soragni, Joel M Gottesfeld, David R Lynch.

  Introduction: Friedreich ataxia (FRDA) is a recessive neurodegenerative disease characterized by progressive ataxia, dyscoordination, and loss of vision. The variable length of the pathogenic GAA triplet repeat expansion in the FXN gene in part explains the interindividual variability in the severity of disease. The GAA repeat expansion leads to epigenetic silencing of FXN; therefore, variability in properties of epigenetic effector proteins could also regulate the severity of FRDA. Methods: In an exploratory analysis, DNA from 88 individuals with FRDA was analyzed to determine if any of five non-synonymous SNPs in HDACs/SIRTs predicted FRDA disease severity. Results suggested the need for a full analysis at the rs352493 locus in SIRT6 (p.Asn46Ser). In a cohort of 569 subjects with FRDA, disease features were compared between subjects homozygous for the common thymine SIRT6 variant (TT) and those with the less common cytosine variant on one allele and thymine on the other (CT). The biochemical properties of both variants of SIRT6 were analyzed and compared. Results: Linear regression in the exploratory cohort suggested that an SNP (rs352493) in SIRT6 correlated with neurological severity in FRDA. The follow-up analysis in a larger cohort agreed with the initial result that the genotype of SIRT6 at the locus rs352493 predicted the severity of disease features of FRDA. Those in the CT SIRT6 group performed better on measures of neurological and visual function over time than those in the more common TT SIRT6 group. The Asn to Ser amino acid change resulting from the SNP in SIRT6 did not alter the expression or enzymatic activity of SIRT6 or frataxin, but iPSC-derived neurons from people with FRDA in the CT SIRT6 group showed whole transcriptome differences compared to those in the TT SIRT6 group. Conclusion: People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.

Keywords:  SIRT6; ataxia; clinical trial; epigenetic; mRNA profiling; mitochondrion; modifier

DOI:  https://doi.org/10.3389/fmolb.2022.933788
Neuroreport. 2022 Oct 12. 33(15): 635-640

Enhancing oxidative phosphorylation over glycolysis for energy production in cultured mesenchymal stem cells.

Molly Monsour, Anna Gorsky, Hung Nguyen, Vanessa Castelli, Jea-Young Lee, Cesar V Borlongan.

OBJECTIVE: Strokes represent as one of the leading causes of death and disability in the USA, however, there is no optimal treatment to reduce the occurrence or improve prognosis. Preconditioning of tissues triggers ischemic tolerance, a physiological state that may involve a metabolic switch (i.e. from glycolysis to oxidative phosphorylation or OxPhos) to preserve tissue viability under an ischemic insult. Here, we hypothesized that metabolic switching of energy source from glucose to galactose in cultured mesenchymal stem cells (MSCs) stands as an effective OxPhos-enhancing strategy.
METHODS: MSCs were grown under ambient condition (normal MSCs) or metabolic switching paradigm (switched MSCs) and then assayed for oxygen consumption rates (OCR) and extracellular acidification rate (ECAR) using the Seahorse technology to assess mitochondrial respiration.
RESULTS: Normal MSCs showed a lower OCR/ECAR ratio than switched MSCs at baseline (P < 0.0001), signifying that there were greater levels of OxPhos compared to glycolysis in switched MSCs. By modulating the mitochondrial metabolism with oligomycin (time points 4-6), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (7-9), and rotenone and antimycin (time points 10-12), switched MSCs greater reliance on OxPhos was further elucidated (time points 5-12; P < 0.0001; time point 4; P < 0.001).
CONCLUSION: The metabolic switch from glycolytic to oxidative metabolism amplifies the OxPhos potential of MSCs, which may allow these cells to afford more robust therapeutic effects against neurological disorders that benefit from ischemic tolerance.

DOI: https://doi.org/10.1097/WNR.0000000000001828
Antioxidants (Basel). 2022 Aug 24. pii: 1637. [Epub ahead of print]11(9):

Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies.

Borut Poljšak, Vito Kovač, Irina Milisav.

  Precursors of nicotinamide adenine dinucleotide (NAD+), modulators of enzymes of the NAD+ biosynthesis pathways and inhibitors of NAD+ consuming enzymes, are the main boosters of NAD+. Increasing public awareness and interest in anti-ageing strategies and health-promoting lifestyles have grown the interest in the use of NAD+ boosters as dietary supplements, both in scientific circles and among the general population. Here, we discuss the current trends in NAD+ precursor usage as well as the uncertainties in dosage, timing, safety, and side effects. There are many unknowns regarding pharmacokinetics and pharmacodynamics, particularly bioavailability, metabolism, and tissue specificity of NAD+ boosters. Given the lack of long-term safety studies, there is a need for more clinical trials to determine the proper dose of NAD+ boosters and treatment duration for aging prevention and as disease therapy. Further research will also need to address the long-term consequences of increased NAD+ and the best approaches and combinations to increase NAD+ levels. The answers to the above questions will contribute to the more efficient and safer use of NAD+ boosters.

Keywords:  NAD+ boosters; NAD+ precursors; nicotinamide adenine dinucleotide (NAD+); safety; side effects

DOI:  https://doi.org/10.3390/antiox11091637
Sci Adv. 2022 Sep 23. 8(38): eabn4704

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders.

Jihad El Andari, Edith Renaud-Gabardos, Warut Tulalamba, Jonas Weinmann, Louise Mangin, Quang Hong Pham, Susanne Hille, Antonette Bennett, Esther Attebi, Emanuele Bourges, Christian Leborgne, Nicolas Guerchet, Julia Fakhiri, Chiara Krämer, Ellen Wiedtke, Robert McKenna, Laurence Guianvarc'h, Magali Toueille, Giuseppe Ronzitti, Matthias Hebben, Federico Mingozzi, Thierry VandenDriessche, Mavis Agbandje-McKenna, Oliver J Müller, Marinee K Chuah, Ana Buj-Bello, Dirk Grimm.

Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors-AAVMYO2 and AAVMYO3-prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.

DOI: https://doi.org/10.1126/sciadv.abn4704
Vet Sci. 2022 Sep 13. pii: 501. [Epub ahead of print]9(9):

Maternal and Fetal PI3K-p110α Deficiency Induces Sex-Specific Changes in Conceptus Growth and Placental Mitochondrial Bioenergetic Reserve in Mice.

Daniela Pereira-Carvalho, Esteban Salazar-Petres, Jorge Lopez-Tello, Amanda N Sferruzzi-Perri.

  Fetal growth is reliant on placental formation and function, which, in turn, requires the energy produced by the mitochondria. Prior work has shown that both mother and fetus operate via the phosphoinositol 3-kinase (PI3K)-p110α signalling pathway to modify placental development, function, and fetal growth outcomes. This study in mice used genetic inactivation of PI3K-p110α (α/+) in mothers and fetuses and high resolution respirometry to investigate the influence of maternal and fetal PI3K-p110α deficiency on fetal and placental growth, in relation to placental mitochondrial bioenergetics, for each fetal sex. The effect of PI3K-p110α deficiency on maternal body composition was also determined to understand more about the maternal-driven changes in feto-placental development. These data show that male fetuses were more sensitive than females to fetal PI3K-p110α deficiency, as they had greater reductions in fetal and placental weight, when compared to their WT littermates. Placental weight was also altered in males only of α/+ dams. In addition, α/+ male, but not female, fetuses showed an increase in mitochondrial reserve capacity, when compared to their WT littermates in α/+ dams. Finally, α/+ dams exhibited reduced adipose depot masses, compared to wild-type dams. These findings, thus, demonstrate that maternal nutrient reserves and ability to apportion nutrients to the fetus are reduced in α/+ dams. Moreover, maternal and fetal PI3K-p110α deficiency impacts conceptus growth and placental mitochondrial bioenergetic function, in a manner dependent on fetal sex.

Keywords:  fetal PI3K-p110α; fetus; maternal PI3K-p110α; mitochondria; placenta; sex; signaling

DOI:  https://doi.org/10.3390/vetsci9090501
Front Immunol. 2022 ;13 981917

Enhancement of liver mitochondrial complex I and energy metabolism induced by enteritis: The key role of gut microbiota derived endotoxins.

Lele Fu, Haokun Liu, Wen Chen, Jamie Marie Hooft, Margareth Øverland, Wanjie Cai, Dong Han, Xiaoming Zhu, Yunxia Yang, Junyan Jin, Shouqi Xie.

  Inflammation is an energy-intensive process and the liver is a key organ in energy regulation. Since the intestine and liver exchange nutrients and metabolites, enteritis can affect the liver. To investigate the correlation between enteritis and liver metabolism, we developed an intestinal inflammation model with concentration-dependent 2,4,6-trinitrobenzene sulfonic acid (TNBS) in gibel carp (Carassius gibelio). The results showed the dysregulation of intestinal tight junction, increased permeability of the gut barrier, and apoptosis of epithelial cells during the development of enteritis. The liver metabolome was analyzed by LC-MS and the live respiration was determined using Oxygraph-2k. The results showed that glycolysis, the TCA cycle and pyrimidine metabolism were affected by intestinal inflammation. In particular, the activity of hepatic mitochondrial respiratory chain complex I was significantly increased. Structure and abundance changes of gut microbiota were analyzed by 16S rRNA sequencing analysis. Pathogenic bacteria in the intestine, as well as plasma LPS, increased significantly. Using a liver cell line, we verified that the dysfunctional metabolism of the liver is related to the dislocation of LPS. All results imply the existence of a connection between enteritis and liver metabolism in gibel carp, and the gut microbiome plays a critical role in this process.

Keywords:  endotoxin; intestinal inflammation; intestinal permeability; metabolism; mitochondrial complex I

DOI:  https://doi.org/10.3389/fimmu.2022.981917
Biomedicines. 2022 Aug 24. pii: 2069. [Epub ahead of print]10(9):

Metabolic Profile Variations along the Differentiation of Human-Induced Pluripotent Stem Cells to Dopaminergic Neurons.

Emma Veronica Carsana, Matteo Audano, Silvia Breviario, Silvia Pedretti, Massimo Aureli, Giulia Lunghi, Nico Mitro.

  In recent years, the availability of induced pluripotent stem cell-based neuronal models has opened new perspectives on the study and therapy of neurological diseases such as Parkinson's disease. In particular, P. Zhang set up a protocol to efficiently generate dopaminergic neurons from induced pluripotent stem cells. Although the differentiation process of these cells has been widely investigated, there is scant information related to the variation in metabolic features during the differentiation process of pluripotent stem cells to mature dopaminergic neurons. For this reason, we analysed the metabolic profile of induced pluripotent stem cells, neuronal precursors and mature neurons by liquid chromatography-tandem mass spectrometry. We found that induced pluripotent stem cells primarily rely on fatty acid beta-oxidation as a fuel source. Upon progression to neuronal progenitors, it was observed that cells began to shut down fatty acid β-oxidation and preferentially catabolised glucose, which is the principal source of energy in fully differentiated neurons. Interestingly, in neuronal precursors, we observed an increase in amino acids that are likely the result of increased uptake or synthesis, while in mature dopaminergic neurons, we also observed an augmented content of those amino acids needed for dopamine synthesis. In summary, our study highlights a metabolic rewiring occurring during the differentiation stages of dopaminergic neurons.

Keywords:  dopaminergic neurons; iPSCs; mass spectrometry; metabolism; neuronal differentiation

DOI:  https://doi.org/10.3390/biomedicines10092069
J Clin Invest. 2022 Sep 20. pii: e161638. [Epub ahead of print]

A Mitofusin 2 - Hif1α axis sets a maturation checkpoint in regenerating skeletal muscle.

Xun Wang, Yuemeng Jia, Jiawei Zhao, Nicholas P Lesner, Cameron J Menezes, Spencer D Shelton, Siva Sai Krishna Venigalla, Jian Xu, Chunyu Cai, Prashant Mishra.

  A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration which pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), whose expression is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of Hypoxia-induced Factor 1α (Hif1α), which is induced in the setting of muscle damage. Sustained Hif1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of Hif1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint which regulates the speed of myofiber maturation in response to Mitofusin 2 and Hif1α activity.

Keywords:  Epigenetics; Mitochondria; Muscle Biology; Stem cells

DOI:  https://doi.org/10.1172/JCI161638