Proteostatic and Metabolic Control of Stemness

García‐Prat, Laura; Sousa‐Victor, Pedro; Muñoz‐Cánoves, Pura

doi:10.1016/j.stem.2017.04.011

Cited by 107 publications

(112 citation statements)

References 176 publications

(243 reference statements)

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“…The insulin growth factor 1 (Igf‐1) and its receptor (Igf‐1r; Kenyon, 2005; Longo & Finch, 2003; Milman, Huffman, & Barzilai, 2016), as well as the stemness potential of stem cells (Garcia‐Prat et al, 2016; Garcia‐Prat, Sousa‐Victor, & Munoz‐Canoves, 2017), represent already established age‐associated pathways. To determine whether they were mechanistically involved—at least in part—in the AT‐1 sTg phenotype, we analyzed whole tissue activation of Igf‐1r signaling (Supporting Information Figure S4a,b); we also treated cultured MEF with Igf‐1 (Supporting Information Figure S4c,d).…”

Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…The lifelong accumulation of altered or damaged proteins is an important factor in age‐related stem cell dysfunction, affecting multiple intracellular signaling pathways and ultimately driving genomic instability, senescence, and apoptosis . Satellite cells, mostly quiescent throughout life, cannot eliminate toxic organelles and protein aggregates through cell division and are therefore particularly susceptible to proteostatic stress .…”

Section: How Muscle Stem Cells Agementioning

confidence: 99%

“…Satellite cells, mostly quiescent throughout life, cannot eliminate toxic organelles and protein aggregates through cell division and are therefore particularly susceptible to proteostatic stress . As a consequence, mechanisms of intracellular macromolecular clearance, such as autophagy, play a fundamental role in the maintenance of satellite cell quiescence . Impairment of autophagy causes the accumulation of damaged mitochondria and the generation of high reactive oxygen species (ROS) levels, further propagating protein and DNA damage.…”

Section: How Muscle Stem Cells Agementioning

confidence: 99%

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

2020

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Aging is characterized by the progressive dysfunction of most tissues and organs, which has been linked to the regenerative decline of their resident stem cells over time. Skeletal muscle provides a stark example of this decline. Its stem cells, also called satellite cells, sustain muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons.Here, we discuss current understanding of the molecular processes regulating satellite cell maintenance throughout life and how age-related failure of these processes contributes to muscle aging. We also highlight the emerging field of rejuvenating biology to restore features of youthfulness in satellite cells, with the ultimate goal of slowing down or reversing the age-related decline in muscle regeneration.

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“…This metabolic priming is suited to respond to the demands of cell growth and proliferation (Lunt & Vander Heiden, 2011). Important evidence also links stemness to mitochondrial dynamics and protein homeostasis (García-Prat, Sousa-Victor, & Muñoz-Cánoves, 2017).…”

mentioning

confidence: 99%

Wnt signaling reprograms metabolism in dental pulp stem cells

Uribe-Etxebarria

Agliano

Unda

et al. 2018

Journal Cellular Physiology

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Human dental pulp stem cells (DPSCs) can differentiate to a wide range of different cell lineages, and share some gene expression and functional similarities with pluripotent stem cells. The stemness of DPSCs can also be pharmacologically enhanced by the activation of canonical Wnt signaling. Here, we examined the metabolic profile of DPSCs during reprogramming linked to Wnt activation, by a short (48 hr) exposure to either the GSK3‐β inhibitor BIO (6‐bromoindirubin‐3´‐oxine) or human recombinant protein WNT‐3A. Both treatments largely increased glucose consumption, and induced a gene overexpression of pyruvate and mitochondrial acetyl‐coA producing enzymes, thus activating mitochondrial tricarboxylic acid cycle (TCA) metabolism in DPSCs. This ultimately led to an accumulation of reducing power and a mitochondrial hyperpolarization in DPSCs. Interestingly, Nile Red staining showed that lipid fuel reserves were being stored in Wnt‐activated DPSCs. We associate this metabolic reprogramming with an energy‐priming state allowing DPSCs to better respond to subsequent high demands of energy and biosynthesis metabolites for cellular growth. These results show that enhancement of the stemness of DPSCs by Wnt activation comes along with a profound metabolic remodeling, which is distinctly characterized by a crucial participation of mitochondrial metabolism.

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Proteostatic and Metabolic Control of Stemness

Cited by 107 publications

References 176 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

Wnt signaling reprograms metabolism in dental pulp stem cells

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