Mitochondrial fusion regulates lipid homeostasis and stem cell maintenance in the Drosophila testis

Demarco, Rafael Sênos; Uyemura, Bradley; D'Alterio, Cecilia; Jones, D. Leanne

doi:10.1038/s41556-019-0332-3

Cited by 64 publications

(76 citation statements)

References 73 publications

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“…To further explore the dysfunction of fragmented mitochondria, we also examined lipid accumulation in marf ‐KD GSCs by TEM and a lipophilic dye (BODIPY 493/503 staining), as fatty acid oxidation takes place in mitochondria (Pakhomov et al, 2017). We observed a clear increase in number and size of oil droplets in marf ‐KD GSCs as compared to control or drp1 ‐KD GSCs one and 2 weeks after eclosion (Figure 5c–h,l, and Figure ), similar to previous observations in male GSCs (Sênos Demarco, Uyemura, D’Alterio, & Jones, 2019). Interestingly, promoting lipid reentry into mitochondria of 1‐week‐old marf ‐KD GSCs, by feeding flies with L‐carnitine for 1 week (Longo, Frigeni, & Pasquali, 2016), eliminated lipid accumulation and partially rescued GSC number (Figure 5m, and Figure ).…”

Section: Resultssupporting

confidence: 89%

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss

et al. 2020

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Section: Resultssupporting

confidence: 89%

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss

et al. 2020

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“…Male germline stem cells (GSCs) in Drosophila melanogaster have been recently characterized to also rely on the mitochondrial uptake of lipids to prevent the switch to lipid anabolism and consequent loss of stem cell identity (Sênos Demarco et al, 2019). In order to be catabolized, free fatty acids (FFAs) must first travel to the mitochondrial matrix through the carnitine shuttle.…”

Section: Fatty Acid Oxidationmentioning

confidence: 99%

“…Similar to the proposed mechanism of mitochondrial control of FAO utilization seen in HSCs (Ito et al, 2016), active mitochondria are required to promote lipid catabolism and GSC maintenance. Disruption of mitochondrial activity in these cells, via blocking mitochondrial fusion, led to the accumulation of LDs, activation of Target of Rapamycin (TOR), and precocious germ cell differentiation (Sênos Demarco et al, 2019).…”

Section: Fatty Acid Oxidationmentioning

confidence: 99%

“…Of note, it was suggested that cholesterol biosynthesis, which occurs through an independent pathway, is also required for NSPC self-renewal and maintenance in the developing mouse forebrain, as NSPCs with mutations in enzymes involved in this pathway exhibit premature differentiation into neurons, causing exhaustion of the stem cell pool (Driver et al, 2016). Importantly, as in the case of NSPCs, increased lipid anabolism in Drosophila GSCs through the activation of SREBP also resulted in stem cell loss (Sênos Demarco et al, 2019), suggesting that a conserved mechanism may be at play across stem cell populations.…”

Section: De Novo Lipid Synthesis In Stem Cellsmentioning

confidence: 99%

“…However, there is little evidence of a variation in LD accumulation during differentiation of adult stem cells that could be implicated in changes in gene expression. In Drosophila male GSCs, an abnormal increase of LDs resulting from perturbation of mitochondrial function appears to correlate with precocious differentiation (Sênos Demarco et al, 2019). A more detailed analysis and profile of LDs and their contents in stem cells and differentiating progeny could provide additional insights into a potential role of LDs in regulating stem cell function under homeostatic conditions.…”

Section: Lipids and Regulation Of The Transcriptome And Epigenomementioning

confidence: 99%

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Lipid Mediated Regulation of Adult Stem Cell Behavior

Clémot

Demarco

Jones

2020

Front. Cell Dev. Biol.

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Adult stem cells constitute an important reservoir of self-renewing progenitor cells and are crucial for maintaining tissue and organ homeostasis. The capacity of stem cells to self-renew or differentiate can be attributed to distinct metabolic states, and it is now becoming apparent that metabolism plays instructive roles in stem cell fate decisions. Lipids are an extremely vast class of biomolecules, with essential roles in energy homeostasis, membrane structure and signaling. Imbalances in lipid homeostasis can result in lipotoxicity, cell death and diseases, such as cardiovascular disease, insulin resistance and diabetes, autoimmune disorders and cancer. Therefore, understanding how lipid metabolism affects stem cell behavior offers promising perspectives for the development of novel approaches to control stem cell behavior either in vitro or in patients, by modulating lipid metabolic pathways pharmacologically or through diet. In this review, we will first address how recent progress in lipidomics has created new opportunities to uncover stem-cell specific lipidomes. In addition, genetic and/or pharmacological modulation of lipid metabolism have shown the involvement of specific pathways, such as fatty acid oxidation (FAO), in regulating adult stem cell behavior. We will describe and compare findings obtained in multiple stem cell models in order to provide an assessment on whether unique lipid metabolic pathways may commonly regulate stem cell behavior. We will then review characterized and potential molecular mechanisms through which lipids can affect stem cell-specific properties, including self-renewal, differentiation potential or interaction with the niche. Finally, we aim to summarize the current knowledge of how alterations in lipid homeostasis that occur as a consequence of changes in diet, aging or disease can impact stem cells and, consequently, tissue homeostasis and repair.

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Fusobacterium nucleatum Promotes Colorectal Cancer Cell to Acquire Stem Cell‐Like Features by Manipulating Lipid Droplet‐Mediated Numb Degradation

Liu

Chao

et al. 2022

Advanced Science

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Fusobacterium nucleatum is a critical microbe that contributes to colorectal cancer progression and chemoresistance. However, whether and how F. nucleatum regulates colorectal cancer stem‐like cells (CCSCs) remains unknown. Here, the authors show that F. nucleatum promotes CCSC self‐renewal, and non‐CCSCs to acquire CCSC features by manipulating cellular lipid accumulation. F. nucleatum infection decreases lipid accumulation in CCSCs by enhancing fatty acid oxidation, thus promoting CCSC self‐renewal. In contrast, F. nucleatum increases lipid accumulation in non‐CCSCs by promoting fatty acid formation. Lipids are deposited as lipid droplets, which recruits Numb, a key cell fate regulator, through the AP2A/ACSL3 complex, and MDM2, an E3 ubiquitin ligase, though VCP and UBXD8. On lipid droplets, Numb is degraded by MDM2, activating Notch signaling, thus promoting gain of stem‐like cell features. Their findings demonstrate that F. nucleatum directly manipulates colorectal cancer cell fate and reveal the mechanism of lipid droplet‐mediated Numb degradation for activating Notch signaling.

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Mitochondrial fusion regulates lipid homeostasis and stem cell maintenance in the Drosophila testis

Cited by 64 publications

References 73 publications

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss

Lipid Mediated Regulation of Adult Stem Cell Behavior

Fusobacterium nucleatum Promotes Colorectal Cancer Cell to Acquire Stem Cell‐Like Features by Manipulating Lipid Droplet‐Mediated Numb Degradation

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