bims-mecosi 2022-03-13 papers

Issue of 2022–03–13
eight papers selected by
Verena Kohler, Stockholm University

Trends Neurosci. 2022 Mar 03. pii: S0166-2236(22)00017-0. [Epub ahead of print]

Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases.

Jasmine Cisneros, Tayler B Belton, George C Shum, Catherine G Molakal, Yvette C Wong.

Neurons rely heavily on properly regulated mitochondrial and lysosomal homeostasis, with multiple neurodegenerative diseases linked to dysfunction in these two organelles. Interestingly, mitochondria-lysosome membrane contact sites have been identified as a key pathway mediating their crosstalk in neurons. Recent studies have further elucidated the regulation of mitochondria-lysosome contact dynamics via distinct tethering/untethering protein machinery. Moreover, this pathway has been shown to have additional functions in regulating organelle network dynamics and metabolite transfer between lysosomes and mitochondria. In this review, we highlight recent advances in the field of mitochondria-lysosome contact sites and their misregulation across multiple neurodegenerative disorders, which further underscore a potential role for this pathway in neuronal homeostasis and disease.

Keywords: Charcot-Marie-Tooth disease; Parkinson’s disease; inter-organelle contact sites; lysosomal storage disorders; lysosomes; mitochondria

DOI: https://doi.org/10.1016/j.tins.2022.01.005

J Cell Sci. 2022 Mar 01. pii: jcs259357. [Epub ahead of print]135(5):

A possible role for VPS13-family proteins in bulk lipid transfer, membrane expansion and organelle biogenesis.

Thomas J Melia, Karin M Reinisch.

At organelle-organelle contact sites, proteins have long been known to facilitate the rapid movement of lipids. Classically, this lipid transport involves the extraction of single lipids into a hydrophobic pocket on a lipid transport protein. Recently, a new class of lipid transporter has been described with physical characteristics that suggest these proteins are likely to function differently. They possess long hydrophobic tracts that can bind many lipids at once and physically span the entire gulf between membranes at contact sites, suggesting that they may act as bridges to facilitate bulk lipid flow. Here, we review what has been learned regarding the structure and function of this class of lipid transporters, whose best characterized members are VPS13 and ATG2 proteins, and their apparent coordination with other lipid-mobilizing proteins on organelle membranes. We also discuss the prevailing hypothesis in the field, that this type of lipid transport may facilitate membrane expansion through the bulk delivery of lipids, as well as other emerging hypotheses and questions surrounding these novel lipid transport proteins.

Keywords: Membrane contact sites; Membrane homeostasis; Protein-mediated lipid transport

DOI: https://doi.org/10.1242/jcs.259357

Front Cell Dev Biol. 2022 ;10 842285

Yeast Vps13 is Crucial for Peroxisome Expansion in Cells With Reduced Peroxisome-ER Contact Sites.

Wei Yuan, Arman Akşit, Rinse de Boer, Arjen M Krikken, Ida J van der Klei.

In the yeast Hansenula polymorpha the peroxisomal membrane protein Pex11 and three endoplasmic reticulum localized proteins of the Pex23 family (Pex23, Pex24 and Pex32) are involved in the formation of peroxisome-ER contact sites. Previous studies suggested that these contacts are involved in non-vesicular lipid transfer and important for expansion of the peroxisomal membrane. The absence of Pex32 results in a severe peroxisomal phenotype, while cells lacking Pex11, Pex23 or Pex24 show milder defects and still are capable to form peroxisomes and grow on methanol. We performed transposon mutagenesis on H. polymorpha pex11 cells and selected mutants that lost the capacity to grow on methanol and are severely blocked in peroxisome formation. This strategy resulted in the identification of Vps13, a highly conserved contact site protein involved in bulk lipid transfer. Our data show that peroxisome formation and function is normal in cells of a vps13 single deletion strain. However, Vps13 is essential for peroxisome biogenesis in pex11. Notably, Vps13 is also required for peroxisome formation in pex23 and pex24 cells. These data suggest that Vps13 is crucial for peroxisome formation in cells with reduced peroxisome-endoplasmic reticulum contact sites and plays a redundant function in lipid transfer from the ER to peroxisomes.

Keywords: VPS13; contact site; endoplasmic reticulum; peroxisome; yeast

DOI: https://doi.org/10.3389/fcell.2022.842285

Cells. 2022 Mar 01. pii: 842. [Epub ahead of print]11(5):

Pyk2 Regulates MAMs and Mitochondrial Dynamics in Hippocampal Neurons.

Laura López-Molina, Joaquín Fernández-Irigoyen, Carmen Cifuentes-Díaz, Jordi Alberch, Jean-Antoine Girault, Enrique Santamaría, Silvia Ginés, Albert Giralt.

Pyk2 is a non-receptor tyrosine kinase enriched in hippocampal neurons, which can be activated by calcium-dependent mechanisms. In neurons, Pyk2 is mostly localised in the cytosol and dendritic shafts but can translocate to spines and/or to the nucleus. Here, we explore the function of a new localisation of Pyk2 in mitochondria-associated membranes (MAMs), a subdomain of ER-mitochondria surface that acts as a signalling hub in calcium regulation. To test the role of Pyk2 in MAMs' calcium transport, we used full Pyk2 knockout mice (Pyk2-/-) for in vivo and in vitro studies. Here we report that Pyk2-/- hippocampal neurons present increased ER-mitochondrial contacts along with defective calcium homeostasis. We also show how the absence of Pyk2 modulates mitochondrial dynamics and morphology. Taken all together, our results point out that Pyk2 could be highly relevant in the modulation of ER-mitochondria calcium efflux, affecting in turn mitochondrial function.

Keywords: ER-mitochondria contact sites; calcium; hippocampus; neuron

DOI: https://doi.org/10.3390/cells11050842

Curr Opin Physiol. 2021 Dec;pii: 100487. [Epub ahead of print]24

Energy transfer between the mitochondrial network and lipid droplets in insulin resistant skeletal muscle.

Hailey A Parry, Brian Glancy.

Mitochondria and lipid droplets in the insulin resistant skeletal muscle of type 2 diabetic individuals have both been heavily investigated independently and are characterized by more fragmented, dysfunctional mitochondrial networks and larger lipid droplets compared to skeletal muscle of healthy individuals. Specialized contacts between mitochondrial and lipid droplet membranes are known to decrease in diabetic muscle, though it remains unclear how energy transfer at the remaining mitochondria-lipid droplet contact sites may be altered by type 2 diabetes. The purpose of this review is to highlight recent data on mitochondrial structure and function and lipid droplet dynamics in type 2 diabetic skeletal muscle and to underscore the need for more detailed investigations into the functional nature of mitochondria-lipid droplet interactions in type 2 diabetes.

Keywords: Mitochondria; diabetes; insulin resistance; lipid droplets; mitochondrial network

DOI: https://doi.org/10.1016/j.cophys.2022.100487

Theranostics. 2022 ;12(5): 2445-2464

The relevance of organelle interactions in cellular senescence.

Jiewu Huang, Ping Meng, Cheng Wang, Yunfang Zhang, Lili Zhou.

Organelles are tiny structures with specific functions in eukaryotic cells. Since they are covered with membranes, different organelles can perform biological processes that are incompatible. Organelles can also actively communicate with each other to maintain cellular homeostasis via the vesicular trafficking pathways and membrane contact sites (MCSs), which allow the exchange of metabolites and other information required for normal cellular physiology. An imbalance in organelle interactions may result in multiple pathological processes. Growing evidence shows that abnormal organelle communication contributes to cellular senescence and is associated with organ aging. However, the key role of organelle interactions in aging has not yet been broadly reviewed and fully investigated. In this review, we summarize the role of organelle interactions in cellular senescence, and highlight their relevance for cellular calcium homeostasis, protein and lipid homeostasis, and mitochondrial quality control. Our review reveals important mechanisms of organelle interactions in cellular senescence and provides important clues for intervention strategies from a new perspective.

Keywords: MCSs; cellular senescence; communication; interaction; organelle

DOI: https://doi.org/10.7150/thno.70588

J Biomed Sci. 2022 Mar 07. 29(1): 17

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts.

Young Hyun Jung, Chang Woo Chae, Gee Euhn Choi, Him Cha Shin, Jae Ryong Lim, Han Seung Chang, Joonmo Park, Ji Hyeon Cho, Mo Ran Park, Hyun Jik Lee, Ho Jae Han.

BACKGROUND: Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved.
METHODS: DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration.
RESULTS: Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1-IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation.
CONCLUSIONS: C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.

Keywords: Androgen receptor; Cyanidin 3-O-arabinoside; DHT; Mitochondrial calcium; Senescence

DOI: https://doi.org/10.1186/s12929-022-00800-7

Front Cell Dev Biol. 2022 ;10 796061

Evaluation of Parkin in the Regulation of Myocardial Mitochondria-Associated Membranes and Cardiomyopathy During Endotoxemia.

Matthew Kim, Azadeh Nikouee, Yuxiao Sun, Qing-Jun Zhang, Zhi-Ping Liu, Qun Sophia Zang.

Background: Mitochondrial deficiency is a known pathology in sepsis-induced organ failure. We previously found that mitochondria-associated membranes (MAMs), a subcellular domain supporting mitochondrial status, are impaired in the heart during endotoxemia, suggesting a mechanism of mitochondrial damage occurred in sepsis. Mitophagy pathway via E3 ubiquitin ligase Parkin and PTEN-induced kinase 1 (PINK1) controls mitochondrial quality. Studies described here examined the impact of Parkin on cardiac MAMs and endotoxemia-induced cardiomyopathy. Additionally, point mutation W403A in Parkin was previously identified as a constitutively active mutation in vitro. In vivo effects of forced expression of this mutation were evaluated in the endotoxemia model. Methods: Mice of wild type (WT), Parkin-deficiency (Park2 -/- ), and knock-in expression of Parkin W402A (human Parkin W403A) were given lipopolysaccharide (LPS) challenge. Cardiac function was evaluated by echocardiography. In the harvested heart tissue, MAM fractions were isolated by ultracentrifugation, and their amount and function were quantified. Ultrastructure of MAMs and mitochondria was examined by electron microscopy. Mitochondrial respiratory activities were measured by enzyme assays. Myocardial inflammation was estimated by levels of pro-inflammatory cytokine IL-6. Myocardial mitophagy was assessed by levels of mitophagy factors associated with mitochondria and degrees of mitochondria-lysosome co-localization. Parkin activation, signified by phosphorylation on serine 65 of Parkin, was also evaluated. Results: Compared with WT, Park2 -/- mice showed more severely impaired cardiac MAMs during endotoxemia, characterized by disrupted structure, reduced quantity, and weakened transporting function. Endotoxemia-induced cardiomyopathy was intensified in Park2 -/- mice, shown by worsened cardiac contractility and higher production of IL-6. Mitochondria from the Park2 -/- hearts were more deteriorated, indicated by losses in both structural integrity and respiration function. Unexpectedly, mice carrying Parkin W402A showed similar levels of cardiomyopathy and mitochondrial damage when compared with their WT counterparts. Further, Parkin W402A mutation neither enhanced mitophagy nor increased Parkin activation in myocardium under the challenge of endotoxemia. Conclusion: our results suggest that Parkin/PINK1 mitophagy participates in the regulation of cardiac MAMs during endotoxemia. Point mutation W402A (human W403A) in Parkin is not sufficient to alleviate cardiomyopathy induced by endotoxemia in vivo.

Keywords: cardiac dysfunction; endotoxemia; inflammation; mitochondria; mitophagy; parkin; sepsis

DOI: https://doi.org/10.3389/fcell.2022.796061