bims-mireme 2021-05-23 papers

bims-mireme

Biomed News

on Mitochondria in regenerative medicine

Issue of 2021–05–23
eight papers selected by
Brian Spurlock, University of Alabama at Birmingham

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila.
MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism.
FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.
Adhesion-mediated mechanosignaling forces mitohormesis.
A PKD-MFF signaling axis couples mitochondrial fission to mitotic progression.
Actin mixes up mitochondria for inheritance.
Adipose-Derived Mesenchymal Stem Cells From a Hypoxic Culture Improve Neuronal Differentiation and Nerve Repair.
Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia.

Front Cell Dev Biol. 2021 ;9 606639

Mitochondrial Control of Stem Cell State and Fate: Lessons From Drosophila.

Satish Kumar Tiwari, Sudip Mandal.

  Over the years, Drosophila has served as a wonderful genetically tractable model system to unravel various facets of tissue-resident stem cells in their microenvironment. Studies in different stem and progenitor cell types of Drosophila have led to the discovery of cell-intrinsic and extrinsic factors crucial for stem cell state and fate. Though initially touted as the ATP generating machines for carrying various cellular processes, it is now increasingly becoming clear that mitochondrial processes alone can override the cellular program of stem cells. The last few years have witnessed a surge in our understanding of mitochondria's contribution to governing different stem cell properties in their subtissular niches in Drosophila. Through this review, we intend to sum up and highlight the outcome of these in vivo studies that implicate mitochondria as a central regulator of stem cell fate decisions; to find the commonalities and uniqueness associated with these regulatory mechanisms.

Keywords:  Drosophila; differentiation; maintenance; metabolism; mitochondria; regulation; stem cell

DOI:  https://doi.org/10.3389/fcell.2021.606639
Front Immunol. 2021 ;12 626755

MSCs and Inflammatory Cells Crosstalk in Regenerative Medicine: Concerted Actions for Optimized Resolution Driven by Energy Metabolism.

Valerie Planat-Benard, Audrey Varin, Louis Casteilla.

  Mesenchymal stromal cells (MSCs) are currently widely used in cell based therapy regarding to their remarkable efficacy in controlling the inflammatory status in patients. Despite recent progress and encouraging results, inconstant therapeutic benefits are reported suggesting that significant breakthroughs in the understanding of MSCs immunomodulatory mechanisms of action remains to be investigated and certainly apprehended from original point of view. This review will focus on the recent findings regarding MSCs close relationship with the innate immune compartment, i.e. granulocytes and myeloid cells. The review will also consider the intercellular mechanism of communication involved, such as factor secretion, cell-cell contact, extracellular vesicles, mitochondria transfer and efferocytosis. Immune-like-properties of MSCs supporting part of their therapeutic effect in the clinical setting will be discussed, as well as their potentials (immunomodulatory, anti-bacterial, anti-inflammatory, anti-oxidant defenses and metabolic adaptation…) and effects mediated, such as cell polarization, differentiation, death and survival on various immune and tissue cell targets determinant in triggering tissue regeneration. Their metabolic properties in term of sensing, reacting and producing metabolites influencing tissue inflammation will be highlighted. The review will finally open to discussion how ongoing scientific advances on MSCs could be efficiently translated to clinic in chronic and age-related inflammatory diseases and the current limits and gaps that remain to be overcome to achieving tissue regeneration and rejuvenation.

Keywords:  cell therapy; immunomodulation; inflammation; macrophage; mesenchymal stromal cells (MSCs); metabolic reprogramming; regenerative medicine

DOI:  https://doi.org/10.3389/fimmu.2021.626755
Autophagy. 2021 May 19. 1-22

FOXG1 promotes aging inner ear hair cell survival through activation of the autophagy pathway.

Zu-Hong He, Ming Li, Qiao-Jun Fang, Fu-Ling Liao, Sheng-Yu Zou, Xia Wu, Hai-Ying Sun, Xue-Yan Zhao, Yu-Juan Hu, Xiao-Xiang Xu, Sen Chen, Yu Sun, Ren-Jie Chai, Wei-Jia Kong.

  Presbycusis is the cumulative effect of aging on hearing. Recent studies have shown that common mitochondrial gene deletions are closely related to deafness caused by degenerative changes in the auditory system, and some of these nuclear factors are proposed to participate in the regulation of mitochondrial function. However, the detailed mechanisms involved in age-related degeneration of the auditory systems have not yet been fully elucidated. In this study, we found that FOXG1 plays an important role in the auditory degeneration process through regulation of macroautophagy/autophagy. Inhibition of FOXG1 decreased the autophagy activity and led to the accumulation of reactive oxygen species and subsequent apoptosis of cochlear hair cells. Recent clinical studies have found that aspirin plays important roles in the prevention and treatment of various diseases by regulating autophagy and mitochondria function. In this study, we found that aspirin increased the expression of FOXG1, which further activated autophagy and reduced the production of reactive oxygen species and inhibited apoptosis, and thus promoted the survival of mimetic aging HCs and HC-like OC-1 cells. This study demonstrates the regulatory function of the FOXG1 transcription factor through the autophagy pathway during hair cell degeneration in presbycusis, and it provides a new molecular approach for the treatment of age-related hearing loss.Abbreviations: AHL: age-related hearing loss; baf: bafilomycin A1; CD: common deletion; D-gal: D-galactose; GO: glucose oxidase; HC: hair cells; mtDNA: mitochondrial DNA; RAP: rapamycin; ROS: reactive oxygen species; TMRE: tetramethylrhodamine, ethyl ester.

Keywords:  Aging-related hearing loss; FOXG1; ROS; autophagy; hair cell

DOI:  https://doi.org/10.1080/15548627.2021.1916194
Cell Metab. 2021 May 17. pii: S1550-4131(21)00183-2. [Epub ahead of print]

Adhesion-mediated mechanosignaling forces mitohormesis.

Kevin M Tharp, Ryo Higuchi-Sanabria, Greg A Timblin, Breanna Ford, Carlos Garzon-Coral, Catherine Schneider, Jonathon M Muncie, Connor Stashko, Joseph R Daniele, Andrew S Moore, Phillip A Frankino, Stefan Homentcovschi, Sagar S Manoli, Hao Shao, Alicia L Richards, Kuei-Ho Chen, Johanna Ten Hoeve, Gregory M Ku, Marc Hellerstein, Daniel K Nomura, Karou Saijo, Jason Gestwicki, Alexander R Dunn, Nevan J Krogan, Danielle L Swaney, Andrew Dillin, Valerie M Weaver.

  Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.

Keywords:  UPRmt; adhesion; aging; cancer; extracellular matrix; mechanical stress; mechanotabolism; metabolism; oxidative stress; tension

DOI:  https://doi.org/10.1016/j.cmet.2021.04.017
Cell Rep. 2021 May 18. pii: S2211-1247(21)00468-X. [Epub ahead of print]35(7): 109129

A PKD-MFF signaling axis couples mitochondrial fission to mitotic progression.

Evanthia Pangou, Olga Bielska, Lucile Guerber, Stephane Schmucker, Arantxa Agote-Arán, Taozhi Ye, Yongrong Liao, Marta Puig-Gamez, Erwan Grandgirard, Charlotte Kleiss, Yansheng Liu, Emmanuel Compe, Zhirong Zhang, Ruedi Aebersold, Romeo Ricci, Izabela Sumara.

  Mitochondria are highly dynamic organelles subjected to fission and fusion events. During mitosis, mitochondrial fission ensures equal distribution of mitochondria to daughter cells. If and how this process can actively drive mitotic progression remains largely unknown. Here, we discover a pathway linking mitochondrial fission to mitotic progression in mammalian cells. The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells. Phosphorylation of MFF is crucial for chromosome segregation and promotes cell survival by inhibiting adaptation of the mitotic checkpoint. Thus, PKD/MFF-dependent mitochondrial fission is critical for the maintenance of genome integrity during cell division.

Keywords:  MFF; PKD; cell survival; fission; mitochondria; mitosis; mitotic checkpoint

DOI:  https://doi.org/10.1016/j.celrep.2021.109129
Nature. 2021 May 14.

Actin mixes up mitochondria for inheritance.

Andrew S Moore, Erika L F Holzbaur.



Keywords:  Cell biology; Microscopy

DOI:  https://doi.org/10.1038/d41586-021-01115-7
Front Cell Dev Biol. 2021 ;9 658099

Adipose-Derived Mesenchymal Stem Cells From a Hypoxic Culture Improve Neuronal Differentiation and Nerve Repair.

Szu-Hsien Wu, Yu-Ting Liao, Kuang-Kai Hsueh, Hui-Kuang Huang, Tung-Ming Chen, En-Rung Chiang, Shan-Hui Hsu, Ting-Chen Tseng, Jung-Pan Wang.

  Hypoxic expansion has been demonstrated to enhance in vitro neuronal differentiation of bone-marrow derived mesenchymal stem cells (BMSCs). Whether adipose-derived mesenchymal stem cells (ADSCs) increase their neuronal differentiation potential following hypoxic expansion has been examined in the study. Real-time quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were employed to detect the expression of neuronal markers and compare the differentiation efficiency of hypoxic and normoxic ADSCs. A sciatic nerve injury animal model was used to analyze the gastrocnemius muscle weights as the outcomes of hypoxic and normoxic ADSC treatments, and sections of the regenerated nerve fibers taken from the conduits were analyzed by histological staining and immunohistochemical staining. Comparisons of the treatment effects of ADSCs and BMSCs following hypoxic expansion were also conducted in vitro and in vivo. Hypoxic expansion prior to the differentiation procedure promoted the expression of the neuronal markers in ADSC differentiated neuron-like cells. Moreover, the conduit connecting the sciatic nerve gap injected with hypoxic ADSCs showed the highest recovery rate of the gastrocnemius muscle weights in the animal model, suggesting a conceivable treatment for hypoxic ADSCs. The percentages of the regenerated myelinated fibers from the hypoxic ADSCs detected by toluidine blue staining and myelin basic protein (MBP) immunostaining were higher than those of the normoxic ones. On the other hand, hypoxic expansion increased the neuronal differentiation potential of ADSCs compared with that of the hypoxic BMSCs in vitro. The outcomes of animals treated with hypoxic ADSCs and hypoxic BMSCs showed similar results, confirming that hypoxic expansion enhances the neuronal differentiation potential of ADSCs in vitro and improves in vivo therapeutic potential.

Keywords:  ADSC; BMSC; hypoxic culture; nerve repair; neuronal differentiation

DOI:  https://doi.org/10.3389/fcell.2021.658099
Dis Model Mech. 2020 Jan 01. pii: dmm.045229. [Epub ahead of print]

Mitochondrial damage and senescence phenotype of cells derived from a novel frataxin G127V point mutation mouse model of Friedreich's ataxia.

Daniel Fil, Balu K Chacko, Robbie Conley, Xiaosen Ouyang, Jianhua Zhang, Victor M Darley-Usmar, Aamir R Zuberi, Cathleen M Lutz, Marek Napierala, Jill S Napierala.

  Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, while a fraction of patients are compound heterozygotes with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.

Keywords:  Frataxin; Friedreich's ataxia; Mitochondria; Oxidative stress; Point mutation; Senescence

DOI:  https://doi.org/10.1242/dmm.045229