bims-mitlys 2021-08-01 papers

Neurochem Int. 2021 Jul 27. pii: S0197-0186(21)00193-5. [Epub ahead of print] 105147

I Šonský, P Vodička, K Vodičková Kepková, H Hansíková.

Huntington's disease (HD), as well as Parkinson's disease and Alzheimer's disease, belong to a group of neurodegenerative diseases characterized by common features, such as the progressive loss of neurons and the presence of pathogenic forms of misfolded protein aggregates. A quality control system such as autophagy is crucial for the clearance of protein aggregates and dysfunctional organelles and thus essential for the maintenance of neuronal homeostasis. The constant high energy demand of neuronal tissue links neurodegeneration to mitochondria. Inefficient removal of damaged mitochondria is thought to contribute to the pathogenesis of neurodegenerative diseases such as HD. In addition, direct involvement of the huntingtin protein in the autophagic machinery has been described. In this review, we focus on mitophagy, a selective form of autophagy responsible for mitochondrial turnover. We also discuss the relevance of pharmacological regulation of mitophagy in the future therapeutic approach to neurodegenerations, including HD.

Keywords: Huntington's disease; Mitochondria; Mitophagy; Mitophagy adaptors; Pharmacological induction of mitophagy

DOI: https://doi.org/10.1016/j.neuint.2021.105147

Front Cell Dev Biol. 2021 ;9 684526

ER-Phagy: A New Regulator of ER Homeostasis.

Ming Yang, Shilu Luo, Xi Wang, Chenrui Li, Jinfei Yang, Xuejing Zhu, Li Xiao, Lin Sun.

The endoplasmic reticulum (ER) is one of the most important cellular organelles and is essential for cell homeostasis. Upon external stimulation, ER stress induces the unfolded protein response (UPR) and ER-associated degradation (ERAD) to maintain ER homeostasis. However, persistent ER stress can lead to cell damage. ER-phagy is a selective form of autophagy that ensures the timely removal of damaged ER, thereby protecting cells from damage caused by excessive ER stress. As ER-phagy is a newly identified form of autophagy, many receptor-mediated ER-phagy pathways have been discovered in recent years. In this review, we summarize our understanding of the maintenance of ER homeostasis and describe the receptors identified to date. Finally, the relationships between ER-phagy and diseases are also discussed.

Keywords: ER-phagy; ERAD; autophagy; endoplasmic reticulum (ER); unfolded protein response (UPR)

DOI: https://doi.org/10.3389/fcell.2021.684526

Methods Cell Biol. 2021 ;pii: S0091-679X(20)30193-X. [Epub ahead of print]165 153-161

Monitoring selective autophagy of mitochondria using super-resolution microscopy.

Ziyue Li, Nicholas T Ktistakis.

Selective elimination of damaged mitochondria via macroautophagy (mitophagy) is a conserved cellular process that plays an important role in organismal health. In recent years mitophagy has been studied in parallel to the more general, non-selective autophagy pathway induced in response to amino acid starvation with important similarities and differences noted between the two. The elaborate sequence of membrane rearrangements that give rise to autophagosomes in the non-selective pathway have their counterpart in mitophagy, but with the addition of other factors, such as a ubiquitin mark and mitophagy receptors, which mediate cargo recognition. In some types of mitophagy such as the one induced by ivermectin, the forming autophagosomal structure contains six different elements: the targeted mitochondrial fragment, a section of endoplasmic reticulum that provides a cradle, a ubiquitin layer, the mitophagy receptors and the early and late autophagosomal proteins/membranes. Super-resolution microscopy is ideally suited to investigate the spatial relationships between these elements that converge together but retain some distinctive localization, and we provide here a general protocol that can be used for mammalian cells.

Keywords: Autophagy; Endoplasmic reticulum; Ivermectin; Mitochondria; Mitophagy; Structured illumination microscopy

DOI: https://doi.org/10.1016/bs.mcb.2020.10.010

ASN Neuro. 2021 Jan-Dec;13:13 17590914211028364

Mitochondrial and Organellar Crosstalk in Parkinson's Disease.

Bipul Ray, Abid Bhat, Arehally Marappa Mahalakshmi, Sunanda Tuladhar, Muhammed Bishir, Surapaneni Krishna Mohan, Vishnu Priya Veeraraghavan, Ramesh Chandra, Musthafa Mohamed Essa, Saravana Babu Chidambaram, Meena Kishore Sakharkar.

Mitochondrial dysfunction is a well-established pathological event in Parkinson's disease (PD). Proteins misfolding and its impaired cellular clearance due to altered autophagy/mitophagy/pexophagy contribute to PD progression. It has been shown that mitochondria have contact sites with endoplasmic reticulum (ER), peroxisomes and lysosomes that are involved in regulating various physiological processes. In pathological conditions, the crosstalk at the contact sites initiates alterations in intracellular vesicular transport, calcium homeostasis and causes activation of proteases, protein misfolding and impairment of autophagy. Apart from the well-reported molecular changes like mitochondrial dysfunction, impaired autophagy/mitophagy and oxidative stress in PD, here we have summarized the recent scientific reports to provide the mechanistic insights on the altered communications between ER, peroxisomes, and lysosomes at mitochondrial contact sites. Furthermore, the manuscript elaborates on the contributions of mitochondrial contact sites and organelles dysfunction to the pathogenesis of PD and suggests potential therapeutic targets.

Keywords: Parkinson’s disease; endoplasmic reticulum; lysosome; mitochondria; mitochondrial contact sites; peroxisome

DOI: https://doi.org/10.1177/17590914211028364

Cell Biol Toxicol. 2021 Jul 26.

Ca2+ transfer via the ER-mitochondria tethering complex in neuronal cells contribute to cadmium-induced autophagy.

Tao Wang, Qiaoping Zhu, Binbin Cao, Yao Cai, Shuangquan Wen, Jianchun Bian, Hui Zou, Ruilong Song, Jianhong Gu, Xuezhong Liu, Zongping Liu, Yan Yuan.

Mitochondrial-associated endoplasmic reticulum (ER) membranes (MAMs) play a key role in several physiological functions, including calcium ion (Ca2+) transfer and autophagy; however, the molecular mechanism controlling this interaction in cadmium (Cd)-induced neurotoxicity is unknown. This study shows that Cd induces alterations in MAMs and mitochondrial Ca2+ levels in PC12 cells and primary neurons. Ablation or silencing of mitofusin 2 (Mfn2) in PC12 cells or primary neurons blocks the colocalization of ER and mitochondria while reducing the efficiency of mitochondrial Ca2+ uptake. Moreover, Mfn2 defects reduce interactions or colocalization between GRP75 and VDAC1. Interestingly, the enhancement of autophagic protein levels, colocalization of LC3 and Lamp2, and GFP-LC3 puncta induced by Cd decreased in Mfn2-/- or Grp75-/- PC12 cells and Mfn2- or Grp75-silenced primary neurons. Notably, the specific Ca2+ uniporter inhibitor RuR blocked both mitochondrial Ca2+ uptake and autophagy induced by Cd. Finally, this study proves that the mechanism by which IP3R-Grp75-VDAC1 tethers in MAMs is associated with the regulation of autophagy by Mfn2 and involves their role in mediating mitochondrial Ca2+ uptake from ER stores. These results give new evidence into the organelle metabolic process by demonstrating that Ca2+ transport between ER-mitochondria is important in autophagosome formation in Cd-induced neurodegeneration.

Keywords: Autophagy; Calcium; Cd; MAMs; PC12 cells; Primary neurons

DOI: https://doi.org/10.1007/s10565-021-09623-y

Oxid Med Cell Longev. 2021 ;2021 5595652

Pink1/PARK2/mROS-Dependent Mitophagy Initiates the Sensitization of Cancer Cells to Radiation.

Lei Yu, Xiangshan Yang, Xin Li, Lijing Qin, Weiqiang Xu, Hongli Cui, Zhen Jia, Qiang He, Zhicheng Wang.

Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na+K+ ATPase, Ca2+Mg2+ ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.

DOI: https://doi.org/10.1155/2021/5595652