Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle

Tournaire, Guillaume; Loopmans, Shauni; Stegen, Steve; Rinaldi, Gianmarco; Eelen, Guy; Torrekens, Sophie; Moermans, Karen; Carmeliet, Peter; Ghesquière, Bart; Thienpont, Bernard; Fendt, Sarah-Maria; Gastel, Nick van; Carmeliet, Geert

doi:10.1016/j.celrep.2022.111105

Cited by 15 publications

(14 citation statements)

References 43 publications

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“…There are several recent studies underlying the importance of studying metabolism as a critical regulator for bone regeneration process. Chondrocyte metabolism and more specifically glutamine metabolism controls the collagen synthesis and modification 39 and targeting skeletal metabolism has been shown as advantageous for the expansion and self‐renewal of skeletal progenitors 40 . In this study, we aim for exometabolomic analysis, as a first effort to illustrate changes in the metabolome in the dynamic culture and due to the mechanical stimulation.…”

Section: Discussionmentioning

confidence: 99%

Stirred culture of cartilaginous microtissues promotes chondrogenic hypertrophy through exposure to intermittent shear stress

Loverdou

Cuvelier

Hall

et al. 2022

Bioengineering & Transla Med

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Cartilage microtissues are promising tissue modules for bottom up biofabrication of implants leading to bone defect regeneration. Hitherto, most of the protocols for the development of these cartilaginous microtissues have been carried out in static setups, however, for achieving higher scales, dynamic process needs to be investigated. In the present study, we explored the impact of suspension culture on the cartilage microtissues in a novel stirred microbioreactor system. To study the effect of the process shear stress, experiments with three different impeller velocities were carried out. Moreover, we used mathematical modeling to estimate the magnitude of shear stress on the individual microtissues during dynamic culture. Identification of appropriate mixing intensity allowed dynamic bioreactor culture of the microtissues for up to 14 days maintaining microtissue suspension. Dynamic culture did not affect microtissue viability, although lower proliferation was observed as opposed to the statically cultured ones. However, when assessing cell differentiation, gene expression values showed significant upregulation of both Indian Hedgehog (IHH) and collagen type X (COLX), well known markers of chondrogenic hypertrophy, for the dynamically cultured microtissues. Exometabolomics analysis revealed similarly distinct metabolic profiles between static and dynamic conditions. Dynamic cultured microtissues showed a higher glycolytic profile compared with the statically cultured

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Section: Discussionmentioning

confidence: 99%

Stirred culture of cartilaginous microtissues promotes chondrogenic hypertrophy through exposure to intermittent shear stress

Loverdou

Cuvelier

Hall

et al. 2022

Bioengineering & Transla Med

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“…[10] As a result of all these, fumarate, 2-hydroxyglutarate and, especially, succinate, whose concentration can be 11-fold higher, accumulate, signaling hypoxia in the cell and throughout the body. [108] Meanwhile, under oxidative stress, the activity of AKGDH is decreased by c. 40%, [86,87] causing AKG levels to rise. [110] This is likely adaptive in that AKG is an antioxidant, becoming nonenzymatically oxidized to succinate: [111] AKG…”

Section: Succinate Hypoxic Signaling and Oxidative Stressmentioning

confidence: 99%

“…These preserve stemness by inhibiting the TET DNA demethylases, thus keeping differentiation-associated genes in an inhibited, hypermethylated state. [108,137] Conversely, increases in AKG promote demethylation, differentiation, and exiting of the stem cell pool. [137] Thus, if AKG is converted to succinyl-CoA and then succinate there is the risk of interfering with DNA repair and causing inflammatory signaling.…”

Section: Alpha-ketoglutarate and Stem Cell Maintenance And Exhaustionmentioning

confidence: 99%

“…The TCA cycle reconfigures itself to contend with this. [ 108 ] Specifically: (1)Pyruvate enters the TCA cycle via conversion to oxaloacetate by pyruvate carboxylase (Figure 2). This bypasses PDH, which would otherwise generate NADH.…”

Section: Mechanisms Connecting the Tca Cycle To Aging And Longevitymentioning

confidence: 99%

“…As a result of all these, fumarate, 2‐hydroxyglutarate and, especially, succinate, whose concentration can be 11‐fold higher, accumulate, signaling hypoxia in the cell and throughout the body. [ 108 ]…”

Section: Mechanisms Connecting the Tca Cycle To Aging And Longevitymentioning

confidence: 99%

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The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Borkum

2023

Advanced Biology

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Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high‐capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha‐ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double‐strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia‐inducible factor‐1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

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Oxidative phosphorylation in bone cells

et al. 2023

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Skeletal progenitors preserve proliferation and self-renewal upon inhibition of mitochondrial respiration by rerouting the TCA cycle

Cited by 15 publications

References 43 publications

Stirred culture of cartilaginous microtissues promotes chondrogenic hypertrophy through exposure to intermittent shear stress

Stirred culture of cartilaginous microtissues promotes chondrogenic hypertrophy through exposure to intermittent shear stress

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Oxidative phosphorylation in bone cells

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