bims-mitmed 2023-05-21 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2023–05–21
thirty-six papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial Dynamics during Development.
Mitochondria: It is all about energy.
Molecular analysis of gene variants in an Iranian family with psychomotor retardation mitochondrial disorder patient.
Mitochondria and the eye-manifestations of mitochondrial diseases and their management.
Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators.
First baby born in the UK using mitochondrial donation therapy.
Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.
Recent advances and new perspectives in mitochondrial dysfunction.
Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.
The role of the proteasome in mitochondrial protein quality control.
Mitochondrial dysfunction in aging.
Mitochondria Transplantation from Stem Cell for Mitigating Sarcopenia.
USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.
Mitochondrial quality control in abdominal aortic aneurysm: From molecular mechanisms to therapeutic strategies.
Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.
Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.
A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.
Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.
New avenues for therapy in mitochondrial optic neuropathies.
Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.
[Therapeutics for Mitochondrial Encephalomyopathy].
Lab-grown monkey embryos reveal in 3D how organs begin.
Mitochondria are midfield players in steroid synthesis.
A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.
Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.
Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.
Maternal and Fetal Mitochondrial Gene Dysregulation in Hypertensive Disorders of Pregnancy.
Mitochondrial small fiber neuropathy as a novel phenotypic trait of Leigh-like syndrome due to the variant m.10191T>C in MT-ND3.
Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review.
Mitochondrial Bcl-xL promotes brain synaptogenesis by controlling non-lethal caspase activation.
The Y831C Mutation of the POLG Gene in Dementia.
An in vivo neuroimmune organoid model to study human microglia phenotypes.
Paving a way to treat spastic paraplegia 50.
Adult progenitor rejuvenation with embryonic factors.

Newborn (Clarksville). 2023 Jan-Mar;2(1):2(1): 19-44

Mitochondrial Dynamics during Development.

Ling He, Karl Johan Tronstad, Akhil Maheshwari.

  Mitochondria are dynamic membrane-bound organelles in eukaryotic cells. These are important for the generation of chemical energy needed to power various cellular functions and also support metabolic, energetic, and epigenetic regulation in various cells. These organelles are also important for communication with the nucleus and other cellular structures, to maintain developmental sequences and somatic homeostasis, and for cellular adaptation to stress. Increasing information shows mitochondrial defects as an important cause of inherited disorders in different organ systems. In this article, we provide an extensive review of ontogeny, ultrastructural morphology, biogenesis, functional dynamics, important clinical manifestations of mitochondrial dysfunction, and possibilities for clinical intervention. We present information from our own clinical and laboratory research in conjunction with information collected from an extensive search in the databases PubMed, EMBASE, and Scopus.

Keywords:  Archezoan; Inner membrane; Intermembrane space; Matrix; Mitochondrial DNA; Mitophagy; Neonate; Ontogeny; Outer membrane; Parkin

DOI:  https://doi.org/10.5005/jp-journals-11002-0053
Front Physiol. 2023 ;14 1114231

Mitochondria: It is all about energy.

Amaloha Casanova, Anne Wevers, Santiago Navarro-Ledesma, Leo Pruimboom.

  Mitochondria play a key role in both health and disease. Their function is not limited to energy production but serves multiple mechanisms varying from iron and calcium homeostasis to the production of hormones and neurotransmitters, such as melatonin. They enable and influence communication at all physical levels through interaction with other organelles, the nucleus, and the outside environment. The literature suggests crosstalk mechanisms between mitochondria and circadian clocks, the gut microbiota, and the immune system. They might even be the hub supporting and integrating activity across all these domains. Hence, they might be the (missing) link in both health and disease. Mitochondrial dysfunction is related to metabolic syndrome, neuronal diseases, cancer, cardiovascular and infectious diseases, and inflammatory disorders. In this regard, diseases such as cancer, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and chronic pain are discussed. This review focuses on understanding the mitochondrial mechanisms of action that allow for the maintenance of mitochondrial health and the pathways toward dysregulated mechanisms. Although mitochondria have allowed us to adapt to changes over the course of evolution, in turn, evolution has shaped mitochondria. Each evolution-based intervention influences mitochondria in its own way. The use of physiological stress triggers tolerance to the stressor, achieving adaptability and resistance. This review describes strategies that could recover mitochondrial functioning in multiple diseases, providing a comprehensive, root-cause-focused, integrative approach to recovering health and treating people suffering from chronic diseases.

Keywords:  hormesis; mitochondria; mitochondrial dysfunction; mitochondrial hormesis; mitochondrial metabolism

DOI:  https://doi.org/10.3389/fphys.2023.1114231
Clin Case Rep. 2023 May;11(5): e7308

Molecular analysis of gene variants in an Iranian family with psychomotor retardation mitochondrial disorder patient.

Forough Shabannejadian, Seyedeh Zahra Masoomizadeh, Behnaz Andashti.

  In 1-year-old girl presenting with neurodegenerative mitochondrial disease (Leigh syndrome), mutation analysis was performed by whole exome sequencing. Pathogenic variants were then analyzed in parents and relatives by Sanger sequencing. We identified a point mutation c.G484A in NDUFS8 gene which was homozygous in patient and heterozygous in parents.

Keywords:  Leigh syndrome; mitochondrial disease; whole exome sequencing

DOI:  https://doi.org/10.1002/ccr3.7308
Eye (Lond). 2023 Apr 25.

Mitochondria and the eye-manifestations of mitochondrial diseases and their management.

Benson S Chen, Joshua P Harvey, Michael J Gilhooley, Neringa Jurkute, Patrick Yu-Wai-Man.

Historically, distinct mitochondrial syndromes were recognised clinically by their ocular features. Due to their predilection for metabolically active tissue, mitochondrial diseases frequently involve the eye, resulting in a range of ophthalmic manifestations including progressive external ophthalmoplegia, retinopathy and optic neuropathy, as well as deficiencies of the retrochiasmal visual pathway. With the wider availability of genetic testing in clinical practice, it is now recognised that genotype-phenotype correlations in mitochondrial diseases can be imprecise: many classic syndromes can be associated with multiple genes and genetic variants, and the same genetic variant can have multiple clinical presentations, including subclinical ophthalmic manifestations in individuals who are otherwise asymptomatic. Previously considered rare diseases with no effective treatments, considerable progress has been made in our understanding of mitochondrial diseases with new therapies emerging, in particular, gene therapy for inherited optic neuropathies.

DOI: https://doi.org/10.1038/s41433-023-02523-x
Aging Dis. 2023 Jun 01. 14(3): 794-824

Sirtuins at the Crossroads between Mitochondrial Quality Control and Neurodegenerative Diseases: Structure, Regulation, Modifications, and Modulators.

Hui Xu, Yi-Yang Liu, Lin-Seng Li, You-Shuo Liu.

Sirtuins (SIRT1-SIRT7), a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes, are key regulators of life span and metabolism. In addition to acting as deacetylates, some sirtuins have the properties of deacylase, decrotonylase, adenosine diphosphate (ADP)-ribosyltransferase, lipoamidase, desuccinylase, demalonylase, deglutarylase, and demyristolyase. Mitochondrial dysfunction occurs early on and acts causally in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Sirtuins are implicated in the regulation of mitochondrial quality control, which is highly associated with the pathogenesis of neurodegenerative diseases. There is growing evidence indicating that sirtuins are promising and well-documented molecular targets for the treatment of mitochondrial dysfunction and neurodegenerative disorders by regulating mitochondrial quality control, including mitochondrial biogenesis, mitophagy, mitochondrial fission/fusion dynamics, and mitochondrial unfolded protein responses (mtUPR). Therefore, elucidation of the molecular etiology of sirtuin-mediated mitochondrial quality control points to new prospects for the treatment of neurodegenerative diseases. However, the mechanisms underlying sirtuin-mediated mitochondrial quality control remain obscure. In this review, we update and summarize the current understanding of the structure, function, and regulation of sirtuins with an emphasis on the cumulative and putative effects of sirtuins on mitochondrial biology and neurodegenerative diseases, particularly their roles in mitochondrial quality control. In addition, we outline the potential therapeutic applications for neurodegenerative diseases of targeting sirtuin-mediated mitochondrial quality control through exercise training, calorie restriction, and sirtuin modulators in neurodegenerative diseases.

DOI: https://doi.org/10.14336/AD.2022.1123
BMJ. 2023 05 12. 381 1091

First baby born in the UK using mitochondrial donation therapy.

Jacqui Wise.

DOI: https://doi.org/10.1136/bmj.p1091
J Physiol. 2023 May 18.

Exploring mitochondrial morphology in skeletal muscle: Implications for highly trained individuals.

Blair MacLeod.



Keywords:  mitochondria; mitochondrial cristae; resistance exercise; skeletal muscle; strength training; weightlifting

DOI:  https://doi.org/10.1113/JP284873
Sci Rep. 2023 May 17. 13(1): 7977

Recent advances and new perspectives in mitochondrial dysfunction.

Cecilia Giulivi, Kezhong Zhang, Hirofumi Arakawa.

DOI: https://doi.org/10.1038/s41598-023-34624-8
CNS Neurosci Ther. 2023 May 19.

Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.

Yitong Li, Yue Li, Lei Chen, Yi Li, Kaixi Liu, Jingshu Hong, Qian Wang, Ning Kang, Yanan Song, Xinning Mi, Yi Yuan, Dengyang Han, Taotao Liu, Ning Yang, Xiangyang Guo, Zhengqian Li.

   INTRODUCTION: Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats.
METHODS: Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function.
RESULTS: Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function.
CONCLUSION: Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.

Keywords:  aged rats; delayed neurocognitive recovery; mitochondrial dysfunction; mitochondrial fission; mitophagy

DOI:  https://doi.org/10.1111/cns.14261
IUBMB Life. 2023 May 13.

The role of the proteasome in mitochondrial protein quality control.

Saskia Rödl, Johannes M Herrmann.

  The abundance of each cellular protein is dynamically adjusted to the prevailing metabolic and stress conditions by modulation of their synthesis and degradation rates. The proteasome represents the major machinery for the degradation of proteins in eukaryotic cells. How the ubiquitin-proteasome system (UPS) controls protein levels and removes superfluous and damaged proteins from the cytosol and the nucleus is well characterized. However, recent studies showed that the proteasome also plays a crucial role in mitochondrial protein quality control. This mitochondria-associated degradation (MAD) thereby acts on two layers: first, the proteasome removes mature, functionally compromised or mis-localized proteins from the mitochondrial surface; and second, the proteasome cleanses the mitochondrial import pore of import intermediates of nascent proteins that are stalled during translocation. In this review, we provide an overview about the components and their specific functions that facilitate proteasomal degradation of mitochondrial proteins in the yeast Saccharomyces cerevisiae. Thereby we explain how the proteasome, in conjunction with a set of intramitochondrial proteases, maintains mitochondrial protein homeostasis and dynamically adapts the levels of mitochondrial proteins to specific conditions.

Keywords:  mitochondria; mitochondria-associated degradation; proteasome; protein degradation; protein import; ubiquitin

DOI:  https://doi.org/10.1002/iub.2734
Ageing Res Rev. 2023 May 15. pii: S1568-1637(23)00114-9. [Epub ahead of print] 101955

Mitochondrial dysfunction in aging.

Ying Guo, Teng Guan, Kashfia Shafiq, Qiang Yu, Xin Jiao, Donghui Na, Meiyu Li, Guohui Zhang, Jiming Kong.

  Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPRmt). Mitochondrial-derived vesicles (MDVs) are the first line of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.

Keywords:  Aging; mitochondrial dysfunction; mitochondrial quality control; reactive oxygen species

DOI:  https://doi.org/10.1016/j.arr.2023.101955
Aging Dis. 2023 Feb 13.

Mitochondria Transplantation from Stem Cell for Mitigating Sarcopenia.

Xiulin Tian, Mengxiong Pan, Mengting Zhou, Qiaomin Tang, Miao Chen, Wenwu Hong, Fangling Zhao, Kaiming Liu.

Sarcopenia is defined as the age-related loss of muscle mass and function that can lead to prolonged hospital stays and decreased independence. It is a significant health and financial burden for individuals, families, and society as a whole. The accumulation of damaged mitochondria in skeletal muscle contributes to the degeneration of muscles with age. Currently, the treatment of sarcopenia is limited to improving nutrition and physical activity. Studying effective methods to alleviate and treat sarcopenia to improve the quality of life and lifespan of older people is a growing area of interest in geriatric medicine. Therapies targeting mitochondria and restoring mitochondrial function are promising treatment strategies. This article provides an overview of stem cell transplantation for sarcopenia, including the mitochondrial delivery pathway and the protective role of stem cells. It also highlights recent advances in preclinical and clinical research on sarcopenia and presents a new treatment method involving stem cell-derived mitochondrial transplantation, outlining its advantages and challenges.

DOI: https://doi.org/10.14336/AD.2023.0210
Cells. 2023 04 13. pii: 1143. [Epub ahead of print]12(8):

USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons.

Sofia Mauri, Greta Bernardo, Aitor Martinez, Mariavittoria Favaro, Marta Trevisan, Gael Cobraiville, Marianne Fillet, Federico Caicci, Alexander J Whitworth, Elena Ziviani.

  Stress-induced mitophagy, a tightly regulated process that targets dysfunctional mitochondria for autophagy-dependent degradation, mainly relies on two proteins, PINK1 and Parkin, which genes are mutated in some forms of familiar Parkinson's Disease (PD). Upon mitochondrial damage, the protein kinase PINK1 accumulates on the organelle surface where it controls the recruitment of the E3-ubiquitin ligase Parkin. On mitochondria, Parkin ubiquitinates a subset of mitochondrial-resident proteins located on the outer mitochondrial membrane, leading to the recruitment of downstream cytosolic autophagic adaptors and subsequent autophagosome formation. Importantly, PINK1/Parkin-independent mitophagy pathways also exist that can be counteracted by specific deubiquitinating enzymes (DUBs). Down-regulation of these specific DUBs can presumably enhance basal mitophagy and be beneficial in models in which the accumulation of defective mitochondria is implicated. Among these DUBs, USP8 is an interesting target because of its role in the endosomal pathway and autophagy and its beneficial effects, when inhibited, in models of neurodegeneration. Based on this, we evaluated autophagy and mitophagy levels when USP8 activity is altered. We used genetic approaches in D. melanogaster to measure autophagy and mitophagy in vivo and complementary in vitro approaches to investigate the molecular pathway that regulates mitophagy via USP8. We found an inverse correlation between basal mitophagy and USP8 levels, in that down-regulation of USP8 correlates with increased Parkin-independent mitophagy. These results suggest the existence of a yet uncharacterized mitophagic pathway that is inhibited by USP8.

Keywords:  DUBs; Parkin; USP8; autophagy; mitophagy

DOI:  https://doi.org/10.3390/cells12081143
FASEB J. 2023 06;37(6): e22969

Mitochondrial quality control in abdominal aortic aneurysm: From molecular mechanisms to therapeutic strategies.

Ding Wang, Longyuan Jia, Chengdong Zhao, Huitao Wang, Zhengnan Dai, Yuchen Jing, Bo Jiang, Shijie Xin.

  Mitochondria are the energy supply sites of cells and are crucial for eukaryotic life. Mitochondrial dysfunction is involved in the pathogenesis of abdominal aortic aneurysm (AAA). Multiple mitochondrial quality control (MQC) mechanisms, including mitochondrial DNA repair, biogenesis, antioxidant defense, dynamics, and autophagy, play vital roles in maintaining mitochondrial homeostasis under physiological and pathological conditions. Abnormalities in these mechanisms may induce mitochondrial damage and dysfunction leading to cell death and tissue remodeling. Recently, many clues suggest that dysregulation of MQC is closely related to the pathogenesis of AAA. Therefore, specific interventions targeting MQC mechanisms to maintain and restore mitochondrial function have become promising therapeutic methods for the prevention and treatment of AAA.

Keywords:  abdominal aortic aneurysm; mitochondrial quality control; molecular mechanisms; therapeutic strategies

DOI:  https://doi.org/10.1096/fj.202202158RR
J Transl Med. 2023 May 19. 21(1): 331

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

Emily B Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Melissa L Schlein, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.

   BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.
METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways.
RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction.
CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.

Keywords:  Anti-viral signaling; Inflammation; Interferon; Mitochondrial disease; PBMCs

DOI:  https://doi.org/10.1186/s12967-023-04180-w
Mitochondrion. 2023 May 10. pii: S1567-7249(23)00038-7. [Epub ahead of print]

MitoQuicLy: a high-throughput method for quantifying cell-free DNA from human plasma, serum, and saliva.

Jeremy Michelson, Shannon Rausser, Amanda Peng, Temmie Yu, Gabriel Sturm, Caroline Trumpff, Brett A Kaufman, Alex J Rai, Martin Picard.

  Circulating cell-free mitochondrial DNA (cf-mtDNA) is an emerging biomarker of psychobiological stress and disease which predicts mortality and is associated with various disease states. To evaluate the contribution of cf-mtDNA to health and disease states, standardized high-throughput procedures are needed to quantify cf-mtDNA in relevant biofluids. Here, we describe MitoQuicLy: Mitochondrial DNA Quantification in cell-free samples by Lysis. We demonstrate high agreement between MitoQuicLy and the commonly used column-based method, although MitoQuicLy is faster, cheaper, and requires a smaller input sample volume. Using 10 µL of input volume with MitoQuicLy, we quantify cf-mtDNA levels from three commonly used plasma tube types, two serum tube types, and saliva. We detect, as expected, significant inter-individual differences in cf-mtDNA across different biofluids. However, cf-mtDNA levels between concurrently collected plasma, serum, and saliva from the same individual differ on average by up to two orders of magnitude and are poorly correlated with one another, pointing to different cf-mtDNA biology or regulation between commonly used biofluids in clinical and research settings. Moreover, in a small sample of healthy women and men (n=34), we show that blood and saliva cf-mtDNAs correlate with clinical biomarkers differently depending on the sample used. The biological divergences revealed between biofluids, together with the lysis-based, cost-effective, and scalable MitoQuicLy protocol for biofluid cf-mtDNA quantification, provide a foundation to examine the biological origin and significance of cf-mtDNA to human health.

Keywords:  Cell-free DNA; Circulating nucleic acids; DNA isolation; Mitochondria; Mitochondrial DNA; Protocol

DOI:  https://doi.org/10.1016/j.mito.2023.05.001
MedComm (2020). 2023 Jun;4(3): e217

Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.

Wenzhi Li, Xiaoyu Liao, Kaibo Lin, Renfei Cai, Haiyan Guo, Meng Ma, Yao Wang, Yating Xie, Shaozhen Zhang, Zhiguang Yan, Jiqiang Si, Hongyuan Gao, Leiwen Zhao, Li Chen, Weina Yu, Chen Chen, Yun Wang, Yanping Kuang, Qifeng Lyu.

  The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle-protrusion-retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal-karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live-born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.

Keywords:  assisted reproductive technology; mitochondrial disease inheritance; mitochondrial genetic drift; mitochondrial replacement therapy; second polar body transfer

DOI:  https://doi.org/10.1002/mco2.217
Sci Adv. 2023 May 19. 9(20): eadg2235

A histone deacetylase 3 and mitochondrial complex I axis regulates toxic formaldehyde production.

Niek Wit, Ewa Gogola, James A West, Tristan Vornbäumen, Rachel V Seear, Peter S J Bailey, Guillermo Burgos-Barragan, Meng Wang, Patrycja Krawczyk, Daphne H E W Huberts, Fanni Gergely, Nicholas J Matheson, Arthur Kaser, James A Nathan, Ketan J Patel.

Cells produce considerable genotoxic formaldehyde from an unknown source. We carry out a genome-wide CRISPR-Cas9 genetic screen in metabolically engineered HAP1 cells that are auxotrophic for formaldehyde to find this cellular source. We identify histone deacetylase 3 (HDAC3) as a regulator of cellular formaldehyde production. HDAC3 regulation requires deacetylase activity, and a secondary genetic screen identifies several components of mitochondrial complex I as mediators of this regulation. Metabolic profiling indicates that this unexpected mitochondrial requirement for formaldehyde detoxification is separate from energy generation. HDAC3 and complex I therefore control the abundance of a ubiquitous genotoxic metabolite.

DOI: https://doi.org/10.1126/sciadv.adg2235
Cells. 2023 05 06. pii: 1329. [Epub ahead of print]12(9):

Cellular and Mitochondrial NAD Homeostasis in Health and Disease.

Jaylyn Waddell, Rehana Khatoon, Tibor Kristian.

  The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.

Keywords:  NAD; brain; mitochondria

DOI:  https://doi.org/10.3390/cells12091329
Mol Cell. 2023 May 06. pii: S1097-2765(23)00316-7. [Epub ahead of print]

The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy.

Tomoyuki Fukuda, Kentaro Furukawa, Tatsuro Maruyama, Shun-Ichi Yamashita, Daisuke Noshiro, Chihong Song, Yuta Ogasawara, Kentaro Okuyama, Jahangir Md Alam, Manabu Hayatsu, Tetsu Saigusa, Keiichi Inoue, Kazuho Ikeda, Akira Takai, Lin Chen, Vikramjit Lahiri, Yasushi Okada, Shinsuke Shibata, Kazuyoshi Murata, Daniel J Klionsky, Nobuo N Noda, Tomotake Kanki.

  Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.

Keywords:  Atg44; autophagy; crystal structure analysis; dynamin-related protein; high-speed atomic force microscopy; mitochondria; mitochondrial fission; mitofissin; mitophagy; yeast

DOI:  https://doi.org/10.1016/j.molcel.2023.04.022
Ther Adv Rare Dis. 2021 Jan-Dec;2:2 26330040211029037

New avenues for therapy in mitochondrial optic neuropathies.

Wing Sum Vincent Ng, Matthieu Trigano, Thomas Freeman, Carmine Varrichio, Dinesh Kumar Kandaswamy, Ben Newland, Andrea Brancale, Malgorzata Rozanowska, Marcela Votruba.

  Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed.
Plain language summary: Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.

Keywords:  LHON; OPA1; mitochondria; mitochondrial dysfunction; optic neuropathy; therapy

DOI:  https://doi.org/10.1177/26330040211029037
Sci Transl Med. 2023 May 17. 15(696): eade6509

Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging.

Tanes I Lima, Pirkka-Pekka Laurila, Martin Wohlwend, Jean David Morel, Ludger J E Goeminne, Hao Li, Mario Romani, Xiaoxu Li, Chang-Myung Oh, Dohyun Park, Sandra Rodríguez-López, Julijana Ivanisevic, Hector Gallart-Ayala, Barbara Crisol, Florence Delort, Sabrina Batonnet-Pichon, Leonardo R Silveira, Lakshmi Sankabattula Pavani Veera Venkata, Anil K Padala, Suresh Jain, Johan Auwerx.

Disruption of mitochondrial function and protein homeostasis plays a central role in aging. However, how these processes interact and what governs their failure in aging remain poorly understood. Here, we showed that ceramide biosynthesis controls the decline in mitochondrial and protein homeostasis during muscle aging. Analysis of transcriptome datasets derived from muscle biopsies obtained from both aged individuals and patients with a diverse range of muscle disorders revealed that changes in ceramide biosynthesis, as well as disturbances in mitochondrial and protein homeostasis pathways, are prevalent features in these conditions. By performing targeted lipidomics analyses, we found that ceramides accumulated in skeletal muscle with increasing age across Caenorhabditis elegans, mice, and humans. Inhibition of serine palmitoyltransferase (SPT), the rate-limiting enzyme of the ceramide de novo synthesis, by gene silencing or by treatment with myriocin restored proteostasis and mitochondrial function in human myoblasts, in C. elegans, and in the skeletal muscles of mice during aging. Restoration of these age-related processes improved health and life span in the nematode and muscle health and fitness in mice. Collectively, our data implicate pharmacological and genetic suppression of ceramide biosynthesis as potential therapeutic approaches to delay muscle aging and to manage related proteinopathies via mitochondrial and proteostasis remodeling.

DOI: https://doi.org/10.1126/scitranslmed.ade6509
Brain Nerve. 2023 May;75(5): 523-525

[Therapeutics for Mitochondrial Encephalomyopathy].

Yoshihide Sunada.

In MELAS, taurine modification defect in the anticodon of mitochondrial leucine tRNA causes codon translation failure. An investigator-started clinical trials of high-dose taurine therapy, that showed its efficacy in preventing stroke-like episodes, and improving the taurine modification rate. The drug was found to be safe. Taurine has been approved as a drug covered by public insurance for prevention of stroke-like episodes since 2019. Recently, L-arginine hydrochloride has also been approved for off-label use as a treatment for both acute and intermittent stages of stroke-like episodes.

DOI: https://doi.org/10.11477/mf.1416202371
Nature. 2023 May 11.

Lab-grown monkey embryos reveal in 3D how organs begin.

Gemma Conroy.



Keywords:  Biological techniques; Developmental biology

DOI:  https://doi.org/10.1038/d41586-023-01544-6
Int J Biochem Cell Biol. 2023 May 17. pii: S1357-2725(23)00070-5. [Epub ahead of print] 106431

Mitochondria are midfield players in steroid synthesis.

Philipp Melchinger, Bruna Martins Garcia.

  Steroids are important membrane components and signaling metabolites and thus are required for cellular homeostasis. All mammalian cells retain the ability to uptake and synthesize steroids. Dysregulation of steroid levels leads to profound effects on cellular function and organismal health. Hence it comes as no surprise that steroid synthesis is tightly regulated. It is well established that the main site for steroid synthesis and regulation is the endoplasmic reticulum. However, mitochondria are essential for: (1) cholesterol production (the precursor of all steroids) by exporting citrate and; (2) the products of steroidogenesis (such as mineralocorticoids and glucocorticoids). In this review, we describe the midfield player role of mitochondria in steroid synthesis and bring the idea of mitochondria actively participating in steroid synthesis regulation. A better understanding of the mitochondrial regulatory roles in steroid synthesis would open new avenues to targeted approaches aiming to control steroid levels.

Keywords:  Cholesterol synthesis; Mitochondria-ER contact; Steroid hormones

DOI:  https://doi.org/10.1016/j.biocel.2023.106431
Mol Genet Genomic Med. 2023 Apr 25. e2190

A case of infantile Barth syndrome with severe heart failure: Importance of splicing variants in the TAZ gene.

Atsuhito Takeda, Masahiro Ueki, Jiro Abe, Kazuhiro Maeta, Tomoko Horiguchi, Hirokuni Yamazawa, Gaku Izumi, Ayako Chida-Nagai, Daisuke Sasaki, Takao Tsujioka, Itsumi Sato, Masahiro Shiraishi, Masafumi Matsuo.

  Barth syndrome (BTHS) is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and 3-methylglutaconic aciduria. The causative pathogenic variants for BTHS are in TAZ, which encodes a putative acyltransferase named tafazzin and is involved in the remodeling of cardiolipin in the inner mitochondrial membranes. Pathogenic variants in TAZ result in mitochondrial structural and functional abnormalities. We report a case of infantile BTHS with severe heart failure, left ventricular noncompaction, and lactic acidosis, having a missense c.640C>T (p.His214Tyr) variant in TAZ, which is considered a pathogenic variant based on the previously reported amino acid substitution at the same site (c.641A>G, p.His214Arg). However, in this previously reported case, heart function was compensated and not entirely similar to the present case. Silico prediction analysis suggested that c.640C>T could alter the TAZ messenger RNA (mRNA) splicing process. TAZ mRNAs in isolated peripheral mononuclear cells from the patient and in vitro splicing analysis using minigenes of TAZ found an 8 bp deletion at the 3' end of exon 8, which resulted in the formation of a termination codon in the coding region of exon 9 (H214Nfs*3). These findings suggest that splicing abnormalities should always be considered in BTHS.

Keywords:  Barth syndrome; cardiomyopathy; left ventricular noncompaction; minigene; splicing variants

DOI:  https://doi.org/10.1002/mgg3.2190
Clin Transl Sci. 2023 May 12.

Identification of peripheral vascular function measures and circulating biomarkers of mitochondrial function in patients with mitochondrial disease.

Sebastiaan J W van Kraaij, Diana R Pereira, Bastiaan Smal, Luciana Summo, Anne Konkel, Janine Lossie, Andreas Busjahn, Tom N Grammatopoulos, Erica Klaassen, Robert Fischer, Wolf-Hagen Schunck, Pim Gal, Matthijs Moerland.

The development of pharmacological therapies for mitochondrial diseases is hampered by the lack of tissue-level and circulating biomarkers reflecting effects of compounds on endothelial and mitochondrial function. This phase 0 study aimed to identify biomarkers differentiating between patients with mitochondrial disease and healthy volunteers (HVs). In this cross-sectional case-control study, eight participants with mitochondrial disease and eight HVs matched on age, sex, and body mass index underwent study assessments consisting of blood collection for evaluation of plasma and serum biomarkers, mitochondrial function in peripheral blood mononuclear cells (PBMCs), and an array of imaging methods for assessment of (micro)circulation. Plasma biomarkers GDF-15, IL-6, NT-proBNP, and cTNI were significantly elevated in patients compared to HVs, as were several clinical chemistry and hematology markers. No differences between groups were found for mitochondrial membrane potential, mitochondrial reactive oxygen production, oxygen consumption rate, or extracellular acidification rate in PBMCs. Imaging revealed significantly higher nicotinamide-adenine-dinucleotide-hydrogen (NADH) content in skin as well as reduced passive leg movement-induced hyperemia in patients. This study confirmed results of earlier studies regarding plasma biomarkers in mitochondrial disease and identified several imaging techniques that could detect functional differences at the tissue level between participants with mitochondrial disease and HVs. However, assays of mitochondrial function in PBMCs did not show differences between participants with mitochondrial disease and HVs, possibly reflecting compensatory mechanisms and heterogeneity in mutational load. In future clinical trials, using a mix of imaging and blood-based biomarkers may be advisable, as well as combining these with an in vivo challenge to disturb homeostasis.

DOI: https://doi.org/10.1111/cts.13530
Hepatol Commun. 2023 Jun 01. pii: e0139. [Epub ahead of print]7(6):

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

Childhood Liver Disease Research Network (ChiLDReN)

BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH.
METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.
RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported.
CONCLUSIONS: Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

DOI: https://doi.org/10.1097/HC9.0000000000000139
Physiol Genomics. 2023 May 15.

Maternal and Fetal Mitochondrial Gene Dysregulation in Hypertensive Disorders of Pregnancy.

Contessa A Ricci, Danielle M Reid, Jie Sun, Donna A Santillan, Mark K Santillan, Nicole R Phillips, Styliani Goulopoulou.

  Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) were conducted in publicly available high throughput sequencing transcriptomic datasets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, while 9 were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, while fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.

Keywords:  Hypertension; Placenta; Preeclampsia; mitochondrial DNA

DOI:  https://doi.org/10.1152/physiolgenomics.00005.2023
Clinics (Sao Paulo). 2023 May 15. pii: S1807-5932(23)00042-X. [Epub ahead of print]78 100206

Mitochondrial small fiber neuropathy as a novel phenotypic trait of Leigh-like syndrome due to the variant m.10191T>C in MT-ND3.

Shaundra M Newstead, Carla A Scorza, Ana C Fiorini, Fulvio A Scorza, Josef Finsterer.

DOI: https://doi.org/10.1016/j.clinsp.2023.100206
Ther Adv Rare Dis. 2022 Jan-Dec;3:3 26330040221139872

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review.

Paridhi Jain, Lohit Badgujar, Jelle Spoorendonk, Katharina Buesch.

   Objectives: The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.
Methods: Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.
Results: Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone (n = 11), followed by recombinant erythropoietin (n = 6), omaveloxolone (n = 3), and amantadine hydrochloride (n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation (n = 1), craniocerebral injury (n = 1), and ventricular tachycardia (n = 1).
Conclusion: Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

Keywords:  FARS; Friedreich ataxia; Friedreich’s ataxia; ataxia; genetic; rare disease

DOI:  https://doi.org/10.1177/26330040221139872
iScience. 2023 May 19. 26(5): 106674

Mitochondrial Bcl-xL promotes brain synaptogenesis by controlling non-lethal caspase activation.

Trang Thi Minh Nguyen, Rudy Gadet, Marine Lanfranchi, Romane A Lahaye, Sozerko Yandiev, Olivier Lohez, Ivan Mikaelian, Lea Jabbour, Ruth Rimokh, Julien Courchet, Frédéric Saudou, Nikolay Popgeorgiev, Germain Gillet.

  Non-lethal caspase activation (NLCA) has been linked to neurodevelopmental processes. However, how neurons control NLCA remains elusive. Here, we focused on Bcl-xL, a Bcl-2 homolog regulating caspase activation through the mitochondria. We generated a mouse model, referred to as ER-xL, in which Bcl-xL is absent in the mitochondria, yet present in the endoplasmic reticulum. Unlike bclx knockout mice that died at E13.5, ER-xL mice survived embryonic development but died post-partum because of altered feeding behavior. Enhanced caspase-3 activity was observed in the brain and the spinal cord white matter, but not the gray matter. No increase in cell death was observed in ER-xL cortical neurons, suggesting that the observed caspase-3 activation was apoptosis-independent. ER-xL neurons displayed increased caspase-3 activity in the neurites, resulting in impaired axon arborescence and synaptogenesis. Together, our findings suggest that mitochondrial Bcl-xL finely tunes caspase-3 through Drp-1-dependent mitochondrial fission, which is critical to neural network design.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.106674
Biomedicines. 2023 Apr 13. pii: 1172. [Epub ahead of print]11(4):

The Y831C Mutation of the POLG Gene in Dementia.

Eugenia Borgione, Mariangela Lo Giudice, Sandro Santa Paola, Marika Giuliano, Giuseppe Lanza, Mariagiovanna Cantone, Raffaele Ferri, Carmela Scuderi.

   BACKGROUND: The POLG gene encodes the catalytic subunit of DNA polymerase γ, which is crucial for mitochondrial DNA (mtDNA) repair and replication. Gene mutation alters the stability of mtDNA and is associated with several clinical presentations, such as dysarthria and ophthalmoplegia (SANDO), progressive external ophthalmoplegia (PEO), spinocerebellar ataxia and epilepsy (SCAE), Alpers syndrome, and sensory ataxic neuropathy. Recent evidence has also indicated that POLG mutations may be involved in some neurodegenerative disorders, although systematic screening is currently lacking.
METHODS: To investigate the frequency of POLG gene mutations in neurodegenerative disorders, we screened a group of 33 patients affected by neurodegenerative diseases, including Parkinson's disease, some atypical parkinsonisms, and dementia of different types.
RESULTS: Mutational analysis revealed the presence of the heterozygous Y831C mutation in two patients, one with frontotemporal dementia and one with Lewy body dementia. The allele frequency of this mutation reported by the 1000 Genomes Project in the healthy population is 0.22%, while in our group of patients, it was 3.03%, thus showing a statistically significant difference between the two groups.
CONCLUSIONS: Our results may expand the genotype-phenotype spectrum associated with mutations in the POLG gene and strengthen the hypothesis of a pathogenic role of the Y831C mutation in neurodegeneration.

Keywords:  POLG; Y831C; dementia; movement disorders; neurodegeneration

DOI:  https://doi.org/10.3390/biomedicines11041172
Cell. 2023 May 11. pii: S0092-8674(23)00418-X. [Epub ahead of print]186(10): 2111-2126.e20

An in vivo neuroimmune organoid model to study human microglia phenotypes.

Simon T Schafer, Abed AlFatah Mansour, Johannes C M Schlachetzki, Monique Pena, Saeed Ghassemzadeh, Lisa Mitchell, Amanda Mar, Daphne Quang, Sarah Stumpf, Irene Santisteban Ortiz, Addison J Lana, Clara Baek, Raghad Zaghal, Christopher K Glass, Axel Nimmerjahn, Fred H Gage.

  Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.

Keywords:  Human microglia; autism spectrum disorders; brain organoids; iPSCs; microglia in vivo identity; microglia surveillance; neuro-immune interactions; organoid transplantation; xenotransplantation

DOI:  https://doi.org/10.1016/j.cell.2023.04.022
J Clin Invest. 2023 May 15. pii: e170226. [Epub ahead of print]133(10):

Paving a way to treat spastic paraplegia 50.

Jonathan R Brent, Han-Xiang Deng.

Spastic paraplegia 50 (SPG50) is a rare neurodegenerative disease caused by loss-of-function mutations in AP4M1. There are no effective treatments for SPG50 or any other type of SPG, and current treatments are limited to symptomatic management. In this issue of the JCI, Chen et al. provide promising data from preclinical studies that evaluated the efficacy and safety profiles of an AAV-mediated AP4M1 gene replacement therapy for SPG50. AAV/AP4M1 gene replacement partly rescued functional defects in SPG50 cellular and mouse models, with acceptable safety profiles in rodents and monkeys. This work represents a substantial advancement in therapeutic development of SPG50 treatments, establishing the criteria for taking AAV9/AP4M1 gene therapy to clinical trials.

DOI: https://doi.org/10.1172/JCI170226
Cell Prolif. 2023 May 12. e13459

Adult progenitor rejuvenation with embryonic factors.

Peng Wang, Xupeng Liu, Yu Chen, Elwin Tan Jun-Hao, Ziyue Yao, Jason Chua Min-Wen, Benjamin Chua Yan-Jiang, Shilin Ma, Wenwu Ma, Lanfang Luo, Luyao Guo, Dan Song, Ng Shyh-Chang.

During ageing, adult stem cells' regenerative properties decline, as they undergo replicative senescence and lose both their proliferative and differentiation capacities. In contrast, embryonic and foetal progenitors typically possess heightened proliferative capacities and manifest a more robust regenerative response upon injury and transplantation, despite undergoing many rounds of mitosis. How embryonic and foetal progenitors delay senescence and maintain their proliferative and differentiation capacities after numerous rounds of mitosis, remains unknown. It is also unclear if defined embryonic factors can rejuvenate adult progenitors to confer extended proliferative and differentiation capacities, without reprogramming their lineage-specific fates or inducing oncogenic transformation. Here, we report that a minimal combination of LIN28A, TERT, and sh-p53 (LTS), all of which are tightly regulated and play important roles during embryonic development, can delay senescence in adult muscle progenitors. LTS muscle progenitors showed an extended proliferative capacity, maintained a normal karyotype, underwent myogenesis normally, and did not manifest tumorigenesis nor aberrations in lineage differentiation, even in late passages. LTS treatment promoted self-renewal and rescued the pro-senescence phenotype of aged cachexia patients' muscle progenitors, and promoted their engraftment for skeletal muscle regeneration in vivo. When we examined the mechanistic basis for LIN28A's role in the LTS minimum combo, let-7 microRNA suppression could not fully explain how LIN28A promoted muscle progenitor self-renewal. Instead, LIN28A was promoting the translation of oxidative phosphorylation mRNAs in adult muscle progenitors to optimize mitochondrial reactive oxygen species (mtROS) and mitohormetic signalling. Optimized mtROS induced a variety of mitohormetic stress responses, including the hypoxic response for metabolic damage, the unfolded protein response for protein damage, and the p53 response for DNA damage. Perturbation of mtROS levels specifically abrogated the LIN28A-driven hypoxic response in Hypoxia Inducible Factor-1α (HIF1α) and glycolysis, and thus LTS progenitor self-renewal, without affecting normal or TS progenitors. Our findings connect embryonically regulated factors to mitohormesis and progenitor rejuvenation, with implications for ageing-related muscle degeneration.

DOI: https://doi.org/10.1111/cpr.13459