bims-mireme 2021-10-31 papers

Issue of 2021‒10‒31
five papers selected by
Brian Spurlock
The University of North Carolina at Chapel Hill

Mol Cell. 2021 Oct 15. pii: S1097-2765(21)00800-5. [Epub ahead of print]

Temporal proteomics during neurogenesis reveals large-scale proteome and organelle remodeling via selective autophagy.

Alban Ordureau, Felix Kraus, Jiuchun Zhang, Heeseon An, Sookhee Park, Tim Ahfeldt, Joao A Paulo, J Wade Harper.

Cell state changes are associated with proteome remodeling to serve newly emergent cell functions. Here, we show that NGN2-driven conversion of human embryonic stem cells to induced neurons (iNeurons) is associated with increased PINK1-independent mitophagic flux that is temporally correlated with metabolic reprogramming to support oxidative phosphorylation. Global multiplex proteomics during neurogenesis revealed large-scale remodeling of functional modules linked with pluripotency, mitochondrial metabolism, and proteostasis. Differentiation-dependent mitophagic flux required BNIP3L and its LC3-interacting region (LIR) motif, and BNIP3L also promoted mitophagy in dopaminergic neurons. Proteomic analysis of ATG12-/- iNeurons revealed accumulation of endoplasmic reticulum, Golgi, and mitochondria during differentiation, indicative of widespread organelle remodeling during neurogenesis. This work reveals broad organelle remodeling of membrane-bound organelles during NGN2-driven neurogenesis via autophagy, identifies BNIP3L's central role in programmed mitophagic flux, and provides a proteomic resource for elucidating how organelle remodeling and autophagy alter the proteome during changes in cell state.

Keywords: autophagy; iNeurons; mitophagy; proteomics

DOI: https://doi.org/10.1016/j.molcel.2021.10.001

J Histochem Cytochem. 2021 Oct 29. 221554211054585

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow.

Cornelis J F van Noorden, Barbara Breznik, Metka Novak, Amber J van Dijck, Saloua Tanan, Miloš Vittori, Urban Bogataj, Noëlle Bakker, Joseph D Khoury, Remco J Molenaar, Vashendriya V V Hira.

Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.

Keywords: angiogenesis; bone marrow; brain tumors; cancer stem cells; hematopoietic stem cells; leukemia; leukemic stem cells; metabolism; neural stem cells; niches; stem cells; stemness; tumor heterogeneity; tumor immune infiltrate; tumor microenvironment

DOI: https://doi.org/10.1369/00221554211054585

Development. 2021 Oct 15. pii: dev199909. [Epub ahead of print]148(20):

Microtubule-dependent subcellular organisation of pluripotent cells.

Azelle Hawdon, Asma Aberkane, Jennifer Zenker.

With the advancement of cutting-edge live imaging technologies, microtubule remodelling has evolved as an integral regulator for the establishment of distinct differentiated cells. However, despite their fundamental role in cell structure and function, microtubules have received less attention when unravelling the regulatory circuitry of pluripotency. Here, we summarise the role of microtubule organisation and microtubule-dependent events required for the formation of pluripotent cells in vivo by deciphering the process of early embryogenesis: from fertilisation to blastocyst. Furthermore, we highlight current advances in elucidating the significance of specific microtubule arrays in in vitro culture systems of pluripotent stem cells and how the microtubule cytoskeleton serves as a highway for the precise intracellular movement of organelles. This Review provides an informed understanding of the intrinsic role of subcellular architecture of pluripotent cells and accentuates their regenerative potential in combination with innovative light-inducible microtubule techniques.

Keywords: CAMSAP3; Live imaging; Microtubule cytoskeleton; Organelles; Pluripotency; Pre-implantation embryo; Stem cells

DOI: https://doi.org/10.1242/dev.199909

FEBS J. 2021 Oct 24.

Prolonged disturbance of proteostasis induces cellular senescence via temporal mitochondrial dysfunction and subsequent mitochondrial accumulation in human fibroblasts.

Yasuhiro Takenaka, Ikuo Inoue, Takanari Nakano, Masaaki Ikeda, Yoshihiko Kakinuma.

Proteolytic activity declines with age, resulting in the accumulation of aggregated proteins in aged organisms. To investigate how disturbance in proteostasis causes cellular senescence, we developed a stress-induced premature senescence (SIPS) model, in which normal human fibroblast MRC-5 cells were treated with the proteasome inhibitor MG132 or the V-ATPase inhibitor bafilomycin A1 (BAFA1) for 5 days. Time-course studies revealed a significant increase in intracellular reactive oxygen species (ROS) and mitochondrial superoxide during and after drug treatment. Mitochondrial membrane potential initially decreased, suggesting temporal mitochondrial dysfunction during drug treatment, but was restored along with mitochondrial accumulation after drug treatment. AMP-activated protein kinase alpha (AMPKα) was notably activated during treatment; thereafter, intracellular ATP levels significantly increased. SIPS induction by MG132 or BAFA1 was partially attenuated by co-treatment with vitamin E or rapamycin, in which the levels of ROS, mitochondrial accumulation, and protein aggregates were suppressed, implying the critical involvement of oxidative stress and mitochondrial function in SIPS progression. Rapamycin co-treatment also augmented the expression of HSP70 and activation of AKT, which could recover proteostasis and promote cell survival, respectively. Our study proposes a possible pathway from the disturbed proteostasis to cellular senescence via excess ROS production as well as functional and quantitative changes in mitochondria.

Keywords: DNA damage response; aggregate; lysosome; oxidative stress; proteasome

DOI: https://doi.org/10.1111/febs.16249

Front Cardiovasc Med. 2021 ;8 750604

Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes.

Chiara Bongiovanni, Francesca Sacchi, Silvia Da Pra, Elvira Pantano, Carmen Miano, Marco Bruno Morelli, Gabriele D'Uva.

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

Keywords: cardiomyocyte dedifferentiation; cardiomyocyte proliferation; direct cardiogenesis; endogenous cardiac repair; heart development; heart regeneration

DOI: https://doi.org/10.3389/fcvm.2021.750604