bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2022–08–21
fourteen papers selected by
Catalina Vasilescu, University of Helsinki
  1. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids.
  2. UBXD8 mediates mitochondria-associated degradation to restrain apoptosis and mitophagy.
  3. Metabolic analyses reveal dysregulated NAD+ metabolism and altered mitochondrial state in ulcerative colitis.
  4. The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
  5. Editorial: Mitochondrial therapy in neurological diseases.
  6. Mitochondrial microproteins link metabolic cues to respiratory chain biogenesis.
  7. Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
  8. Regulation of nuclear DNA damage response by mitochondrial morphofunctional pathway.
  9. Efficacy and Safety of the Ketogenic Diet for Mitochondrial Disease With Epilepsy: A Prospective, Open-labeled, Controlled Study.
  10. The efficacy of coenzyme Q10 treatment in alleviating the symptoms of primary coenzyme Q10 deficiency: A systematic review.
  11. No evidence of extensive non-CpG methylation in mtDNA.
  12. Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.
  13. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
  14. Biological activity reduction and mitochondrial and lysosomal dysfunction of mesenchymal stem cells aging in vitro.
  1. 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
  2. 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
  3. 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
  4. 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
  5. Front Mol Neurosci. 2022 ;15 988792
    Editorial: Mitochondrial therapy in neurological diseases.
    Jui-Chih Chang, Linyi Chen, Chuang-Rung Chang.
      
    Keywords:  brain injury; metabolic disease; mitochondrial dysfunction; neurological diseases; reactive oxygen species
    DOI:  https://doi.org/10.3389/fnmol.2022.988792
  6. 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
  7. PLoS Comput Biol. 2022 Aug 19. 18(8): e1010413
    Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
    Ximena G Arceo, Elena F Koslover, Brian M Zid, Aidan I Brown.
      For many nuclear-encoded mitochondrial genes, mRNA localizes to the mitochondrial surface co-translationally, aided by the association of a mitochondrial targeting sequence (MTS) on the nascent peptide with the mitochondrial import complex. For a subset of these co-translationally localized mRNAs, their localization is dependent on the metabolic state of the cell, while others are constitutively localized. To explore the differences between these two mRNA types we developed a stochastic, quantitative model for MTS-mediated mRNA localization to mitochondria in yeast cells. This model includes translation, applying gene-specific kinetics derived from experimental data; and diffusion in the cytosol. Even though both mRNA types are co-translationally localized we found that the steady state number, or density, of ribosomes along an mRNA was insufficient to differentiate the two mRNA types. Instead, conditionally-localized mRNAs have faster translation kinetics which modulate localization in combination with changes to diffusive search kinetics across metabolic states. Our model also suggests that the MTS requires a maturation time to become competent to bind mitochondria. Our work indicates that yeast cells can regulate mRNA localization to mitochondria by controlling mitochondrial volume fraction (influencing diffusive search times) and gene translation kinetics (adjusting mRNA binding competence) without the need for mRNA-specific binding proteins. These results shed light on both global and gene-specific mechanisms that enable cells to alter mRNA localization in response to changing metabolic conditions.
    DOI:  https://doi.org/10.1371/journal.pcbi.1010413
  8. 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
  9. 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
  10. J Cell Mol Med. 2022 Aug 19.
    The efficacy of coenzyme Q10 treatment in alleviating the symptoms of primary coenzyme Q10 deficiency: A systematic review.
    Ying Wang, Siegfried Hekimi.
      Coenzyme Q10 (CoQ10 ) is necessary for mitochondrial electron transport. Mutations in CoQ10 biosynthetic genes cause primary CoQ10 deficiency (PCoQD) and manifest as mitochondrial disorders. It is often stated that PCoQD patients can be treated by oral CoQ10 supplementation. To test this, we compiled all studies describing PCoQD patients up to May 2022. We excluded studies with no data on CoQ10 treatment, or with insufficient description of effectiveness. Out of 303 PCoQD patients identified, we retained 89 cases, of which 24 reported improvements after CoQ10 treatment (27.0%). In five cases, the patient's condition was reported to deteriorate after halting of CoQ10 treatment. 12 cases reported improvement in the severity of ataxia and 5 cases in the severity of proteinuria. Only a subjective description of improvement was reported for 4 patients described as responding. All reported responses were partial improvements of only some symptoms. For PCoQD patients, CoQ10 supplementation is replacement therapy. Yet, there is only very weak evidence for the efficacy of the treatment. Our findings, thus, suggest a need for caution when seeking to justify the widespread use of CoQ10 for the treatment of any disease or as dietary supplement.
    Keywords:  CoQ biosynthesis; CoQ10 supplementation; coenzyme Q; mitochondrial disorders; primary CoQ10 deficiency; ubiquinone
    DOI:  https://doi.org/10.1111/jcmm.17488
  11. Nucleic Acids Res. 2022 Aug 18. pii: gkac701. [Epub ahead of print]
    No evidence of extensive non-CpG methylation in mtDNA.
    Romain Guitton, Gonzalo S Nido, Charalampos Tzoulis.
      While most research suggests mitochondrial DNA (mtDNA) harbors low or no methylation, a few studies claim to report evidence of high-level methylation in the mtDNA. The reasons behind these contradictory results are likely to be methodological but remain largely unexplored. Here, we critically reanalyzed a recent study by Patil et al. (2019) reporting extensive methylation in human mtDNA in a non-CpG context. Our analyses refute the original findings and show that these do not reflect the biology of the tested samples, but rather stem from a combination of methodological and technical pitfalls. The authors employ an oversimplified model that defines as methylated all reference positions with methylation proportions above an arbitrary cutoff of 9%. This substantially exacerbates the overestimation of methylated cytosines due to the selective degradation of unmethylated cytosine-rich regions. Additional limitations are the small sample sizes and lack of sample-specific controls for bisulfite conversion efficiency. In conclusion, using the same dataset employed in the original study by Patil et al., we find no evidence supporting the existence of extensive non-CpG methylation in the human mtDNA.
    DOI:  https://doi.org/10.1093/nar/gkac701
  12. EBioMedicine. 2022 Aug 01. pii: S2352-3964(22)00373-5. [Epub ahead of print] 104192
    Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.
    Chantal A Pileggi, Denis P Blondin, Breana G Hooks, Gaganvir Parmar, Irina Alecu, David A Patten, Alexanne Cuillerier, Conor O'Dwyer, A Brianne Thrush, Morgan D Fullerton, Steffany Al Bennett, Éric Doucet, François Haman, Miroslava Cuperlovic-Culf, Ruth McPherson, Robert R M Dent, Mary-Ellen Harper.
       BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss.
    METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention.
    FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training.
    INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes.
    FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).
    Keywords:  Exercise; Metabolomics; Mitochondria; Mitochondrial supercomplexes; Muscle physiology; Obesity; Serine; Sphingolipids; Uncoupling; Weight loss
    DOI:  https://doi.org/10.1016/j.ebiom.2022.104192
  13. Mol Cell. 2022 Aug 12. pii: S1097-2765(22)00703-1. [Epub ahead of print]
    Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
    Yahui Wang, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P Shriver, Gary J Patti.
      Proliferating cells exhibit a metabolic phenotype known as "aerobic glycolysis," which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
    Keywords:  NADH shuttles; aerobic glycolysis; cancer metabolism; glycerol 3-phosphate shuttle; isotope-tracer analysis; malate-aspartate shuttle; metabolic flux; metabolomics; the Warburg effect
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.007
  14. Stem Cell Res Ther. 2022 Aug 13. 13(1): 411
    Biological activity reduction and mitochondrial and lysosomal dysfunction of mesenchymal stem cells aging in vitro.
    Ge Zhang, Yuli Wang, Jianhua Lin, Bo Wang, Ali Mohsin, Zhimin Cheng, Weijie Hao, Wei-Qiang Gao, Huiming Xu, Meijin Guo.
       BACKGROUND: Mesenchymal stem cells (MSCs) have been extensively used for the treatment of various diseases in preclinical and clinical trials. In vitro propagation is needed to attain enough cells for clinical use. However, cell aging and viability reduction caused by long-time culture have not been thoroughly investigated, especially for the function of mitochondria and lysosomes. Therefore, this study was designed to detect mitochondrial and lysosomal activity, morphological and functional changes in human umbilical cord MSCs (UMSCs) after long-time culture.
    METHODS: First, we examined cell activities, including proliferation and immigration ability, differentiation potential, and immunosuppressive capacity of UMSCs at an early and late passages as P4 (named UMSC-P4) and P9 (named UMSC-P9), respectively. Then, we compared the mitochondrial morphology of UMSC-P4 and UMSC-P9 using the electronic microscope and MitoTracker Red dyes. Furthermore, we investigated mitochondrial function, including mitochondrial membrane potential, antioxidative ability, apoptosis, and ferroptosis detected by respective probe. Cell energy metabolism was tested by mass spectrometry. In addition, we compared the lysosomal morphology of UMSC-P4 and UMSC-P9 by electronic microscope and lysoTracker Red dyes. Finally, the transcriptome sequence was performed to analyze the total gene expression of these cells.
    RESULTS: It was found that UMSC-P9 exhibited a reduced biological activity and showed an impaired mitochondrial morphology with disordered structure,  reduced mitochondrial crista, and mitochondrial fragments. They also displayed decreased mitochondrial membrane potential, antioxidative ability, tricarboxylic acid cycle activity and energy production. At the same time, apoptosis and ferroptosis were increased. In addition, UMSC-P9, relative to UMSC-P4, showed undegraded materials in their lysosomes, the enhancement in lysosomal membrane permeability, the reduction in autophagy and phagocytosis. Moreover, transcriptome sequence analysis also revealed a reduction of cell function, metabolism, mitochondrial biogenesis, DNA replication and repair, and an increase of gene expression related to cell senescence, cancer, diseases, and infection in UMSC-P9.
    CONCLUSION: This study indicates that in vitro long-time culturing of MSCs can cause mitochondrial and lysosomal dysfunction, probably contributing to the decline of cell activity and cell aging. Therefore, the morphology and function of mitochondria and lysosomes can be regarded as two important parameters to monitor cell viability, and they can also serve as two important indicators for optimizing in vitro culture conditions.
    Keywords:  Cell activity; Human umbilical cord mesenchymal stem cells; Lysosomal dysfunction; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1186/s13287-022-03107-4
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