CPT1C promotes human mesenchymal stem cells survival under glucose deprivation through the modulation of autophagy

Abstract

Human mesenchymal stem cells (hMSCs) are widely used in regenerative medicine. In some applications, they must survive under low nutrient conditions engendered by avascularity. Strategies to improve hMSCs survival may be of high relevance in tissue engineering. Carnitine palmitoyltransferase 1 C (CPT1C) is a pseudoenzyme exclusively expressed in neurons and cancer cells. In the present study, we show that CPT1C is also expressed in hMSCs and protects them against glucose starvation, glycolysis inhibition, and oxygen/glucose deprivation. CPT1C overexpression in hMSCs did not increase fatty acid oxidation capacity, indicating that the role of CPT1C in these cells is different from that described in tumor cells. The increased survival of CPT1C-overexpressing hMSCs observed during glucose deficiency was found to be the result of autophagy enhancement, leading to a greater number of lipid droplets and increased intracellular ATP levels. In fact, inhibition of autophagy or lipolysis was observed to completely block the protective effects of CPT1C. Our results indicate that CPT1C-mediated autophagy enhancement in glucose deprivation conditions allows a greater availability of lipids to be used as fuel substrate for ATP generation, revealing a new role of CPT1C in stem cell adaptation to low nutrient environments.

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

“…Lipid droplet biogenesis must, therefore, be essential for cell survival, but it was not clear until recently why a futile cycle of FA esterification into TAG and lipolysis would be necessary for energy production and cell survival. Studies in starved MEFs have shown that structural lipids are mobilised through autophagy of membranous organelles and that lipid droplets are necessary for at least two main reasons: (1) to prevent the lipotoxicity of FAs released by autophagy into the cytosol [ 31 ] and (2) to enable efficient transfer of FAs from lipid droplets to the network of tubulated mitochondria for oxidation [ 25 , 31 , 34 , 41 ]. The lipid droplet biogenesis in starved MEFs depends on the activation of autophagy (see discussion in Section 8.3 ) and on DGAT1 activity.…”

“…Since lipid droplets are central to lipid homeostasis, there are also multiple ways of crosstalk between lipid droplets and autophagy ( Figure 5 ). Autophagy may participate in lipid droplet biogenesis [ 25 , 31 , 34 , 241 , 242 ] and breakdown [ 62 ], but lipid droplets may also promote autophagy through several mechanisms [ 58 , 59 , 60 , 61 ]. Indeed, recent studies have shown that lipid droplets may be sites for autophagy initiation or provide lipids for the assembly of the autophagic machinery.…”

“…These may be instigated by different stressors, such as complete or partial nutrient deprivation, nutrient overload, oxygen deprivation, treatments with pro-oxidants, ceramides, chemotherapeutic agents, and inducers of endoplasmic reticulum (ER) stress [ 7 , 8 , 9 , 16 , 23 , 24 , 25 , 26 , 27 ] ( Figure 1 ). These conditions lead to the activation of stress-response pathways and result in different cellular defects that have been shown to induce lipid droplet biogenesis: oxidative stress [ 8 , 24 , 26 , 28 , 29 ], ER stress [ 30 ], activation of autophagy [ 31 , 32 , 33 , 34 ], inflammation [ 13 , 35 ], mitochondrial dysfunction, and cell death [ 36 , 37 , 38 ]. The fact that cells undergo a seemingly futile cycle of lipid droplet biogenesis and breakdown during such challenging conditions suggests that the benefits of lipid droplets must outweigh the expense of their biogenesis.…”

“…On the one hand, lipid droplets have been shown to provide lipids for the formation of autophagosomal membranes, manage ER stress, or stimulate signalling processes that promote autophagy [ 58 , 59 , 60 , 61 ]. On the other hand, autophagy drives lipid droplet biogenesis by providing lipids recycled from membranous organelles [ 25 , 31 , 34 ], but it may also participate in their breakdown through lipophagy, a lipid droplet-selective form of autophagy [ 62 ].…”

AMPK: An Epigenetic Landscape Modulator

“…This exposes TP53 or tumor protein (p53) DNA binding sites and subsequent association with RNA polymerase II ( Figure 1 ) [ 26 , 27 ]. These events enhance CPT1C and p21 expression, which play a role in cellular survival via activating autophagy and transporting long-chain fatty acids to the mitochondria, collectively enhancing β-oxidation and energy production [ 28 , 29 , 30 ]. Related to cellular survival, charged multivesicular body protein 1B (CHMP1b) is phosphorylated by AMPK, forms a “shell” around nucleosomes enriched with H3 phosphorylation and acetylation, and influences gene transcription [ 25 ].…”