Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress

Park, Kihyoun; Lim, Hyejin; Kim, Jinyoung; Hwang, Yeseong; Lee, Yu Seol; Bae, Soo Han; Kim, Hyeongseok; Kim, Hail; Kang, Shin Wook; Kim, Joo Young; Lee, Myung-Shik

doi:10.1038/s41467-022-28874-9

Cited by 33 publications

(62 citation statements)

References 72 publications

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“…PA can induce reactive oxygen species (ROS) by compromising mitochondrial complex I and III [ 11 , 16 ], which can activate lysosomal Ca 2+ channel [ 12 , 17 ]. Lysosomal Ca 2+ release due to lysosomal Ca 2+ exit channel activation can increase cytosolic Ca 2+ content ([Ca 2+ ] i ), which, in turn, can induce mitophagy, lysosomal stress response [ 11 , 12 ] or diverse types of cell death [ 18 – 20 ]. Hence, we studied whether PA-induced lipotoxicity entails mitochondrial ROS-induced lysosomal Ca 2+ release and increased [Ca 2+ ] i .…”

Section: Resultsmentioning

confidence: 99%

Lysosomal Ca2+ as a mediator of palmitate-induced lipotoxicity

Hwang

Hur

et al. 2023

Cell Death Discov.

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While the mechanism of lipotoxicity by palmitic acid (PA), an effector of metabolic stress in vitro and in vivo, has been extensively investigated, molecular details of lipotoxicity are still not fully characterized. Since recent studies reported that PA can exert lysosomal stress in addition to well-known ER and mitochondrial stress, we studied the role of lysosomal events in lipotoxicity by PA, focusing on lysosomal Ca2+. We found that PA induced accumulation of mitochondrial ROS and that mitochondrial ROS induced release of lysosomal Ca2+ due to lysosomal Ca2+ exit channel activation. Lysosomal Ca2+ release led to increased cytosolic Ca2+ which induced mitochondrial permeability transition (mPT). Chelation of cytoplasmic Ca2+ or blockade of mPT with olesoxime or decylubiquinone (DUB) suppressed lipotoxicity. Lysosomal Ca2+ release led to reduced lysosomal Ca2+ content which was replenished by ER Ca2+, the largest intracellular Ca2+ reservoir (ER → lysosome Ca2+ refilling), which in turn activated store-operated Ca2+ entry (SOCE). Inhibition of ER → lysosome Ca2+ refilling by blockade of ER Ca2+ exit channel using dantrolene or inhibition of SOCE using BTP2 inhibited lipotoxicity in vitro. Dantrolene or DUB also inhibited lipotoxic death of hepatocytes in vivo induced by administration of ethyl palmitate together with LPS. These results suggest a novel pathway of lipotoxicity characterized by mPT due to lysosomal Ca2+ release which was supplemented by ER → lysosome Ca2+ refilling and subsequent SOCE, and also suggest the potential role of modulation of ER → lysosome Ca2+ refilling by dantrolene or other blockers of ER Ca2+ exit channels in disease conditions characterized by lipotoxicity such as metabolic syndrome, diabetes, cardiomyopathy or nonalcoholic steatohepatitis.

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Section: Resultsmentioning

confidence: 99%

Lysosomal Ca2+ as a mediator of palmitate-induced lipotoxicity

Hwang

Hur

et al. 2023

Cell Death Discov.

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“…8-oxoG, another marker indicating ROS-mediated DNA damage, was similarly increased in the liver of Atg7 DHep Fgf21 +/+ mice, which was further increased in that of Atg7 DHep Fgf21 −/− mice (Figure 4D). We also evaluated mitochondrial activity in the liver tissue by staining of mitochondrial COX activity (11), since dysfunctional mitochondria, which has been observed in Atg7-KO hepatocytes (11), could be the source of ROS production (32)(33)(34). ROS could be produced at the mitochondrial complexes I and III by partial inhibition of electron transport (33,35).…”

Section: Further Increased Ros-mediated Dna Damage Of Autophagy-defic...mentioning

confidence: 99%

Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

Kim

Lee

2022

Front. Oncol.

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Mice with hepatocyte-specific deletion of autophagy-related 7 (Atg7ΔHep mice) develop hepatoma, suggesting that autophagy deficiency could be a factor in the initiation of tumorigenesis. We have shown that FGF21 is induced as a ‘mitokine’ when Atg7 is disrupted in insulin target tissues such as the liver, which could affect systemic metabolism through endocrine activity. Since FGF21 or other endocrine FGF such as FGF19 can affect tumor growth, we hypothesized that FGF21 produced by Atg7-knockout (KO) hepatocytes may affect the behavior of Atg7-KO hepatoma in an autocrine manner. We, thus, crossed Atg7ΔHep mice with systemic Fgf21-KO (Fgf21−/−) mice to generate Atg7ΔHepFgf21−/− mice. The number and size of hepatoma of Atg7ΔHep mice were significantly increased by additional Fgf21 KO. The proliferation of Atg7-KO hepatocyte was significantly increased by Fgf21 KO. pYAP1/YAP1 representing YAP1 degradation was significantly decreased in the liver of Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice. Consistently, expression of YAP1/TAZ downstream genes was significantly increased in the liver of Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice, which could explain the increased size of hepatoma in Atg7ΔHepFgf21−/− mice. Accumulation of ROS and ROS-mediated DNA damage were increased in the liver of Atg7ΔHepFgf21+/+ mice, which was further aggravated by additional Fgf21 KO probably due to the absence of positive effect of FGF21 on mitochondrial function, explaining the increased number of hepatoma in Atg7ΔHepFgf21−/− mice compared to Atg7ΔHepFgf21+/+ mice. These results show that FGF21 produced by autophagy-deficient hepatocytes could have autocrine or paracrine effects on the number and proliferation of autophagy-deficient hepatoma, suggesting that hormones or factors released from autophagy-deficient tumors can influence the behavior or prognosis of the tumor in addition to the effects on host metabolism.

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“…Overall, these pieces of evidence suggest that basal clearance of cytosolic waste through autophagy is crucial for preventing the accumulation of cytoplasmic inclusion in neurons, and in astrocytes and microglia, which are involved in the clearance of brain waste via phagocytosis [ 93 ]. Therefore, the upregulation of autophagy may have beneficial effects and many research efforts in the field are aimed at finding molecular modulators of this process, possibly in a cell-type specific manner [ 6 , 7 ].…”

Section: Tfeb and Autophagy In Neurodegenerationmentioning

confidence: 99%

“…Multiple other roles have been associated with the members of the MiTF/TFE family, including the regulation of mitophagy [ 7 ], lipid catabolism [ 8 , 9 ], and mitochondrial biogenesis [ 10 ]. Although some of their activities may overlap, each homolog of the MiTF/TFE family seems to have a specific pattern of expression and individual functions, which will be addressed in the following sections.…”

Section: Introductionmentioning

confidence: 99%

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

et al. 2022

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The microphthalmia/transcription factor E (MiTF/TFE) transcription factors are responsible for the regulation of various key processes for the maintenance of brain function, including autophagy-lysosomal pathway, lipid catabolism, and mitochondrial homeostasis. Among them, autophagy is one of the most relevant pathways in this frame; it is evolutionary conserved and crucial for cellular homeostasis. The dysregulation of MiTF/TFE proteins was shown to be involved in the development and progression of neurodegenerative diseases. Thus, the characterization of their function is key in the understanding of the etiology of these diseases, with the potential to develop novel therapeutics targeted to MiTF/TFE proteins and to the autophagic process. The fact that these proteins are evolutionary conserved suggests that their function and dysfunction can be investigated in model organisms with a simpler nervous system than the mammalian one. Building not only on studies in mammalian models but also in complementary model organisms, in this review we discuss (1) the mechanistic regulation of MiTF/TFE transcription factors; (2) their roles in different regions of the central nervous system, in different cell types, and their involvement in the development of neurodegenerative diseases, including lysosomal storage disorders; (3) the overlap and the compensation that occur among the different members of the family; (4) the importance of the evolutionary conservation of these protein and the process they regulate, which allows their study in different model organisms; and (5) their possible role as therapeutic targets in neurodegeneration.

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Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress

Cited by 33 publications

References 72 publications

Lysosomal Ca2+ as a mediator of palmitate-induced lipotoxicity

Lysosomal Ca2+ as a mediator of palmitate-induced lipotoxicity

Suppressive Effect of Autocrine FGF21 on Autophagy-Deficient Hepatic Tumorigenesis

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

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