bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2023–01–01
25 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Incompatibilities between common mtDNA variants in human disease.
  2. Overcoming mitochondrial dysfunction in neurodegenerative diseases.
  3. Mitochondrial quality control in the brain: The physiological and pathological roles.
  4. Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.
  5. Mitochondrial function of human embryo: Decline in their quality with maternal aging.
  6. Mitochondria in Huntington's disease: implications in pathogenesis and mitochondrial-targeted therapeutic strategies.
  7. Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.
  8. Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.
  9. Dissection of the autophagic route in oocytes from atretic follicles.
  10. A review of protocols for brain organoids and applications for disease modeling.
  11. High-frequency and functional mitochondrial DNA mutations at the single-cell level.
  12. The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
  13. Age-associated alterations of brain mitochondria energetics.
  14. Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.
  15. Mitochondria and peroxisomes: partners in autophagy.
  16. Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes.
  17. Mitochondrial dynamics, elimination and biogenesis during post-ischemic recovery in ischemia-resistant and ischemia-vulnerable gerbil hippocampal regions.
  18. Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort.
  19. Low disease risk and penetrance in Leber hereditary optic neuropathy.
  20. Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.
  21. Mitochondrial Calcium Homeostasis in the Pathology and Therapeutic Application in Friedreich's Ataxia.
  22. MRI Findings in a Patient with Known SCAR-16 Type STUB1 Associated Cerebellar Ataxia.
  23. Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.
  24. Organoid technology and applications in lung diseases: Models, mechanism research and therapy opportunities.
  25. Generation of an iPSC line from a patient with spastic paraplegia type 10 carrying a novel mutation in KIF5A gene.
  1. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2217452119
    Incompatibilities between common mtDNA variants in human disease.
    Weilin Pu, Zhenglong Gu.
      
    DOI:  https://doi.org/10.1073/pnas.2217452119
  2. Neural Regen Res. 2023 Jul;18(7): 1486-1488
    Overcoming mitochondrial dysfunction in neurodegenerative diseases.
    João Pessoa, Ana I Duarte.
      
    DOI:  https://doi.org/10.4103/1673-5374.360279
  3. Front Neurosci. 2022 ;16 1075141
    Mitochondrial quality control in the brain: The physiological and pathological roles.
    Xurui Shen, Peixin Sun, Hao Zhang, Hanting Yang.
      The human brain has high energetic expenses and consumes over 20% of total oxygen metabolism. Abnormal brain energy homeostasis leads to various brain diseases. Among multiple factors that contribute to these diseases, mitochondrial dysfunction is one of the most common causes. Maintenance of mitochondrial integrity and functionality is of pivotal importance to brain energy generation. Mitochondrial quality control (MQC), employing the coordination of multiple mechanisms, is evolved to overcome many mitochondrial defects. Thus, not surprisingly, aberrant mitochondrial quality control results in a wide range of brain disorders. Targeting MQC to preserve and restore mitochondrial function has emerged as a promising therapeutic strategy for the prevention and treatment of brain diseases. Here, we set out to summarize the current understanding of mitochondrial quality control in brain homeostasis. We also evaluate potential pharmaceutically and clinically relevant targets in MQC-associated brain disorders.
    Keywords:  brain disorders; mitochondrial dysfunction; mitochondrial homeostasis; mitochondrial quality control; therapeutic target
    DOI:  https://doi.org/10.3389/fnins.2022.1075141
  4. Curr Opin Cell Biol. 2022 Dec 27. pii: S0955-0674(22)00103-X. [Epub ahead of print]80 102150
    Mitochondrial movers and shapers: Recent insights into regulators of fission, fusion and transport.
    Nida Ul Fatima, Vaishnavi Ananthanarayanan.
      Mitochondria are highly dynamic organelles that undergo rapid morphological adaptations influencing their number, transport, cellular distribution, and function, which in turn facilitate the integration of mitochondrial function with physiological changes in the cell. These mitochondrial dynamics are dependent on tightly regulated processes such as fission, fusion, and attachment to the cytoskeleton, and their defects are observed in various pathophysiological conditions including cancer, cardiovascular disease, and neurodegeneration. Various studies over the years have identified key molecular players and uncovered the mechanisms that mediate and regulate these processes and have highlighted their complexity and context-specificity. This review focuses on the recent studies that have contributed to the understanding of processes that influence mitochondrial morphology including fission, fusion, and transport in the cell.
    Keywords:  Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Mitochondrial transport
    DOI:  https://doi.org/10.1016/j.ceb.2022.102150
  5. Reprod Med Biol. 2022 Jan-Dec;21(1):21(1): e12491
    Mitochondrial function of human embryo: Decline in their quality with maternal aging.
    Shu Hashimoto, Yoshiharu Morimoto.
       Background: Female fertility declines with age, due to increased chromosomal aneuploidy and possible reduced mitochondrial function in the embryo.
    Methods: This review outlines how mitochondrial function in human embryos, as predicted from oxygen consumption rate (OCR) measurements, changes in preimplantation stage, and what factors, particularly maternal age, affect mitochondrial function in embryos.
    Main findings: The structure of the mitochondrial inner membrane and its respiratory function developed with embryo development, while the copy number of mitochondrial DNA per specimen was transiently reduced compared with that of the oocyte. The undifferentiated state of the inner cell mass cells appears to be associated with a low OCR. In contrast, the copy number of mitochondrial DNA increased in trophoblast cells and mitochondrial aerobic metabolism increased.The OCRs at morulae stage decreased with maternal age, but there was no relationship between maternal age and the copy number of mitochondrial DNA at any stages. The higher oxygen spent at the morula stage; the shorter time was needed for development to the mid-stage blastocyst.
    Conclusions: The mitochondrial respiratory function of human embryos developed along with embryonic growth. Mitochondrial function at morula stage declined with their maternal age and reduced mitochondrial function decreased the rate of development from morula to blastocyst.
    Keywords:  human embryo; maternal age; mitochondrial function; morula; oxygen consumption rate
    DOI:  https://doi.org/10.1002/rmb2.12491
  6. Neural Regen Res. 2023 Jul;18(7): 1472-1477
    Mitochondria in Huntington's disease: implications in pathogenesis and mitochondrial-targeted therapeutic strategies.
    Anamaria Jurcau, Carolina Maria Jurcau.
      Huntington's disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4. Compelling evidence implicates impaired mitochondrial energetics, altered mitochondrial biogenesis and quality control, disturbed mitochondrial trafficking, oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder. Unfortunately, conventional mitochondrial-targeted molecules, such as cysteamine, creatine, coenzyme Q10, or triheptanoin, yielded negative or inconclusive results. However, future therapeutic strategies, aiming to restore mitochondrial biogenesis, improving the fission/fusion balance, and improving mitochondrial trafficking, could prove useful tools in improving the phenotype of Huntington's disease and, used in combination with genome-editing methods, could lead to a cure for the disease.
    Keywords:  Huntington’s disease; SS peptides; antioxidants; calcium homeostasis; mitochondrial biogenesis; mitochondrial fission/fusion; mitochondrial trafficking; oxidative phosphorylation; oxidative stress; therapeutic intervention
    DOI:  https://doi.org/10.4103/1673-5374.360289
  7. J Clin Lab Anal. 2022 Dec 29. e24827
    Detecting mitochondrial mutations associated with aminoglycoside ototoxicity by noninvasive prenatal testing.
    Quanfei Huang, Yanhui Liu, Wei Lei, Jiajie Liang, Yang Wang, Minhua Zheng, Xiaoyan Huang, Yuanru Liu, Kaisheng Huang, Min Huang.
       OBJECTIVES: Numerous diseases and disorders are associated with mitochondrial DNA (mtDNA) mutations, among which m.1555A > G and m.1494C > T mutations in the 12 S ribosomal RNA gene contribute to aminoglycoside-induced and nonsyndromic hearing loss worldwide.
    METHODS: A total of 76,842 qualified non-invasive prenatal (NIPT) samples were subjected to mtDNA mutation and haplogroup analysis.
    RESULTS: We detected 181 m.1555A > G and m.1494C > T mutations, 151 of which were subsequently sequenced for full-length mitochondrial genome verification. The positive predictive values for the m.1555A > G and m.1494C > T mutations were 90.78% and 90.00%, respectively, a performance comparable to that attained with newborn hearing screening. Furthermore, mitochondrial haplogroup analysis revealed that the 12 S rRNA 1555A > G mutation was enriched in sub-haplotype D5[p = 0, OR = 4.6706(2.81-7.78)].
    CONCLUSIONS: Our findings indicate that the non-invasive prenatal testing of cell-free DNA obtained from maternal plasma can successfully detect m.1555A > G and m.1494C > T mutations.
    Keywords:  PPV; mitochondrial DNA (mtDNA); newborn hearing screening (NBHS); noninvasive prenatal testing (NIPT); secondary finding
    DOI:  https://doi.org/10.1002/jcla.24827
  8. Life Sci. 2022 Dec 26. pii: S0024-3205(22)01025-6. [Epub ahead of print] 121325
    Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.
    Hasan Turkez, Ozlem Altay, Serkan Yildirim, Xiangyu Li, Hong Yang, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Muhammad Arif, Burak Yulug, Lutfu Hanoglu, Seyda Cankaya, Simon Lam, Halil Aziz Velioglu, Ebru Coskun, Ezgi Idil, Rahim Nogaylar, Ahmet Ozsimsek, Ahmet Hacimuftuoglu, Saeed Shoaie, Cheng Zhang, Jens Nielsen, Jan Borén, Mathias Uhlén, Adil Mardinoglu.
       BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism.
    METHODS: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation.
    FINDINGS: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats.
    INTERPRETATION: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.
    Keywords:  Animal model; Combined metabolic activators; Genome-scale metabolic model; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.lfs.2022.121325
  9. Biol Cell. 2022 Dec 26.
    Dissection of the autophagic route in oocytes from atretic follicles.
    Abraham Castro-Cruz, Olga M Echeverría, Luis Sánchez-Sánchez, Israel Muñoz-Velasco, Silvia Juárez-Chavero, Nayeli Torres-Ramírez, Gerardo H Vázquez-Nin, M Luisa Escobar.
       BACKGROUND INFORMATION: Various types of stress initially induce a state of cardiac hypertrophy (CH) in the heart. But, persistent escalation of cardiac stress leads to progression from an adaptive physiological to a maladaptive pathological state. So, elucidating molecular mechanisms that can attenuate CH is imperative in developing cardiac therapies. Previously, we showed that Prohibitin1 (PHB1) has a protective role in CH-induced oxidative stress. Nevertheless, it is unclear how PHB1, a mitochondrial protein, has a protective role in CH. Therefore, we hypothesized that PHB1 maintains mitochondrial quality in CH. To test this hypothesis, we used Isoproterenol (ISO) to induce CH in H9C2 cells overexpressing PHB1 and elucidated mitochondrial quality control pathways.
    RESULTS: We found that overexpressing PHB1 attenuates ISO-induced CH and restores mitochondrial morphology in H9C2 cells. In addition, PHB1 blocks the pro-hypertrophic IGF1R/AKT pathway and restores the mitochondrial membrane polarization in ISO-treated cells. We observed that overexpressing PHB1 promotes mitochondrial biogenesis, improves mitochondrial respiratory capacity, and triggers mitophagy.
    CONCLUSION: We conclude that PHB1 maintains mitochondrial quality in ISO-induced CH in H9C2 cells.
    Keywords:  atresia; autophagy; cell death; oocyte; ovary
    DOI:  https://doi.org/10.1111/boc.202200046
  10. STAR Protoc. 2022 Dec 23. pii: S2666-1667(22)00740-7. [Epub ahead of print]4(1): 101860
    A review of protocols for brain organoids and applications for disease modeling.
    Christopher N Mayhew, Richa Singhania.
      Recent breakthroughs in human stem cell technologies have enabled the generation of 3D brain organoid platforms for modeling human neurodevelopment and disease. Here, we review advances in brain organoid development, approaches for generating whole-brain or cerebral organoids and region-specific brain organoids, and their applications in disease modeling. We present a comprehensive overview of various brain organoid generation protocols, including culture steps, media, timelines, and technical considerations associated with each protocol, and highlight the advantages and disadvantages of each protocol. We also discuss the current limitations as well as increasing sophistication of brain organoid technology, and future directions for the field. These insights provide a valuable assessment of multiple commonly used brain organoid models and main considerations for investigators who are considering implementing brain organoid technologies in their laboratories.
    Keywords:  cell culture; organoids; stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101860
  11. Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2201518120
    High-frequency and functional mitochondrial DNA mutations at the single-cell level.
    Xiaoxian Guo, Weilin Xu, Weiping Zhang, Cuiping Pan, Anna E Thalacker-Mercer, Hongxiang Zheng, Zhenglong Gu.
      Decline in mitochondrial function underlies aging and age-related diseases, but the role of mitochondrial DNA (mtDNA) mutations in these processes remains elusive. To investigate patterns of mtDNA mutations, it is particularly important to quantify mtDNA mutations and their associated pathogenic effects at the single-cell level. However, existing single-cell mtDNA sequencing approaches remain inefficient due to high cost and low mtDNA on-target rates. In this study, we developed a cost-effective mtDNA targeted-sequencing protocol called single-cell sequencing by targeted amplification of multiplex probes (scSTAMP) and experimentally validated its reliability. We then applied our method to assess single-cell mtDNA mutations in 768 B lymphocytes and 768 monocytes from a 76-y-old female. Across 632 B lymphocyte and 617 monocytes with medium mtDNA coverage over >100×, our results indicated that over 50% of cells carried at least one mtDNA mutation with variant allele frequencies (VAFs) over 20%, and that cells carried an average of 0.658 and 0.712 such mutation for B lymphocytes and monocytes, respectively. Surprisingly, more than 20% of the observed mutations had VAFs of over 90% in either cell population. In addition, over 60% of the mutations were in protein-coding genes, of which over 70% were nonsynonymous, and more than 50% of the nonsynonymous mutations were predicted to be highly pathogenic. Interestingly, about 80% of the observed mutations were singletons in the respective cell populations. Our results revealed mtDNA mutations with functional significance might be prevalent at advanced age, calling further investigation on age-related mtDNA mutation dynamics at the single-cell level.
    Keywords:  aging; mitochondrial DNA; single cell
    DOI:  https://doi.org/10.1073/pnas.2201518120
  12. Sci Rep. 2022 Dec 27. 12(1): 22433
    The membrane domain of respiratory complex I accumulates during muscle aging in Drosophila melanogaster.
    Kaniz Fatima Binte Hossain, Anjaneyulu Murari, Bibhuti Mishra, Edward Owusu-Ansah.
      The boot-shaped respiratory complex I (CI) consists of a mitochondrial matrix and membrane domain organized into N-, Q- and P-modules. The N-module is the most distal part of the matrix domain, whereas the Q-module is situated between the N-module and the membrane domain. The proton-pumping P-module is situated in the membrane domain. We explored the effect of aging on the disintegration of CI and its constituent subcomplexes and modules in Drosophila flight muscles. We find that the fully-assembled complex remains largely intact in aged flies. And while the effect of aging on the stability of many Q- and N-module subunits in subcomplexes was stochastic, NDUFS3 was consistently down-regulated in subcomplexes with age. This was associated with an accumulation of many P-module subunits in subcomplexes. The potential significance of these studies is that genetic manipulations aimed at boosting, perhaps, a few CI subunits may suffice to restore the whole CI biosynthesis pathway during muscle aging.
    DOI:  https://doi.org/10.1038/s41598-022-26414-5
  13. Biochem Biophys Res Commun. 2022 Dec 23. pii: S0006-291X(22)01741-7. [Epub ahead of print]643 1-7
    Age-associated alterations of brain mitochondria energetics.
    Timur Gainutdinov, Zemfira Gizatullina, Grazyna Debska-Vielhaber, Stefan Vielhaber, Robert Feldmann, Zulfiya Orynbayeva, Frank Norbert Gellerich.
      The study aimed to explore the role of age-associated elevated cytosolic Ca2+ in changes of brain mitochondria energetic processes. Two groups of rats, young adults (4 months) and advanced old (24 months), were evaluated for potential alterations of mitochondrial parameters, the oxidative phosphorylation (OxPhos), membrane potential, calcium retention capacity, activity of glutamate/aspartate carrier (aralar), and ROS formation. We demonstrated that the brain mitochondria of older animals have a lower resistance to Ca2+ stress with resulting consequences. The suppressed complex I OxPhos and decreased membrane potential were accompanied by reduction of the Ca2+ threshold required for induction of mPTP. The Ca2+ binding sites of mitochondrial aralar mediated a lower activity of old brain mitochondria. The altered interaction between aralar and mPTP may underlie mitochondrial dysregulation leading to energetic depression during aging. At the advanced stages of aging, the declined metabolism is accompanied by the diminished oxidative background.
    Keywords:  Aging; Aralar; Brain mitochondria; Ca(2+); OxPhos; ROS
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.070
  14. Transl Neurodegener. 2022 Dec 28. 11(1): 58
    Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.
    Ankit Verma, Anna Shteinfer-Kuzmine, Nikita Kamenetsky, Srinivas Pittala, Avijit Paul, Edna Nahon Crystal, Alberto Ouro, Vered Chalifa-Caspi, Swaroop Kumar Pandey, Alon Monsengo, Noga Vardi, Shira Knafo, Varda Shoshan-Barmatz.
       BACKGROUND: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.
    METHODS: To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests.
    RESULTS: In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.
    CONCLUSIONS: The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.
    Keywords:  Alzheimer’s disease; Metabolism; Mitochondria; Neuroinflammation; VDAC1
    DOI:  https://doi.org/10.1186/s40035-022-00329-7
  15. Autophagy. 2022 Dec 26. 1-2
    Mitochondria and peroxisomes: partners in autophagy.
    Léa P Wilhelm, Ian G Ganley.
      Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.
    Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2155368
  16. Stem Cell Res Ther. 2022 Dec 27. 13(1): 531
    Small molecule-mediated rapid maturation of human induced pluripotent stem cell-derived cardiomyocytes.
    Nino Chirico, Elise L Kessler, Renée G C Maas, Juntao Fang, Jiabin Qin, Inge Dokter, Mark Daniels, Tomo Šarić, Klaus Neef, Jan-Willem Buikema, Zhiyong Lei, Pieter A Doevendans, Joost P G Sluijter, Alain van Mil.
       BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature primary cardiomyocytes, especially the ability to use fatty acids (FA) as an energy source, containing high mitochondrial mass, presenting binucleation and increased DNA content per nuclei (polyploidism), and synchronized electrical conduction. This immaturity represents a bottleneck to their application in (1) disease modelling-as most cardiac (genetic) diseases have a middle-age onset-and (2) clinically relevant models, where integration and functional coupling are key. So far, several methods have been reported to enhance iPSC-CM maturation; however, these protocols are laborious, costly, and not easily scalable. Therefore, we developed a simple, low-cost, and rapid protocol to promote cardiomyocyte maturation using two small molecule activators of the peroxisome proliferator-activated receptor β/δ and gamma coactivator 1-alpha (PPAR/PGC-1α) pathway: asiatic acid (AA) and GW501516 (GW). METHODS AND RESULTS: Monolayers of iPSC-CMs were incubated with AA or GW every other day for ten days resulting in increased expression of FA metabolism-related genes and markers for mitochondrial activity. AA-treated iPSC-CMs responsiveness to the mitochondrial respiratory chain inhibitors increased and exhibited higher flexibility in substrate utilization. Additionally, structural maturity improved after treatment as demonstrated by an increase in mRNA expression of sarcomeric-related genes and higher nuclear polyploidy in AA-treated samples. Furthermore, treatment led to increased ion channel gene expression and protein levels.
    CONCLUSIONS: Collectively, we developed a fast, easy, and economical method to induce iPSC-CMs maturation via PPAR/PGC-1α activation. Treatment with AA or GW led to increased metabolic, structural, functional, and electrophysiological maturation, evaluated using a multiparametric quality assessment.
    Keywords:  Asiatic acid; GW501516; Human induced pluripotent stem cell-derived cardiomyocyte; Maturation; PGC-1α; PPAR
    DOI:  https://doi.org/10.1186/s13287-022-03209-z
  17. Biochim Biophys Acta Mol Basis Dis. 2022 Dec 22. pii: S0925-4439(22)00304-0. [Epub ahead of print]1869(3): 166633
    Mitochondrial dynamics, elimination and biogenesis during post-ischemic recovery in ischemia-resistant and ischemia-vulnerable gerbil hippocampal regions.
    Maria Kawalec, Piotr Wojtyniak, Ewelina Bielska, Anita Lewczuk, Anna Boratyńska-Jasińska, Małgorzata Beręsewicz-Haller, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Barbara Zabłocka.
      Transient ischemic attacks (TIA) result from a temporary blockage in blood circulation in the brain. As TIAs cause disabilities and often precede full-scale strokes, the effects of TIA are investigated to develop neuroprotective therapies. We analyzed changes in mitochondrial network dynamics, mitophagy and biogenesis in sections of gerbil hippocampus characterized by a different neuronal survival rate after 5-minute ischemia-reperfusion (I/R) insult. Our research revealed a significantly greater mtDNA/nDNA ratio in CA2-3, DG hippocampal regions (5.8 ± 1.4 vs 3.6 ± 0.8 in CA1) that corresponded to a neuronal resistance to I/R. During reperfusion, an increase of pro-fission (phospho-Ser616-Drp1/Drp1) and pro-fusion proteins (1.6 ± 0.5 and 1.4 ± 0.3 for Mfn2 and Opa1, respectively) was observed in CA2-3, DG. Selective autophagy markers, PINK1 and SQSTM1/p62, were elevated 24-96 h after I/R and accompanied by significant elevation of transcription factors proteins PGC-1α and Nrf1 (1.2 ± 0.4, 1.78 ± 0.6, respectively) and increased respiratory chain proteins (e.g., 1.5 ± 0.3 for complex IV at I/R 96 h). Contrastingly, decreased enzymatic activity of citrate synthase, reduced Hsp60 protein level and electron transport chain subunits (0.88 ± 0.03, 0.74 ± 0.1 and 0.71 ± 0.1 for complex IV at I/R 96 h, respectively) were observed in I/R-vulnerable CA1. The phospho-Ser616-Drp1/Drp1 was increased while Mfn2 and total Opa1 reduced to 0.88 ± 0.1 and 0.77 ± 0.17, respectively. General autophagy, measured as LC3-II/I ratio, was activated 3 h after reperfusion reaching 2.37 ± 0.9 of control. This study demonstrated that enhanced mitochondrial fusion, followed by late and selective mitophagy and mitochondrial biogenesis might together contribute to reduced susceptibility to TIA.
    Keywords:  Autophagy; Electron transport chain; Mitochondrial biogenesis; Mitophagy; Transient brain ischemia; hippocampus; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166633
  18. Front Aging Neurosci. 2022 ;14 1085406
    Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort.
    Giacomina Rossi, Erika Salvi, Elkadia Mehmeti, Martina Ricci, Cristina Villa, Sara Prioni, Fabio Moda, Giuseppe Di Fede, Pietro Tiraboschi, Veronica Redaelli, Cinzia Coppola, Giacomo Koch, Elisa Canu, Massimo Filippi, Federica Agosta, Giorgio Giaccone, Paola Caroppo.
      Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1. Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype-phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD.
    Keywords:  frontotemporal dementia; genetic variant; mutation; next generation sequencing; pathogenic; right temporal variant; semantic variant
    DOI:  https://doi.org/10.3389/fnagi.2022.1085406
  19. Am J Hum Genet. 2022 Dec 21. pii: S0002-9297(22)00504-3. [Epub ahead of print]
    Low disease risk and penetrance in Leber hereditary optic neuropathy.
    Eloise C Watson, Ryan L Davis, Shyamsundar Ravishankar, Joseph Copty, Sarah Kummerfeld, Carolyn M Sue.
      The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.
    Keywords:  LHON; Leber hereditary optic neuropathy; mitochondrial disease; penetrance; prevalence; risk; vision los
    DOI:  https://doi.org/10.1016/j.ajhg.2022.11.013
  20. Front Neurol. 2022 ;13 1066040
    Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.
    Louise Sloth Kodal, Sophia Hammer-Hansen, Sonja Holm-Yildiz, Karen Grønskov, Helena Gásdal Karstensen, Tina Dysgaard.
      SLC25A46 is a mitochondrial protein involved in mitochondrial dynamics. Recently, bi-allelic variants have been identified as a pathogenic cause in a spectrum of neurological syndromes. We report a novel homozygous SLC25A46 variant in two siblings, originating from Iraq. Both presented with optic atrophy and varying neurological symptoms. The neurological examination and nerve conduction studies were consistent with sensorimotor polyneuropathy, one having mild polyneuropathy and the other pronounced polyneuropathy. The cases illustrate the disease spectrum and provide substantial information to the knowledge of polyneuropathy caused by SLC25A46 variants. It further highlights the diagnostic potentials of whole exome sequencing which can improve future understanding of disease mechanisms.
    Keywords:  case report; hereditary neuropathy; optic atrophy; polyneuropathy; whole exome sequencing
    DOI:  https://doi.org/10.3389/fneur.2022.1066040
  21. Neurosci Bull. 2022 Dec 28.
    Mitochondrial Calcium Homeostasis in the Pathology and Therapeutic Application in Friedreich's Ataxia.
    Hongting Zhao, Zhuoyuan Li, Yutong Liu, Meng Zhang, Kuanyu Li.
      
    DOI:  https://doi.org/10.1007/s12264-022-01007-4
  22. J Belg Soc Radiol. 2022 ;106(1): 131
    MRI Findings in a Patient with Known SCAR-16 Type STUB1 Associated Cerebellar Ataxia.
    Alexander Thorvaldsson, Pir Abdul Ahad Aziz Qureshi, Vikram Rao Bollineni.
      Our case report describes a 34-year-old patient sent for magnetic resonance imaging (MRI) after four years of slow onset neurological symptoms. An MRI of her brain showed moderate to severe atrophy of the cerebellum and brainstem. She has a family history of spinocerebellar ataxia and has known STUB1 mutation. Imaging features, genetic analysis, and clinical history are in keeping with the SCAR-16 type of STUB1-associated cerebellar ataxia.
    Teaching Point: This case report will help the radiologist to familiarize themselves with the CT and MRI features of STUB1-associated cerebellar ataxia and will provide suggestions to further differentiate between the SCAR-16 and SCA-48 types of STUB1-associated cerebellar ataxia.
    Keywords:  STUB1; cerebellar ataxia; magnetic resonance imaging; spinocerebellar ataxias
    DOI:  https://doi.org/10.5334/jbsr.2902
  23. Cell Mol Neurobiol. 2022 Dec 26.
    Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.
    Rishi R Agrawal, Delfina Larrea, Yimeng Xu, Lingyan Shi, Hylde Zirpoli, Leslie G Cummins, Valentina Emmanuele, Donghui Song, Taekyung D Yun, Frank P Macaluso, Wei Min, Steven G Kernie, Richard J Deckelbaum, Estela Area-Gomez.
      Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.
    Keywords:  Alzheimer’s; Brain injury; Contact sites; Lipids; Mitochondria; Neurodegeneration
    DOI:  https://doi.org/10.1007/s10571-022-01299-0
  24. Front Bioeng Biotechnol. 2022 ;10 1066869
    Organoid technology and applications in lung diseases: Models, mechanism research and therapy opportunities.
    Jingyao Chen, Feifei Na.
      The prevalency of lung disease has increased worldwide, especially in the aging population. It is essential to develop novel disease models, that are superior to traditional models. Organoids are three-dimensional (3D) in vitro structures that produce from self-organizing and differentiating stem cells, including pluripotent stem cells (PSCs) or adult stem cells (ASCs). They can recapitulate the in vivo cellular heterogeneity, genetic characteristics, structure, and functionality of original tissues. Drug responses of patient-derived organoids (PDOs) are consistent with that of patients, and show correlations with genetic alterations. Thus, organoids have proven to be valuable in studying the biology of disease, testing preclinical drugs and developing novel therapies. In recent years, organoids have been successfully applied in studies of a variety of lung diseases, such as lung cancer, influenza, cystic fibrosis, idiopathic pulmonary fibrosis, and the recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. In this review, we provide an update on the generation of organoid models for these diseases and their applications in basic and translational research, highlighting these signs of progress in pathogenesis study, drug screening, personalized medicine and immunotherapy. We also discuss the current limitations and future perspectives in organoid models of lung diseases.
    Keywords:  SARS-CoV-2; drug discovery; lung cancer; lung diseases; organoids
    DOI:  https://doi.org/10.3389/fbioe.2022.1066869
  25. Stem Cell Res. 2022 Dec 21. pii: S1873-5061(22)00357-9. [Epub ahead of print]66 103008
    Generation of an iPSC line from a patient with spastic paraplegia type 10 carrying a novel mutation in KIF5A gene.
    Serena Santangelo, Patrizia Bossolasco, Stefania Magri, Claudia Colombrita, Sabrina Invernizzi, Cinzia Gellera, Lorenzo Nanetti, Daniela Di Bella, Vincenzo Silani, Franco Taroni, Antonia Ratti.
      We generated an iPSC line from a patient with spastic paraplegia type 10 (SPG10) carrying the novel missense variant c.50G > A (p.R17Q) in the N-terminal motor domain of the kinesin family member 5A (KIF5A) gene. This patient-derived in vitro cell model will help to investigate the role of different KIF5A mutations in inducing neurodegeneration in spastic paraplegia and in other KIF5A-related disorders, including Charcot-Marie-Tooth type 2 (CMT2) and amyotrophic lateral sclerosis (ALS).
    DOI:  https://doi.org/10.1016/j.scr.2022.103008
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