bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2022–08–21
23 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.
  2. Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.
  3. Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.
  4. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
  5. The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
  6. Ethical implementation of mitochondrial donation in Australia.
  7. Phase separation may drive mitochondrial nucleoid compartmentation.
  8. Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study.
  9. The role of mtDNA in oocyte quality and embryo development.
  10. Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
  11. UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
  12. Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.
  13. Targeting Mitophagy to Promote Apoptosis is a Potential Therapeutic Strategy for Cancer.
  14. Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.
  15. High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration.
  16. Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.
  17. Single-cell multiomics analyses of spindle-transferred human embryos suggest a mostly normal embryonic development.
  18. Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C or nonalcoholic steatohepatitis.
  19. The A'-helix of CYP11A1 remodels mitochondrial cristae.
  20. Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.
  21. Receptor-mediated mitophagy: An emerging therapeutic target in acute kidney injury.
  22. Improving the differentiation potential of pluripotent stem cells by optimizing culture conditions.
  23. Ensuring a future for gene therapy for rare diseases.
  1. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2120157119
    Noncanonical PDK4 action alters mitochondrial dynamics to affect the cellular respiratory status.
    Themis Thoudam, Dipanjan Chanda, Ibotombi Singh Sinam, Byung-Gyu Kim, Mi-Jin Kim, Chang Joo Oh, Jung Yi Lee, Min-Ji Kim, Soo Yeun Park, Shin Yup Lee, Min-Kyo Jung, Ji Young Mun, Robert A Harris, Naotada Ishihara, Jae-Han Jeon, In-Kyu Lee.
      Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
    Keywords:  OCR; dynamin-related protein 1; mitochondrial fission; pyruvate dehydrogenase kinase 4; septin 2
    DOI:  https://doi.org/10.1073/pnas.2120157119
  2. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01021-X. [Epub ahead of print]40(7): 111204
    Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.
    Chao Liang, Shan Zhang, David Robinson, Matthew Vander Ploeg, Rebecca Wilson, Jiemin Nah, Dale Taylor, Sheryl Beh, Radiance Lim, Lei Sun, Deborah M Muoio, David A Stroud, Lena Ho.
      Electron transport chain (ETC) biogenesis is tightly coupled to energy levels and availability of ETC subunits. Complex III (CIII), controlling ubiquinol:ubiquinone ratio in ETC, is an attractive node for modulating ETC levels during metabolic stress. Here, we report the discovery of mammalian Co-ordinator of mitochondrial CYTB (COM) complexes that regulate the stepwise CIII biogenesis in response to nutrient and nuclear-encoded ETC subunit availability. The COMA complex, consisting of UQCC1/2 and membrane anchor C16ORF91, facilitates translation of CIII enzymatic core subunit CYTB. Subsequently, microproteins SMIM4 and BRAWNIN together with COMA subunits form the COMB complex to stabilize nascent CYTB. Finally, UQCC3-containing COMC facilitates CYTB hemylation and association with downstream CIII subunits. Furthermore, when nuclear CIII subunits are limiting, COMB is required to chaperone nascent CYTB to prevent OXPHOS collapse. Our studies highlight CYTB synthesis as a key regulatory node of ETC biogenesis and uncover the roles of microproteins in maintaining mitochondrial homeostasis.
    Keywords:  CP: Metabolism; CYTB; SEPs; SMIM4; UQCC1; UQCC2; complex III; electron transport chain; microproteins; nuclear-mitochondrial coordination; smORFs
    DOI:  https://doi.org/10.1016/j.celrep.2022.111204
  3. J Neurol. 2022 Aug 18.
    Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.
    V Montano, P Lopriore, F Gruosso, V Carelli, G P Comi, M Filosto, C Lamperti, T Mongini, O Musumeci, S Servidei, P Tonin, A Toscano, G Primiano, M L Valentino, S Bortolani, S Marchet, G Ricci, A Modenese, S Cotti Piccinelli, B Risi, M Meneri, I G Arena, G Siciliano, Michelangelo Mancuso.
       OBJECTIVES: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
    METHODS: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.
    RESULTS: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.
    CONCLUSIONS: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.
    Keywords:  6MWT; Fatigue; Mitochondrial disorders; Outcome measures; Pain; Primary mitochondrial myopathy
    DOI:  https://doi.org/10.1007/s00415-022-11324-3
  4. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01015-4. [Epub ahead of print]40(7): 111198
    Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
    Mahmud O Abdullah, Run X Zeng, Chelsea L Margerum, David Papadopoli, Cian Monnin, Kaylee B Punter, Charles Chu, Mohammad Al-Rofaidi, Naser F Al-Tannak, Domenica Berardi, Zahra Rattray, Nicholas J W Rattray, Sheela A Abraham, Eeva-Liisa Eskelinen, David G Watson, Daina Avizonis, Ivan Topisirovic, Edmond Y W Chan.
      The relationship between nutrient starvation and mitochondrial dynamics is poorly understood. We find that cells facing amino acid starvation display clear mitochondrial fusion as a means to evade mitophagy. Surprisingly, further supplementation of glutamine (Q), leucine (L), and arginine (R) did not reverse, but produced stronger mitochondrial hyperfusion. Interestingly, the hyperfusion response to Q + L + R was dependent upon mitochondrial fusion proteins Mfn1 and Opa1 but was independent of MTORC1. Metabolite profiling indicates that Q + L + R addback replenishes amino acid and nucleotide pools. Inhibition of fumarate hydratase, glutaminolysis, or inosine monophosphate dehydrogenase all block Q + L + R-dependent mitochondrial hyperfusion, which suggests critical roles for the tricarboxylic acid (TCA) cycle and purine biosynthesis in this response. Metabolic tracer analyses further support the idea that supplemented Q promotes purine biosynthesis by serving as a donor of amine groups. We thus describe a metabolic mechanism for direct sensing of cellular amino acids to control mitochondrial fusion and cell fate.
    Keywords:  CP: Cell biology; CP: Metabolism; Drp1; Mfn1; Mfn2; Opa1; amino acid sensing; arginine; dynamics; fusion; glutamine; hyperfusion; leucine; mitochondria; stable isotope tracer
    DOI:  https://doi.org/10.1016/j.celrep.2022.111198
  5. Cell Metab. 2022 Aug 11. pii: S1550-4131(22)00310-2. [Epub ahead of print]
    The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
    Kaili Xue, Dongmei Wu, Yushuang Wang, Yiheng Zhao, Hongyu Shen, Jingfei Yao, Xun Huang, Xinmeng Li, Zhao Zhou, Zihao Wang, Yifu Qiu.
      Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a "thermoporter" that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.
    Keywords:  UCP1; brown adipose tissue; metabolic dysfunction; mitochondrial calcium uniporter; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.011
  6. Aust N Z J Obstet Gynaecol. 2022 Aug 16.
    Ethical implementation of mitochondrial donation in Australia.
    Julian Koplin, Esther Lestrell, Catherine Mills, Chris Degeling, Ezra Kneebone, Karinne Ludlow, Ainsley Newson, Robert Sparrow, Liz Sutton, Narelle Warren.
      Australia has recently legalised mitochondrial donation. However, key ethical and legal issues still need to be addressed. This paper maps the relevant issues and offers some suggestions for how they ought to be resolved.
    Keywords:  Australia; assisted; bioethics; mitochondrial diseases; reproductive techniques; sex selection
    DOI:  https://doi.org/10.1111/ajo.13603
  7. Metabol Open. 2022 Sep;15 100205
    Phase separation may drive mitochondrial nucleoid compartmentation.
    Maria Dalamaga, Junli Liu.
      
    Keywords:  Mitochondrial DNA; Mitochondrion; Nucleoid; Phase separation; Transcription
    DOI:  https://doi.org/10.1016/j.metop.2022.100205
  8. Front Neurol. 2022 ;13 880944
    Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study.
    Lijuan Huang, Hua Li, Jianmin Zhong, Liming Yang, Guohong Chen, Dong Wang, Guo Zheng, Hong Han, Xiong Han, Yiqin Long, Xu Wang, Jianmin Liang, Mei Yu, Xiaoyun Shen, Mengke Fan, Fang Fang, Jianxiang Liao, Dan Sun.
       Background: The ketogenic diet (KD) is increasingly used to treat drug-resistant epilepsy because of its favorable effect on seizure reduction. Patients with mitochondrial diseases tend to experience seizures. Therefore, this study aimed to test the efficacy of the KD on participants with mitochondrial diseases in a controlled trial.
    Methods: Participants from fourteen clinical centers who were diagnosed with mitochondrial disease were semi-randomized to either the intervention (KD) or control group. The KD group followed a 3-month KD intervention, while the control group received a 1-month normal diet initially and then a 3-month KD intervention. The primary outcome measure was seizure reduction. Biomarker changes, cognitive impairments, and side effects were also recorded, if available.
    Result: A total of 33 participants were assigned to the KD (n = 22) and control groups (n = 11). In the KD group, 31.8% (7/22) of participants achieved ≥50% seizure reduction after 1 month of diet intervention, which increased to 40.9% (9/22) at 3 months. In the control group, only 18.2% (2/11) of the participants had ≥50% seizure reduction during the normal diet period. After the control group was transferred to the KD, 63.6% (7/11) of participants had >50% seizure reduction, and this rate increased to 72.7% (8/11) at 3 months. The KD also showed high efficacy in participants with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) or pathogenic variants in mitochondrial DNA (mtDNA) (90% and 93.3% response rates, respectively). The most frequent side effects reported at the 3-month review were vomiting, cold, hyperlipidemia, and bloating.
    Conclusion: The KD is a safe and effective therapy for seizure control in mitochondrial diseases, especially MELAS and pathogenic variants of mtDNA. KD intervention can be considered in the management of these patients.
    Keywords:  MELAS; epilepsy; gene; ketogenic diet; mitochondrial diseases
    DOI:  https://doi.org/10.3389/fneur.2022.880944
  9. Mol Reprod Dev. 2022 Aug 20.
    The role of mtDNA in oocyte quality and embryo development.
    Justin C St John, Takashi Okada, Eryk Andreas, Alexander Penn.
      The mitochondrial genome resides in the mitochondria present in nearly all cell types. The porcine (Sus scrofa) mitochondrial genome is circa 16.7 kb in size and exists in the multimeric format in cells. Individual cell types have different numbers of mitochondrial DNA (mtDNA) copy number based on their requirements for ATP produced by oxidative phosphorylation. The oocyte has the largest number of mtDNA of any cell type. During oogenesis, the oocyte sets mtDNA copy number in order that sufficient copies are available to support subsequent developmental events. It also initiates a program of epigenetic patterning that regulates, for example, DNA methylation levels of the nuclear genome. Once fertilized, the nuclear and mitochondrial genomes establish synchrony to ensure that the embryo and fetus can complete each developmental milestone. However, altering the oocyte's mtDNA copy number by mitochondrial supplementation can affect the programming and gene expression profiles of the developing embryo and, in oocytes deficient of mtDNA, it appears to have a positive impact on the embryo development rates and gene expression profiles. Furthermore, mtDNA haplotypes, which define common maternal origins, appear to affect developmental outcomes and certain reproductive traits. Nevertheless, the manipulation of the mitochondrial content of an oocyte might have a developmental advantage.
    Keywords:  genomic balance; mitochondrial DNA; mitochondrial supplementation; nuclear transfer; oogenesis
    DOI:  https://doi.org/10.1002/mrd.23640
  10. PLoS One. 2022 ;17(8): e0273080
    Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
    Yu Hui Kang, Sarah A Tucker, Silvia F Quevedo, Aslihan Inal, Joshua R Korzenik, Marcia C Haigis.
      Ulcerative colitis (UC) is a complex, multifactorial disease driven by a dysregulated immune response against host commensal microbes. Despite rapid advances in our understanding of host genomics and transcriptomics, the metabolic changes in UC remain poorly understood. We thus sought to investigate distinguishing metabolic features of the UC colon (14 controls and 19 patients). Metabolomics analyses revealed inflammation state as the primary driver of metabolic variation rather than diagnosis, with multiple metabolites differentially regulated between inflamed and uninflamed tissues. Specifically, inflamed tissues were characterized by reduced levels of nicotinamide adenine dinucleotide (NAD+) and enhanced levels of nicotinamide (NAM) and adenosine diphosphate ribose (ADPr). The NAD+/NAM ratio, which was reduced in inflamed patients, served as an effective classifier for inflammation in UC. Mitochondria were also structurally altered in UC, with UC patient colonocytes displaying reduced mitochondrial density and number. Together, these findings suggest a link between mitochondrial dysfunction, inflammation, and NAD+ metabolism in UC.
    DOI:  https://doi.org/10.1371/journal.pone.0273080
  11. EMBO Rep. 2022 Aug 18. e54859
    UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
    Jing Zheng, Yu Cao, Jun Yang, Hui Jiang.
      The hexameric AAA-ATPase valosin-containing protein (VCP) is essential for mitochondrial protein quality control. How VCP is recruited to mammalian mitochondria remains obscure. Here we report that UBXD8, an ER- and lipid droplet-localized VCP adaptor, also localizes to mitochondria and locally recruits VCP. UBXD8 associates with mitochondrial and ER ubiquitin E3 ligases and targets their substrates for degradation. Remarkably, both mitochondria- and ER-localized UBXD8 can degrade mitochondrial and ER substrates in cis and in trans. UBXD8 also associates with the TOM complex but is dispensable for translocation-associated degradation. UBXD8 knockout impairs the degradation of the pro-survival protein Mcl1 but surprisingly sensitizes cells to apoptosis and mitochondrial stresses. UBXD8 knockout also hyperactivates mitophagy. We identify pro-apoptotic BH3-only proteins Noxa, Bik, and Bnip3 as novel UBXD8 substrates and determine that UBXD8 inhibits apoptosis via degrading Noxa and restrains mitophagy via degrading Bnip3. Collectively, our characterizations reveal UBXD8 as the major mitochondrial adaptor of VCP and unveil its role in apoptosis and mitophagy regulation.
    Keywords:  UBXD8; VCP; apoptosis; mitochondria-associated degradation; mitophagy
    DOI:  https://doi.org/10.15252/embr.202254859
  12. Mol Neurobiol. 2022 Aug 15.
    Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.
    Milena Pinto, Francisca Diaz, Nadee Nissanka, Chelsey S Guastucci, Placido Illiano, Roberta Brambilla, Carlos T Moraes.
      For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer's disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer's patients' brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIIIKO) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIIIKO-AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation.
    Keywords:  Alzheimer’s disease; Mitochondria dysfunctions; Mouse model; Oxidative phosphorylation deficiency; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-022-02992-3
  13. Autophagy. 2022 Aug 13.
    Targeting Mitophagy to Promote Apoptosis is a Potential Therapeutic Strategy for Cancer.
    Yancheng Tang, Liming Wang, Jiangjiang Qin, Ying-Ying Lu, Han-Ming Shen, Hu-Biao Chen.
      Many anticancer agents exert cytotoxicity and trigger apoptosis through the induction of mitochondrial dysfunction. Mitophagy, as the key mitochondrial quality control mechanism, can remove damaged mitochondria in an effective and timely manner, which may result in drug resistance. Although the implication of mitophagy in neurodegenerative diseases has been extensively studied, the role and mechanism of mitophagy in tumorigenesis and cancer therapy are largely unknown. In a recent study, we found that the inhibition of PINK1-PRKN-mediated mitophagy can significantly enhance the anticancer efficacy of magnolol, a natural product with potential anticancer properties. On the one hand, magnolol can induce severe mitochondrial dysfunction, including mitochondrial depolarization, excessive mitochondrial fragmentation and the generation of mitochondrial ROS, leading to apoptosis. On the other hand, magnolol induces PINK1-PRKN-dependent mitophagy via activation of two rounds of feedforward amplification loops. The blockage of mitophagy through genetic or pharmacological approaches promotes rather than attenuates magnolol-induced cell death. Furthermore, inhibition of mitophagy by using distinct inhibitors targeting different mitophagic stages effectively enhances magnolol's anticancer efficacy in vivo. Taken together, our findings strongly indicate that manipulation of mitophagy in cancer treatment will be a promising therapeutic strategy for overcoming cancer drug resistance and improving the therapeutic efficacy of anticancer agents.
    DOI:  https://doi.org/10.1080/15548627.2022.2112830
  14. Genet Med. 2022 Aug 19. pii: S1098-3600(22)00843-7. [Epub ahead of print]
    Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.
    Genomics England Research Consortium
       PURPOSE: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses.
    METHODS: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics.
    RESULTS: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts.
    CONCLUSION: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.
    Keywords:  Gene burden; Proteomics; Spastic ataxia; UCHL1
    DOI:  https://doi.org/10.1016/j.gim.2022.07.006
  15. Sci Adv. 2022 Aug 19. 8(33): eabp9245
    High-efficiency quantitative control of mitochondrial transfer based on droplet microfluidics and its application on muscle regeneration.
    Jiayu Sun, Hiu Tung Jessica Lo, Lei Fan, Tsz Lam Yiu, Adnan Shakoor, Gang Li, Wayne Y W Lee, Dong Sun.
      Mitochondrial transfer is a spontaneous process to restore damaged cells in various pathological conditions. The transfer of mitochondria to cell therapy products before their administration can enhance therapeutic outcomes. However, the low efficiency of previously reported methods limits their clinical application. Here, we developed a droplet microfluidics-based mitochondrial transfer technique that can achieve high-efficiency and high-throughput quantitative mitochondrial transfer to single cells. Because mitochondria are essential for muscles, myoblast cells and a muscle injury model were used as a proof-of-concept model to evaluate the proposed technique. In vitro and in vivo experiments demonstrated that C2C12 cells with 31 transferred mitochondria had significant improvements in cellular functions compared to those with 0, 8, and 14 transferred mitochondria and also had better therapeutic effects on muscle regeneration. The proposed technique can considerably promote the clinical application of mitochondrial transfer, with optimized cell function improvements, for the cell therapy of mitochondria-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.abp9245
  16. Nucleic Acids Res. 2022 Aug 18. pii: gkac690. [Epub ahead of print]
    Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.
    Nguyen Thi Kim Oanh, Ho-Soo Lee, Yong-Hyun Kim, Sunwoo Min, Yeon-Ji Park, June Heo, Yong-Yea Park, Won-Chung Lim, Hyeseong Cho.
      Cells are constantly challenged by genotoxic stresses that can lead to genome instability. The integrity of the nuclear genome is preserved by the DNA damage response (DDR) and repair. Additionally, these stresses can induce mitochondria to transiently hyperfuse; however, it remains unclear whether canonical DDR is linked to these mitochondrial morphological changes. Here, we report that the abolition of mitochondrial fusion causes a substantial defect in the ATM-mediated DDR signaling. This deficiency is overcome by the restoration of mitochondria fusion. In cells with fragmented mitochondria, genotoxic stress-induced activation of JNK and its translocation to DNA lesion are lost. Importantly, the mitochondrial fusion machinery of MFN1/MFN2 associates with Sab (SH3BP5) and JNK, and these interactions are indispensable for the Sab-mediated activation of JNK and the ATM-mediated DDR signaling. Accordingly, the formation of BRCA1 and 53BP1 foci, as well as homology and end-joining repair are impaired in cells with fragmented mitochondria. Together, these data show that mitochondrial fusion-dependent JNK signaling is essential for the DDR, providing vital insight into the integration of nuclear and cytoplasmic stress signals.
    DOI:  https://doi.org/10.1093/nar/gkac690
  17. PLoS Biol. 2022 Aug;20(8): e3001741
    Single-cell multiomics analyses of spindle-transferred human embryos suggest a mostly normal embryonic development.
    Shuyue Qi, Wei Wang, Xiaohui Xue, Zhuo Lu, Jia Yan, Yunfei Li, Yu Zhang, Mingming Shu, Chunlan Song, Qihang Wang, Yunhai Chuai, Xinyu Zhai, Shujie Han, Fuchou Tang, Wei Shang.
      Mitochondrial DNA (mtDNA) mutations are often associated with incurable diseases and lead to detectable pathogenic variants in 1 out of 200 babies. Uncoupling of the inheritance of mtDNA and the nuclear genome by spindle transfer (ST) can potentially prevent the transmission of mtDNA mutations from mother to offspring. However, no well-established studies have critically assessed the safety of this technique. Here, using single-cell triple omics sequencing method, we systematically analyzed the genome (copy number variation), DNA methylome, and transcriptome of ST and control blastocysts. The results showed that, compared to that in control embryos, the percentage of aneuploid cells in ST embryos did not significantly change. The epiblast, primitive endoderm, and trophectoderm (TE) of ST blastocysts presented RNA expression profiles that were comparable to those of control blastocysts. However, the DNA demethylation process in TE cells of ST blastocysts was slightly slower than that in the control blastocysts. Collectively, our results suggest that ST seems generally safe for embryonic development, with a relatively minor delay in the DNA demethylation process at the blastocyst stage.
    DOI:  https://doi.org/10.1371/journal.pbio.3001741
  18. Hepatology. 2022 Aug 16.
    Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C or nonalcoholic steatohepatitis.
    Dimitri Loureiro, Issam Tout, Stéphanie Narguet, Cheikh Mohamed Bed, Morgane Roinard, Ahmad Sleiman, Nathalie Boyer, Nathalie Pons-Kerjean, Corinne Castelnau, Nathalie Giuly, Dorothy Tonui, Vassili Soumelis, Jamel El Benna, Patrick Soussan, Richard Moreau, Valérie Paradis, Abdellah Mansouri, Tarik Asselah.
       BACKGROUND & AIMS: Hepatitis B virus infection causes oxidative stress and alters mitochondria in experimental models. Our goal was to investigate if HBV might alter liver mitochondria also in human, and the resulting mitochondrial stress might account for the progression of fibrosis in chronic hepatitis B (CHB).
    APPROACH & RESULTS: The study included 146 treatment-naïve CHB mono-infected patients. Patients with CHB and advanced fibrosis or cirrhosis (F3-F4) were compared to patients with no-mild-moderate fibrosis (F0-F2). Patients with CHB were further compared to patients with chronic hepatitis C (CHC) (n=33), nonalcoholic steatohepatitis (NASH) (n=12) and healthy controls (n=24). We detected oxidative damage to mtDNA including mtDNA strand beaks and identified multiple mtDNA deletions in patients with F3-F4 as compared to patients with F0-F2. Alterations in mitochondrial function, mitochondrial unfolded protein response, biogenesis, mitophagy and liver inflammation were observed in patients with advanced fibrosis or cirrhosis associated with CHB, CHC and NASH. In vitro, significant increases of the mitochondrial formation of superoxide and peroxynitrite as well as mtDNA damage, nitration of the mitochondrial respiratory chain complexes and impairment of complex I occurred in HepG2 cells replicating HBV or transiently expressing Hepatitits B virus X protein. mtDNA damage and complex I impairment were prevented with the superoxide scavenging Mito-Tempo or with iNOS specific inhibitor 1400W.
    CONCLUSION: Our results emphasized the importance of mitochondrial oxidative stress, mtDNA damage and associated alterations in mitochondrial function and dynamics in the advanced fibrosis or cirrhosis in CHB and NASH. Mitochondria might be a target in drug development to stop fibrosis progression.
    DOI:  https://doi.org/10.1002/hep.32731
  19. J Biomed Sci. 2022 Aug 18. 29(1): 61
    The A'-helix of CYP11A1 remodels mitochondrial cristae.
    Karen G Rosal, Wei-Yi Chen, Bon-Chu Chung.
       BACKGROUND: CYP11A1 is a protein located in the inner membrane of mitochondria catalyzing the first step of steroid synthesis. As a marker gene for steroid-producing cells, the abundance of CYP11A1 characterizes the extent of steroidogenic cell differentiation. Besides, the mitochondria of fully differentiated steroidogenic cells are specialized with tubulovesicular cristae. The participation of CYP11A1 in the change of mitochondrial structure and the differentiation of steroid-producing cells, however, has not been investigated.
    METHODS: We engineered nonsteroidogenic monkey kidney COS1 cells to express CYP11A1 upon doxycycline induction and examined the mitochondrial structure of these cells. We also mapped the CYP11A1 domains that confer structural changes of mitochondria. We searched for CYP11A1-interacting proteins and investigated the role of this interacting protein in shaping mitochondrial structure. Finally, we examined the effect of CYP11A1 overexpression on the amount of mitochondrial contact site and cristae organizing system.
    RESULTS: We found that CYP11A1 overexpression led to the formation of tubulovesicular cristae in mitochondria. We also identified the A'-helix located at amino acid #57-68 to be sufficient for membrane insertion and crista remodeling. We identified heat shock protein 60 (Hsp60) as the CYP11A1-interacting protein and showed that Hsp60 is required for CYP11A1 accumulation and crista remodeling. Finally, we found that the small MIC10 subcomplex of the mitochondrial contact site and cristae organizing system was reduced when CYP11A1 was overexpressed.
    CONCLUSIONS: CYP11A1 participates in the formation of tubulovesicular cristae in the mitochondria of steroidogenic cells. Its A'-helix is sufficient for the formation of tubulovesicular cristae and for protein integration into the membrane. CYP11A1 interacts with Hsp60, which is required for CYP11A1 accumulation. The accumulation of CYP11A1 leads to the reduction of MIC10 complex and changes mitochondrial structure.
    Keywords:  Cristae remodeling; Hsp60; MIC10; Membrane; Mitochondrial structure; P450scc; Pregnenolone; Steroidogenesis
    DOI:  https://doi.org/10.1186/s12929-022-00846-7
  20. Nat Commun. 2022 Aug 17. 13(1): 4848
    Direct control of lysosomal catabolic activity by mTORC1 through regulation of V-ATPase assembly.
    Edoardo Ratto, S Roy Chowdhury, Nora S Siefert, Martin Schneider, Marten Wittmann, Dominic Helm, Wilhelm Palm.
      Mammalian cells can acquire exogenous amino acids through endocytosis and lysosomal catabolism of extracellular proteins. In amino acid-replete environments, nutritional utilization of extracellular proteins is suppressed by the amino acid sensor mechanistic target of rapamycin complex 1 (mTORC1) through an unknown process. Here, we show that mTORC1 blocks lysosomal degradation of extracellular proteins by suppressing V-ATPase-mediated acidification of lysosomes. When mTORC1 is active, peripheral V-ATPase V1 domains reside in the cytosol where they are stabilized by association with the chaperonin TRiC. Consequently, most lysosomes display low catabolic activity. When mTORC1 activity declines, V-ATPase V1 domains move to membrane-integral V-ATPase Vo domains at lysosomes to assemble active proton pumps. The resulting drop in luminal pH increases protease activity and degradation of protein contents throughout the lysosomal population. These results uncover a principle by which cells rapidly respond to changes in their nutrient environment by mobilizing the latent catabolic capacity of lysosomes.
    DOI:  https://doi.org/10.1038/s41467-022-32515-6
  21. Mitochondrion. 2022 Aug 16. pii: S1567-7249(22)00073-3. [Epub ahead of print]
    Receptor-mediated mitophagy: An emerging therapeutic target in acute kidney injury.
    Neha Dagar, Ajinath Kale, Stefanie Steiger, Hans-Joachim Anders, Anil Bhanudas Gaikwad.
      Acute kidney injury (AKI) is a global health concern associated with high morbidity and mortality. AKI etiology is linked to mitochondrial dysfunction along with oxidative stress and inflammation. The defective mitochondria are removed via mitophagy for maintaining cellular integrity. The main regulatory mechanisms of mitophagy in response to different stressors are Phosphatase and tensin homolog-induced kinase 1 (PINK1)/Parkin and receptor-mediated. Receptors like B-cell lymphoma 2/adenovirus E1B-interacting protein (BNIP3), BNIP3L, prohibitin2, tacrolimus (FK506)-binding protein8 (FKBP8), autophagy-beclin1-regulator1 (AMBRA1) and SMAD-ubiquitination regulatory factor1 (SMURF1), etc. participate in receptor-mediated mitophagy. In recent studies, receptor-mediated mitophagy showed protective effects in AKI. This review summarizes the evidence related to mitophagy in AKI and outlines the significance of receptor-mediated mitophagy modulation as a possible therapeutic approach in AKI.
    Keywords:  Acute Kidney Injury; Mitochondria; Mitochondrial fusion/fission; Mitophagy; Mitophagy inducers; Receptor-mediated mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2022.08.004
  22. Sci Rep. 2022 Aug 19. 12(1): 14147
    Improving the differentiation potential of pluripotent stem cells by optimizing culture conditions.
    Takako Yamamoto, Mao Arita, Hirotaka Kuroda, Takashi Suzuki, Shin Kawamata.
      Embryoid cells and induced pluripotent stem cells (iPSCs) are pluripotent stem cells (PSCs). They retain differentiation and self-renewal potential. However, the differentiation potential of PSCs can be changed by the culture medium. PSCs retain their differentiation potential when cultured with medium that supports the glycolytic pathway, showing high expression of chromodomain-helicase-DNA-binding protein 7 (CHD7), but lose their differentiation potential with medium that supports mitochondrial function, showing reduced levels of CHD7. Labeling cells by their copy number variant profile revealed that genetically different PSC populations can be cultured by medium selection. Another factor that defines the self-renewal potential of PSCs is culture condition. PSCs form colonies as they grow, and spontaneous differentiation inevitably occurs along the rim of these colonies in areas that lack cell-to-cell contact; because of this, undifferentiated cell populations would diminish if differentiated cells are not removed properly. Seeding cells on a less potent cell-binding material may minimize the inclusion of differentiated cells, exploiting the reduced adhesive properties of differentiated cells. Culturing cells with medium that supports the glycolytic pathway, using CHD7 as a biomarker for differentiation potential, and culturing cells on less sticky material can improve the differentiation potential of already established PSC clones.
    DOI:  https://doi.org/10.1038/s41598-022-18400-8
  23. Nat Med. 2022 Aug 15.
    Ensuring a future for gene therapy for rare diseases.
    Alessandro Aiuti, Francesca Pasinelli, Luigi Naldini.
      
    DOI:  https://doi.org/10.1038/s41591-022-01934-9
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