bims-mitlys 2021-11-14 papers

bims-mitlys

Biomed News

on Mitochondria and Lysosomes

Issue of 2021‒11‒14
nine papers selected by
Nicoletta Plotegher
University of Padova

Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.
The PINK1-Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells.
Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts.
The role of mitochondria in cellular senescence.
Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases.
Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK1.
Sanguinarine impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis in human hepatocellular carcinoma cells.
Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.
Role of mitochondrial dynamics and mitophagy of vascular smooth muscle cell proliferation and migration in progression of atherosclerosis.

Pharmacol Res. 2021 Nov 08. pii: S1043-6618(21)00557-0. [Epub ahead of print] 105973

Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.

Sudhir Kshirsagar, Neha Sawant, Hallie Morton, Arubala P Reddy, P Hemachandra Reddy.

  The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.

Keywords:  Mitochondria: Synaptic activity; Mitochondrial fragmentation; Mitophagy enhancers; Urolithin A

DOI:  https://doi.org/10.1016/j.phrs.2021.105973
PLoS One. 2021 ;16(11): e0259903

The PINK1-Parkin mitophagy signalling pathway is not functional in peripheral blood mononuclear cells.

Aaron V Bradshaw, Philip Campbell, Anthony H V Schapira, Huw R Morris, Jan-Willem Taanman.

Mutations in the PINK1 and PRKN genes are the most common cause of early-onset familial Parkinson disease. These genes code for the PINK1 and Parkin proteins, respectively, which are involved in the degradation of dysfunctional mitochondria through mitophagy. An early step in PINK1 -Parkin mediated mitophagy is the ubiquitination of the mitofusin proteins MFN1 and -2. The ubiquitination of MFN1 and -2 in patient samples may therefore serve as a biomarker to determine the functional effects of PINK1 and PRKN mutations, and to screen idiopathic patients for potential mitophagy defects. We aimed to characterise the expression of the PINK1 -Parkin mitophagy machinery in peripheral blood mononuclear cells (PBMCs) and assess if these cells could serve as a platform to evaluate mitophagy via analysis of MFN1 and -2 ubiquitination. Mitophagy was induced through mitochondrial depolarisation by treatment with the protonophore CCCP and ubiquitinated MFN proteins were analysed by western blotting. In addition, PINK1 and PRKN mRNA and protein expression levels were characterised with reverse transcriptase quantitative PCR and western blotting, respectively. Whilst CCCP treatment led to MFN ubiquitination in primary fibroblasts, SH-SY5Y neuroblastoma cells and Jurkat leukaemic cells, treatment of PBMCs did not induce ubiquitination of MFN. PRKN mRNA and protein was readily detectable in PBMCs at comparable levels to those observed in Jurkat and fibroblast cells. In contrast, PINK1 protein was undetectable and PINK1 mRNA levels were remarkably low in control PBMCs. Our findings suggest that the PINK1 -Parkin mitophagy signalling pathway is not functional in PBMCs. Therefore, PBMCs are not a suitable biosample for analysis of mitophagy function in Parkinson disease patients.

DOI: https://doi.org/10.1371/journal.pone.0259903
Int J Mol Sci. 2021 Oct 28. pii: 11650. [Epub ahead of print]22(21):

Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts.

Hye Eun Lee, Min Kyo Jung, Seul Gi Noh, Hye Bin Choi, Se Hyun Chae, Jae Hyeok Lee, Ji Young Mun.

  Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.

Keywords:  CLEM; WDR45; autophagy; iron overload; lipid metabolism; lysosome; mitochondria

DOI:  https://doi.org/10.3390/ijms222111650
FASEB J. 2021 Dec;35(12): e21991

The role of mitochondria in cellular senescence.

Shohini K Ghosh-Choudhary, Jie Liu, Toren Finkel.

  Mitochondria are intimately connected to cell fate and function. Here, we review how these intracellular organelles participate in the induction and maintenance of the senescent state. In particular, we discuss how alterations in mitochondrial metabolism, quality control and dynamics are all involved in various aspects of cellular senescence. Together, these observations suggest that mitochondria are active participants and are mechanistically linked to the unique biology of senescence. We further describe how these insights can be potentially exploited for therapeutic benefit.

Keywords:  aging; metabolism; mitophagy; reactive oxygen species; senolytic

DOI:  https://doi.org/10.1096/fj.202101462R
Int J Mol Sci. 2021 Oct 23. pii: 11444. [Epub ahead of print]22(21):

Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases.

Lauren Elizabeth Millichap, Elisabetta Damiani, Luca Tiano, Iain P Hargreaves.

  Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders.

Keywords:  Parkinson’s disease; antioxidant defenses; lysosomal storage disorders; methylmalonic acidaemia; mitochondrial biogenesis; mitochondrial dysfunction; mitophagy; neurodegeneration; oxidative stress; therapeutics

DOI:  https://doi.org/10.3390/ijms222111444
Sci Adv. 2021 Nov 12. 7(46): eabj0722

Global ubiquitylation analysis of mitochondria in primary neurons identifies endogenous Parkin targets following activation of PINK1.

Odetta Antico, Alban Ordureau, Michael Stevens, Francois Singh, Raja S Nirujogi, Marek Gierlinski, Erica Barini, Mollie L Rickwood, Alan Prescott, Rachel Toth, Ian G Ganley, J Wade Harper, Miratul M K Muqit.

[Figure: see text].

DOI: https://doi.org/10.1126/sciadv.abj0722
Arch Pharm Res. 2021 Nov 09.

Sanguinarine impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis in human hepatocellular carcinoma cells.

Jingjing Wang, Qi Su, Qing Wu, Kun Chen, Asmat Ullah, Mohsin Ahmad Ghauri, Yanmin Zhang.

  Hepatocellular carcinoma (HCC) is one of the most common tumor types globally. Despite the progress made in surgical procedures and therapeutic options, HCC remains a considerable cause of cancer-related mortality. In this study, we investigated the antitumor effects of sanguinarine (Sang) on HCC and its potential mechanisms. Our findings showed that Sang impairs the acidic environment of lysosomes by inhibiting cathepsin D maturation. In addition, Sang inhibited the formation of autolysosomes in RFP-GFP-LC3 transfected cells, subsequently suppressing late mitophagy. Sang also induced reactive oxygen species (ROS)-dependent autophagy and apoptosis in HCC cells, which was significantly attenuated following treatment with a ROS scavenger. Further investigation using autophagy inhibitors revealed that sanguinarine-induced mitochondrial dysfunction and mitophagy led to mitochondrial apoptosis in HCC cells. Immunohistochemical staining of sanguinarine-treated xenograft samples revealed that it initiated and blocked autophagy. In summary, our findings suggest that in HCC cells, Sang impairs lysosomal function and induces ROS-dependent mitophagy and apoptosis.

Keywords:  Apoptosis; Hepatocellular carcinoma; Lysosomal function; Mitophagy; Reactive oxygen species; Sanguinarine

DOI:  https://doi.org/10.1007/s12272-021-01356-0
Neurobiol Dis. 2021 Nov 09. pii: S0969-9961(21)00309-0. [Epub ahead of print] 105560

Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.

Liting Hang, Ziyin Wang, Aaron S C Foo, Geraldine W Y Goh, Huey Ching Choong, John Thundyil, Shengli Xu, Lam Kong Peng, Kah-Leong Lim.

  Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.

Keywords:  AMPK; Mitochondria; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2021.105560
Arch Pharm Res. 2021 Nov 07.

Role of mitochondrial dynamics and mitophagy of vascular smooth muscle cell proliferation and migration in progression of atherosclerosis.

Diem Thi Ngoc Huynh, Kyung-Sun Heo.

  Vascular smooth muscle cell (VSMC) proliferation and migration are critical events that contribute to the pathogenesis of vascular diseases such as atherosclerosis, restenosis, and hypertension. Recent findings have revealed that VSMC phenotype switching is associated with metabolic switch, which is related to the role of mitochondria. Mitochondrial dynamics are directly associated with mitochondrial function and cellular homeostasis. Interestingly, it has been suggested that mitochondrial dynamics and mitophagy play crucial roles in the regulation of VSMC proliferation and migration through various mechanisms. Especially, dynamin-related protein-1 and mitofusion-2 are two main molecules that play a key role in regulating mitochondrial dynamics to induce VSMC proliferation and migration. Therefore, this review describes the function and role of mitochondrial dynamics and mitophagy in VSMC homeostasis as well as the underlying mechanisms. This will provide insight into the development of innovative approaches to treat atherosclerosis.

Keywords:  Atherosclerosis; Migration; Mitochondrial dynamics; Mitophagy; Proliferation; Vascular smooth muscle cells

DOI:  https://doi.org/10.1007/s12272-021-01360-4