bims-mitlys 2021-03-21 papers

Front Cell Dev Biol. 2021 ;9 613336

Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease.

Paula Díaz, Alejandra Sandoval-Bórquez, Roberto Bravo-Sagua, Andrew F G Quest, Sergio Lavandero.

In recent decades, compelling evidence has emerged showing that organelles are not static structures but rather form a highly dynamic cellular network and exchange information through membrane contact sites. Although high-throughput techniques facilitate identification of novel contact sites (e.g., organelle-organelle and organelle-vesicle interactions), little is known about their impact on cellular physiology. Moreover, even less is known about how the dysregulation of these structures impacts on cellular function and therefore, disease. Particularly, cancer cells display altered signaling pathways involving several cell organelles; however, the relevance of interorganelle communication in oncogenesis and/or cancer progression remains largely unknown. This review will focus on organelle contacts relevant to cancer pathogenesis. We will highlight specific proteins and protein families residing in these organelle-interfaces that are known to be involved in cancer-related processes. First, we will review the relevance of endoplasmic reticulum (ER)-mitochondria interactions. This section will focus on mitochondria-associated membranes (MAMs) and particularly the tethering proteins at the ER-mitochondria interphase, as well as their role in cancer disease progression. Subsequently, the role of Ca2+ at the ER-mitochondria interphase in cancer disease progression will be discussed. Members of the Bcl-2 protein family, key regulators of cell death, also modulate Ca2+ transport pathways at the ER-mitochondria interphase. Furthermore, we will review the role of ER-mitochondria communication in the regulation of proteostasis, focusing on the ER stress sensor PERK (PRKR-like ER kinase), which exerts dual roles in cancer. Second, we will review the relevance of ER and mitochondria interactions with other organelles. This section will focus on peroxisome and lysosome organelle interactions and their impact on cancer disease progression. In this context, the peroxisome biogenesis factor (PEX) gene family has been linked to cancer. Moreover, the autophagy-lysosome system is emerging as a driving force in the progression of numerous human cancers. Thus, we will summarize our current understanding of the role of each of these organelles and their communication, highlighting how alterations in organelle interfaces participate in cancer development and progression. A better understanding of specific organelle communication sites and their relevant proteins may help to identify potential pharmacological targets for novel therapies in cancer control.

Keywords: cancer; endoplasmic reticulum; interorganelle communication; lysosome; mitochondria; peroxisome

DOI: https://doi.org/10.3389/fcell.2021.613336

Front Cell Dev Biol. 2021 ;9 629522

In the Right Place at the Right Time: Regulation of Cell Metabolism by IP3R-Mediated Inter-Organelle Ca2+ Fluxes.

Ulises Ahumada-Castro, Galdo Bustos, Eduardo Silva-Pavez, Andrea Puebla-Huerta, Alenka Lovy, César Cárdenas.

In the last few years, metabolism has been shown to be controlled by cross-organelle communication. The relationship between the endoplasmic reticulum and mitochondria/lysosomes is the most studied; here, inositol 1,4,5-triphosphate (IP3) receptor (IP3R)-mediated calcium (Ca2+) release plays a central role. Recent evidence suggests that IP3R isoforms participate in synthesis and degradation pathways. This minireview will summarize the current findings in this area, emphasizing the critical role of Ca2+ communication on organelle function as well as catabolism and anabolism, particularly in cancer.

Keywords: IP3Rs; calcium; endoplasmic reticulum; inositol triphosphate (IP3) receptors; lysosome; metabolism; mitochondria

DOI: https://doi.org/10.3389/fcell.2021.629522

FASEB J. 2021 Apr;35(4): e21223

The lysosomal membrane protein Sidt2 is a vital regulator of mitochondrial quality control in skeletal muscle.

Lizhuo Wang, Cui Yu, Wenjun Pei, Mengya Geng, Yao Zhang, Zihui Li, Feiteng Liang, Fengbiao Tan, Hui Du, Jialin Gao.

The role of Sidt2 in the process of glucose and lipid metabolism has been recently reported. However, whether Sidt2 is involved in the metabolic regulation in skeletal muscle remains unknown. In this study, for the first time, using skeletal muscle-selective Sidt2 knockout mice, we found that Sidt2 was vital for the quality control of mitochondria in mouse skeletal muscle. These mice showed significantly reduced muscle tolerance and structurally abnormal mitochondria. Deletion of the Sidt2 gene resulted in decreased expression of mitochondrial fusion protein 2 (Mfn2) and Dynamin-related protein 1 (Drp1), as well as peroxisome proliferator-activated receptor γ coactivator-1 (PGC1-α). In addition, the clearance of damaged mitochondria in skeletal muscle was inhibited upon Sidt2 deletion, which was caused by blockade of autophagy flow. Mechanistically, the fusion of autophagosomes and lysosomes was compromised in Sidt2 knockout skeletal muscle cells. In summary, the deletion of the Sidt2 gene not only interfered with the quality control of mitochondria, but also inhibited the clearance of mitochondria and caused the accumulation of a large number of damaged mitochondria, ultimately leading to the abnormal structure and function of skeletal muscle.

Keywords: Sidt2; autophagy; mitochondria; myopathy; quality control

DOI: https://doi.org/10.1096/fj.202000424R

Stem Cells. 2021 Mar 19.

Mitochondrial transfer from MSCs to macrophages restricts inflammation and alleviates kidney injury in diabetic nephropathy mice via PGC-1α activation.

Yujia Yuan, Longhui Yuan, Lan Li, Fei Liu, Jingping Liu, Younan Chen, Jingqiu Cheng, Yanrong Lu.

Mesenchymal stem cells (MSCs) have fueled ample translation for treatment of immune-mediated diseases. Our previous study had demonstrated that MSCs could elicit macrophages (Mϕ) into anti-inflammatory phenotypes, and alleviate kidney injury in diabetic nephropathy mice via improving mitochondrial function of Mϕ, yet the specific mechanism was unclear. Recent evidence indicated that MSCs communicated with their microenvironment through exchanges of mitochondria. By a co-culture system consisting of MSCs and Mϕ, we showed that MSCs-derived mitochondria (MSCs-Mito) were transferred into Mϕ, and the mitochondrial functions were improved, which contributed to M2 polarization. Furthermore, we found that MSCs-Mito transfer activated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis. In addition, PGC-1α interacted with TFEB in high glucose (HG)-induced Mϕ, leading to the elevated lysosome-autophagy, which was essential to removal of damaged mitochondria. As a result, in Mϕ the mitochondrial bioenergy and capacity to combat inflammatory response were enhanced. Whereas, the immune-regulatory activity of MSCs-Mito was significantly blocked in PGC-1α knockdown Mϕ. More importantly, MSCs-Mito transfer could be observed in DN mice, and the adoptive transfer of MSCs-Mito educated Mϕ (MϕMito ) inhibited the inflammatory response and alleviated kidney injury. While the kidney-protective effects of MϕMito were abolished when the MSCs-Mito was impaired with rotenone (Rot), and the similar results were also observed when MϕMito were transfected with sipgc-1α before administration. Collectively, these findings suggested that MSCs elicited Mϕ into anti-inflammatory phenotype and ameliorated kidney injury through mitochondrial transfer in DN mice, and the effects were relied on PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated lysosome-autophagy. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Our previous study had demonstrated that MSCs elicited Mϕ into M2 phenotype via improving mitochondrial function of Mϕ, yet the specific mechanism remained to be elucidated. The current study was the first to assess the potential role of mitochondrial transfer from MSCs to Mϕ and further explore the underlying mechanisms. We found that mitochondrial transfer from MSCs to Mϕ restricted inflammation and alleviated kidney injury in diabetic nephropathy mice via PGC-1α-mediated mitochondrial biogenesis and PGC-1α/TFEB-mediated autophagy. While shedding light on this new immune-regulatory mechanism, our findings offer strategies to improve cell-based therapies or eventual cell-free therapeutic approaches for inflammation-related diseases.

Keywords: PGC-1α; TFEB; macrophages; mesenchymal stem cells; mitochondrial transfer

DOI: https://doi.org/10.1002/stem.3375

Aging (Albany NY). 2021 Mar 10. 13

PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury.

Longhui Yuan, Yujia Yuan, Fei Liu, Lan Li, Jingping Liu, Younan Chen, Jingqiu Cheng, Yanrong Lu.

Because of the key role of impaired mitochondria in the progression of acute kidney injury (AKI), it is striking that peroxisome proliferator γ coactivator 1-α (PGC-1α), a transcriptional coactivator of genes involved in mitochondrial biogenesis and autophagy, protects from kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. In vivo, along with the severe kidney damage, the expression of PGC-1α was decreased in cisplatin-induced AKI mice. Conversely, PGC-1α activator (ZLN005) administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or ZLN005 treatment inhibited cell apoptosis and mitochondrial dysfunction induced by cisplatin. Moreover, ZLN005 treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria, suggesting that the mitophagy was activated. Furthermore, PGC-1α-mediated the activation of mitophagy was reliant on the increased expression of TFEB, and the protective effects were abrogated in TFEB-knockdown cells. These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy.

Keywords: PGC-1α; TFEB; acute kidney injury; autophagy; mitochondrial dysfunction

DOI: https://doi.org/10.18632/aging.202653

Redox Biol. 2021 Mar 03. pii: S2213-2317(21)00059-8. [Epub ahead of print]41 101911

Kaempferol alleviates LD-mitochondrial damage by promoting autophagy: Implications in Parkinson's disease.

Xiaojuan Han, Shengnan Zhao, Hua Song, Tianshu Xu, Qijun Fang, Gang Hu, Linyun Sun.

Emerging evidence indicates that unexpected lipid droplet (LD) deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases (NDDs). In our previous study, we confirmed that kaempferol (Ka), a natural flavonoid small molecule, exhibited neuroprotective effects on mice with LPS-induced Parkinson's disease (PD). In addition, previous studies have shown that autophagy plays an important role in the regulation of cellular LD deposition. In the current study, we showed that Ka protected against TH+ neuronal loss and behavioral deficits in MPTP/p-induced PD mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta (SNpc). In cultured neuronal cells, Ka exhibited a relatively safe concentration range and significantly suppressed LD accumulation and cellular apoptosis induced by MPP+. Further study indicated that the protective effect of Ka was dependent on autophagy, specifically lipophagy. Critically, Ka promoted autophagy to mediate LD degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death. Furthermore, AAV-shAtg5-mediated Atg5 knockdown abolished the neuroprotective effects of Ka against lipid oxidation in PD mice. This work demonstrates that Ka prevents dopaminergic neuronal degeneration in PD via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for PD and related NDDs.

Keywords: Dopaminergic neuron; Kaempferol; LDs; Lipophagy; Parkinson's disease; Peroxidation

DOI: https://doi.org/10.1016/j.redox.2021.101911