Macroautophagy and Cell Responses Related to Mitochondrial Dysfunction, Lipid Metabolism and Unconventional Secretion of Proteins

Demine, Stéphane; Michel, Sébastien; Vannuvel, Kayleen; Wanet, Anaïs; Renard, Patricia; Arnould, Thierry

doi:10.3390/cells1020168

Cited by 8 publications

(9 citation statements)

References 172 publications

(282 reference statements)

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“…Lysosomes are essential for autophagy, and autophagic clearance of dysfunctional mitochondria represents an important element of mitochondrial quality control [ 15 ]. It is easy to speculate that lysosomal dysfunction such as in LSDs [ 16 ] leads to the abnormal accumulation of non-hydrolysed autophagy cargos such as mitochondria and other organelles.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction in Lysosomal Storage Disorders

et al. 2016

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Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm), diminished ATP production and increased generation of reactive oxygen species (ROS). Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD), the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase). Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction in Lysosomal Storage Disorders

et al. 2016

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“…A second mechanism allowing mobilization of FFAs is the macroautophagy of LDs (lipophagy), a process identified both in vitro and in vivo in rat RALA255-10G hepatocytes exposed to oil-rich medium and in liver-specific conditional autophagy-related 7 (Atg7) knock-out mice, respectively (Demine et al, 2012;Singh, Kaushik et al, 2009). In these conditions, the recruitment of light chain 3 (LC3), an autophagosomal marker, to the LD is observed, initiating the formation of autophagosomal engulfment of the LD in an Atg7-dependent manner and allowing the fusion with lysosomes in which lipolytic enzymes digest the TAG contained in LDs (Demine et al, 2012;Singh, Kaushik et al, 2009). So far, the existence of lipophagy has been confirmed in hepatocytes (Singh, Kaushik et al, 2009) (Martinez-Lopez et al, 2016), white (Lettieri Barbato, Tatulli, Aquilano, & Ciriolo, 2013) and brown (Martinez-Lopez et al, 2016) adipocytes, pancreatic β cells (Pearson et al, 2014), T cells (Hubbard et al, 2010), or neurons (Kaushik et al, 2011).…”

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confidence: 99%

Mild mitochondrial uncoupling induces HSL/ATGL‐independent lipolysis relying on a form of autophagy in 3T3‐L1 adipocytes

Demine

Tejerina

Bihin

et al. 2017

Journal Cellular Physiology

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Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet-associated proteins as well as lipolytic enzymes have been identified. Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti-obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3-L1 adipocytes were characterized. Mitochondrial uncoupling-induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial uncoupling relies on a form of autophagy as lipid droplets are captured by endolysosomal vesicles. This new mechanism of triacylglycerol breakdown in adipocytes exposed to mild uncoupling provides new insights on the biology of adipocytes dealing with mitochondria forced to dissipate energy.

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“…This suggests that the reprogramming process may require the consumption of large amounts of lipid, which can provide metabolites or energy. Previous studies have identified a critical function for autophagy during lipid metabolism 24 25 , and this led us to further investigate the effects of Rab32 on autophagy during reprogramming.…”

Section: Resultsmentioning

confidence: 99%

Improvement in Mouse iPSC Induction by Rab32 Reveals the Importance of Lipid Metabolism during Reprogramming

Pei

Yue

Zhang

et al. 2015

Sci Rep

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Induced pluripotent stem cells (iPSCs) have variable expression levels of a series of genes that affect their pluripotent potential, but the regulatory mechanisms controlling reprogramming remain unclear. By testing the efficiency of iPSC generation using Oct4, Sox2, Klf4 (termed OSK) plus one additional gene, we found that Rab32 improved reprogramming efficiency. We established a system for detecting the number and the size of lipid droplets and autophagosomes per cell for tracking their morphological changes during reprogramming. Our results showed that Rab32 increased lipid storage during the early and middle stages, and also increased autophagy during the middle stage of reprogramming. These findings were further confirmed by the up-regulation of lipid biosynthesis and autophagosome formation related genes, of which their expression could improve iPSC induction. The inhibition of lipid biosynthesis and autophagosome formation significantly reduced reprogramming efficiency, and the inhibition of lipid synthesis phenotype could be rescued by the overexpression of Rab32. In addition, the expression of pluripotency genes such as Klf2, Nr5a2 and Tbx3, was up-regulated by Rab32. These results demonstrated that Rab32 could improve the induction of iPSCs through the enhancement of lipid biosynthesis, highlighting the importance of lipid metabolism during reprogramming.

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Macroautophagy and Cell Responses Related to Mitochondrial Dysfunction, Lipid Metabolism and Unconventional Secretion of Proteins

Cited by 8 publications

References 172 publications

Mitochondrial Dysfunction in Lysosomal Storage Disorders

Mitochondrial Dysfunction in Lysosomal Storage Disorders

Mild mitochondrial uncoupling induces HSL/ATGL‐independent lipolysis relying on a form of autophagy in 3T3‐L1 adipocytes

Improvement in Mouse iPSC Induction by Rab32 Reveals the Importance of Lipid Metabolism during Reprogramming

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