bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021‒05‒16
twelve papers selected by
Brian Spurlock
University of Alabama at Birmingham

  1. Transl Psychiatry. 2021 May 08. 11(1): 275
      Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.
  2. J Cell Biol. 2021 Jul 05. pii: e202010006. [Epub ahead of print]220(7):
      The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.
  3. Anal Chim Acta. 2021 Jun 22. pii: S0003-2670(21)00387-1. [Epub ahead of print]1165 338561
      Mitochondria autophagy, also known as mitophagy, is a process in which mitochondria are wrapped by autophagosomes and fused with lysosomes for degradation. This process is essential for mitochondrial quality control. Here, we developed a hybrid aggregate FRET probe through mixed assembly of two cyanine dyes FMOTY and AMTC. In live cells, FMOTY and AMTC exist independently in lysosomes and mitochondria and will not produce interfering FRET background signals. The FRET signal is only generated when mitochondria is transported to lysosomes during mitophagy. This allows the hybridized aggregate to be used as a highly specific probe for monitoring mitophagy.
    Keywords:  Cyanine dye; FRET imaging; Hybrid aggregate; Mitochondria autophagy; Mixed assembly
  4. Front Cell Dev Biol. 2021 ;9 665412
      The regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) have laid a sound foundation for their clinical application in various diseases. However, the clinical efficiency of MSC treatments varies depending on certain cell characteristics. Among these, the roles of cell aging or senescence cannot be excluded. Despite their stemness, evidence of senescence in MSCs has recently gained attention. Many factors may contribute to the senescence of MSCs, including MSC origin (biological niche), donor conditions (age, obesity, diseases, or unknown factors), and culture conditions in vitro. With the rapidly increasing prevalence of diabetes mellitus (DM) and gestational diabetes mellitus (GDM), the effects of hyperglycemia on the senescence of MSCs should be evaluated to improve the application of autologous MSCs. This review aims to present the available data on the senescence of MSCs, its relationship with hyperglycemia, and the strategies to suppress the senescence of MSCs in a hyperglycemic environment.
    Keywords:  diabetes mettitus; hyperglycemia; mesenchymal stem cells; mitochondrial dysfunction; senescence
  5. PLoS Biol. 2021 May 13. 19(5): e3001252
      The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.
  6. Nat Commun. 2021 May 11. 12(1): 2665
      With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.
  7. Stem Cell Reports. 2021 May 11. pii: S2213-6711(21)00149-1. [Epub ahead of print]16(5): 1117-1141
      Detailed studies of the embryo allow an increasingly mechanistic understanding of development, which has proved of profound relevance to human disease. The last decade has seen in vitro cultured stem cell-based models of embryo development flourish, which provide an alternative to the embryo for accessible experimentation. However, the usefulness of any stem cell-based embryo model will be determined by how accurately it reflects in vivo embryonic development, and/or the extent to which it facilitates new discoveries. Stringent benchmarking of embryo models is thus an important consideration for this growing field. Here we provide an overview of means to evaluate both the properties of stem cells, the building blocks of most embryo models, as well as the usefulness of current and future in vitro embryo models.
    Keywords:  embryo models; in vitro; stem cells
  8. Commun Biol. 2021 May 14. 4(1): 584
      Most humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1-2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been implicated. Establishing an in vitro model of early mammalian germ cell development from embryonic stem cells, here we show that the reduction of mtDNA content is modulated by oxygen and reaches a nadir immediately before germ cell specification. The observed genetic bottleneck was accompanied by a decrease in mtDNA replicating foci and the segregation of heteroplasmy, which were both abolished at higher oxygen levels. Thus, differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.
  9. Cardiovasc Toxicol. 2021 May 13.
      Hyperglycaemia, a key metabolic abnormality in diabetes mellitus, is implicated in pathological cardiogenesis during embryological development. However, the underlying mechanisms and potential therapeutic targets remain unknown. We, therefore, studied the effect of hyperglycaemia on mouse embryonic stem cell (mESC) cardiac differentiation. The mESCs were differentiated via embryoid body (EB) formation and cultured under conditions with baseline (25 mM) or high (50 mM) glucose. Time-lapse microscopy images of pulsatile mESCs and Ca2+ transients were recorded. Biomarkers of cellular changes were detected using immunocytochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay, and Western blot analyses. Differentiated, spontaneously beating mESCs stained positive for cardiac troponin T, α-actinin 2, myosin heavy chain, and connexin 43. Hyperglycaemia decreased the EB diameter and number of beating EBs as well as the cellular amplitude of contraction, the Ca2+ transient, and the contractile response to caffeine (1 mM), but had no effect on the expression of the sarco-endoplasmic reticulum calcium transport ATPase 2 (SERCA 2). Furthermore, hyperglycaemia decreased the expression of B cell lymphoma 2 (Bcl-2) and increased the expression of cytoplasmic cytochrome c and the number of TUNEL-positive cells, but had no effect on the expression of one of the mitochondrial fusion regulatory proteins, optic atrophy protein 1 (OPA1). Overall, hyperglycaemia suppressed the mESC cardiomyocyte-like differentiation and induced contractile dysfunction. The results are consistent with mechanisms involving abnormal Ca2+ handling and mitochondrial-dependent apoptosis, factors which represent potential therapeutic targets in developmental diabetic cardiac disease.
    Keywords:  Apoptosis; Ca2+ transient; Cardiac differentiation; Cardiomyocyte; Hyperglycaemia; Stem cell
  10. Biomaterials. 2021 May 06. pii: S0142-9612(21)00206-4. [Epub ahead of print]274 120850
      Extracellular vesicles (EVs) are extracellular nanovesicles that deliver diverse cargoes to the cell and participate in cell communication. Mesenchymal stem cell (MSCs)-derived EVs are considered a therapeutic approach in musculoskeletal degenerative diseases, including intervertebral disc degeneration. However, limited production yield and unstable quality have impeded the clinical application of EVs. In the present study, it is indicated that metformin promotes EVs release and alters the protein profile of EVs. Metformin enhances EVs production via an autophagy-related pathway, concomitantly with the phosphorylation of synaptosome-associated protein 29. More than quantity, quality of MSCs-derived EVs is influenced by metformin treatment. Proteomics analysis reveals that metformin increases the protein content of EVs involved in cell growth. It is shown that EVs derived from metformin-treated MSCs ameliorate intervertebral disc cells senescence in vitro and in vivo. Collectively, these findings demonstrate the great promise of metformin in EVs-based intervertebral disc regeneration.
    Keywords:  Autophagy; Extracellular vesicles; Intervertebral disc degeneration; Mesenchymal stem cells; Metformin
  11. Small. 2021 May 10. e2007959
      Artificial cells (ACs) aim to mimic selected structural and functional features of mammalian cells. In this context, energy generation is an important challenge to be addressed when self-sustained systems are desired. Here, mitochondria isolated from HepG2 cells are employed as natural subunits that facilitate chemically driven adenosine triphosphate (ATP) synthesis. The successful mitochondria isolation is confirmed by monitoring the preserved inner membrane potential, the respiration, and the ATP production ability. The encapsulation of the isolated mitochondria in gelatin-based hydrogels results in similar initial ATP production compared to mitochondria in solution with a sustained ATP production over 24 h. Furthermore, luciferase is coencapsulated with the mitochondria in gelatin-based particles to create ACs and employ the in situ produced ATP to drive the catalytic conversion of d-luciferin. The coencapsulation of luciferase-loaded liposomes with mitochondria in gelatin-based hydrogels is additionally explored where the encapsulation of mitochondria and liposomes resulted in clustering effects that are likely contributing to the functional performance of the active entities. Taken together, mitochondria show potential in cell mimicry to facilitate energy-dependent processes.
    Keywords:  ATP; HepG2 cells; artificial cells; hydrogels; mitochondria
  12. J Appl Toxicol. 2021 May 11.
      Cadmium (Cd) is a toxic heavy metal widely found in the environment. Cd is also a potential neurotoxicant, and its exposure is associated with impairment of cognitive function. However, the underlying mechanisms by which Cd induces neurotoxicity are unclear. In this study, we investigated the in vitro effect of Cd on primary murine neural stem/progenitor cells (mNS/PCs) isolated from the subventricular zone. Our results show that Cd exposure leads to mNS/PCs G1/S arrest, promotes cell apoptosis, and inhibits cell proliferation. In addition, Cd increases intracellular and mitochondrial reactive oxygen species (ROS) that activates mitochondrial oxidative stress, decreases ATP production, and increases mitochondrial proton leak and glycolysis rate in a dose-dependent manner. Furthermore, Cd exposure decreases phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3 beta (GSK3β) in mNS/PCs. In addition, pretreatment mNS/PCs with MitoTEMPO, a mitochondrial-targeted antioxidant, improves mitochondrial morphology and functions and attenuates Cd-induced inhibition of mNS/PCs proliferation. It also effectively reverses Cd-induced changes of phosphorylation of AKT and the expression of β-catenin and its downstream genes. Taken together, our data suggested that AKT/GSK3β/β-catenin signaling pathway is involved in Cd-induced mNS/PCs proliferation inhibition via MitoROS-dependent pattern.
    Keywords:  AKT/GSK-3β/β-catenin signaling pathway; MitoROS; cadmium; cell proliferation; neural stem/progenitor cell