bims-mikwok 2020-12-27 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2020–12–27
ten papers selected by
Avinash N. Mukkala, University of Toronto

Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy.
Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury.
Metastatic TNBC is highly associated with a fused mitochondrial morphology and a glycolytic and lipogenic metabolism programmation.
Miro1-mediated mitochondrial positioning supports subcellular redox status.
Organelle-specific mechanisms of drug-induced autophagy-dependent cell death.
Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy.
Altered mitochondrial calcium handling and cell death by necroptosis: An emerging paradigm.
The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission.
Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults.
Systematic review and meta-analysis of human Transcriptomics reveals Neuroinflammation, deficient energy metabolism, and Proteostasis failure across Neurodegeneration.

Front Physiol. 2020 ;11 608474

Regulatory Roles of PINK1-Parkin and AMPK in Ubiquitin-Dependent Skeletal Muscle Mitophagy.

Alex P Seabright, Yu-Chiang Lai.

  The selective removal of damaged mitochondria, also known as mitophagy, is an important mechanism that regulates mitochondrial quality control. Evidence suggests that mitophagy is adversely affected in aged skeletal muscle, and this is thought to contribute toward the age-related decline of muscle health. While our knowledge of the molecular mechanisms that regulate mitophagy are derived mostly from work in non-muscle cells, whether these mechanisms are conferred in muscle under physiological conditions has not been thoroughly investigated. Recent findings from our laboratory and those of others have made several novel contributions to this field. Herein, we consolidate current literature, including our recent work, while evaluating how ubiquitin-dependent mitophagy is regulated both in muscle and non-muscle cells through the steps of mitochondrial fission, ubiquitylation, and autophagosomal engulfment. During ubiquitin-dependent mitophagy in non-muscle cells, mitochondrial depolarization activates PINK1-Parkin signaling to elicit mitochondrial ubiquitylation. TANK-binding kinase 1 (TBK1) then activates autophagy receptors, which in turn, tether ubiquitylated mitochondria to autophagosomes prior to lysosomal degradation. In skeletal muscle, evidence supporting the involvement of PINK1-Parkin signaling in mitophagy is lacking. Instead, 5'-AMP-activated protein kinase (AMPK) is emerging as a critical regulator. Mechanistically, AMPK activation promotes mitochondrial fission before enhancing autophagosomal engulfment of damaged mitochondria possibly via TBK1. While TBK1 may be a point of convergence between PINK1-Parkin and AMPK signaling in muscle, the critical question that remains is: whether mitochondrial ubiquitylation is required for mitophagy. In future, improving understanding of molecular processes that regulate mitophagy in muscle will help to develop novel strategies to promote healthy aging.

Keywords:  AMPK; PINK1; Parkin; TBK1; ULK1; mitochondrial fission; mitophagy; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2020.608474
J Thorac Cardiovasc Surg. 2020 Dec 01. pii: S0022-5223(20)33142-1. [Epub ahead of print]

Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury.

Alvise Guariento, Breanna L Piekarski, Ilias P Doulamis, David Blitzer, Alessandra M Ferraro, David M Harrild, David Zurakowski, Pedro J Del Nido, James D McCully, Sitaram M Emani.

   OBJECTIVES: To report outcomes in a pilot study of autologous mitochondrial transplantation (MT) in pediatric patients requiring postcardiotomy extracorporeal membrane oxygenation (ECMO) for severe refractory cardiogenic shock after ischemia-reperfusion injury (IRI).
METHODS: A single-center retrospective study of patients requiring ECMO for postcardiotomy cardiogenic shock following IRI between May 2002 and December 2018 was performed. Postcardiotomy IRI was defined as coronary artery compromise followed by successful revascularization. Patients undergoing revascularization and subsequent MT were compared with those undergoing revascularization alone (Control).
RESULTS: Twenty-four patients were included (MT, n = 10; Control, n = 14). Markers of systemic inflammatory response and organ function measured 1 day before and 7 days following revascularization did not differ between groups. Successful separation from ECMO-defined as freedom from ECMO reinstitution within 1 week after initial separation-was possible for 8 patients in the MT group (80%) and 4 in the Control group (29%) (P = .02). Median circumferential strain immediately following IRI but before therapy was not significantly different between groups. Immediately following separation from ECMO, ventricular strain was significantly better in the MT group (-23.0%; range, -20.0% to -28.8%) compared with the Control group (-16.8%; range, -13.0% to -18.4%) (P = .03). Median time to functional recovery after revascularization was significantly shorter in the MT group (2 days vs 9 days; P = .02). Cardiovascular events were lower in the MT group (20% vs 79%; P < .01). Cox regression analysis showed higher composite estimated risk of cardiovascular events in the Control group (hazard ratio, 4.6; 95% confidence interval, 1.0 to 20.9; P = .04) CONCLUSIONS: In this pilot study, MT was associated with successful separation from ECMO and enhanced ventricular strain in patients requiring postcardiotomy ECMO for severe refractory cardiogenic shock after IRI.

Keywords:  ECMO; ischemia reperfusion injury; mitochondrial transplantation; pediatric cardiac surgery

DOI:  https://doi.org/10.1016/j.jtcvs.2020.10.151
Biochem Cell Biol. 2020 Dec 20.

Metastatic TNBC is highly associated with a fused mitochondrial morphology and a glycolytic and lipogenic metabolism programmation.

Perla Pérez-Treviño, Claudia D Aguayo-Millán, Sandra Karina Santuario-Facio, Jorge E Vela-Guajardo, Esteban Salazar, Alberto Camacho-Morales, Rocío Ortiz, Noemí García.

Mitochondria modify their function and morphology to satisfice the bioenergetic demand of the cells. Cancer cells take advantage of these features to sustain their metabolic, proliferative, metastatic, and survival necessities. Therefore, the understanding of mitochondrial morphologic changes of the different grades of Triple-Negative Breast Cancer (TNBC) could be relevant for the design of novel treatments. Consequently, this research aimed to explore the mitochondria morphology and gene expression of some proteins related to mitochondrial dynamics as well as proteins related to oxidative and non-oxidative metabolism of metastatic and non-metastatic TNBC. We found that mitochondrial-morphology and metabolism are different between metastatic and non-metastatic TNBC. Metastatic TNBC showed overexpression of genes related to mitochondrial dynamics, fatty acids, and glycolytic metabolism. These features were accompanied by a fused mitochondrial morphology. In contrast, the non-metastatic TNBC presented a stress-associated mitochondrial morphology, hyperfragmented mitochondria accompanied by upregulated expression of mitochondrial biogenesis-related genes, both characteristics related to the higher ROS production observed in this cell line. These differences found between metastatic and non-metastatic TNBC will allow a better understanding of the metastasis process and the improvement of the development of a specific and personalized TNBC therapy.

DOI: https://doi.org/10.1139/bcb-2020-0439
Redox Biol. 2020 Nov 29. pii: S2213-2317(20)31023-5. [Epub ahead of print]38 101818

Miro1-mediated mitochondrial positioning supports subcellular redox status.

Haya Alshaabi, Nathaniel Shannon, Randi Gravelle, Stephanie Milczarek, Terri Messier, Brian Cunniff.

  Mitochondria are strategically trafficked throughout the cell by the action of microtubule motors, the actin cytoskeleton and adapter proteins. The intracellular positioning of mitochondria supports subcellular levels of ATP, Ca2+ and reactive oxygen species (ROS, i.e. hydrogen peroxide, H2O2). Previous work from our group showed that deletion of the mitochondrial adapter protein Miro1 leads to perinuclear clustering of mitochondria, leaving the cell periphery devoid of mitochondria which compromises peripheral energy status. Herein, we report that deletion of Miro1 significantly restricts subcellular H2O2 levels to the perinuclear space which directly affects intracellular responses to elevated mitochondrial ROS. Using the genetically encoded H2O2-responsive fluorescent biosensor HyPer7, we show that the highest levels of subcellular H2O2 map to sites of increased mitochondrial density. Deletion of Miro1 or disruption of microtubule dynamics with Taxol significantly reduces peripheral H2O2 levels. Following inhibition of mitochondrial complex 1 with rotenone we observe elevated spikes of H2O2 in the cell periphery and complementary oxidation of mitochondrial peroxiredoxin 3 (PRX3) and cytosolic peroxiredoxin 2 (PRX2). Conversely, in cells lacking Miro1, rotenone did not increase peripheral H2O2 or PRX2 oxidation but rather lead to increased nuclear H2O2 and an elevated DNA-damage response. Lastly, local levels of HyPer7 oxidation correlate with the size and abundance of focal adhesions (FAs) in MEFs and cells lacking Miro1 have significantly smaller focal adhesions and reduced phosphorylation levels of vinculin and p130Cas compared to Miro1+/+ MEFs. Together, we present evidence that the intracellular distribution of mitochondria influences subcellular H2O2 levels and local cellular responses dependent on mitochondrial ROS.

Keywords:  Cell migration; Hydrogen peroxide; Miro1; Mitochondrial trafficking; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2020.101818
Matrix Biol. 2020 Dec 13. pii: S0945-053X(20)30118-9. [Epub ahead of print]

Organelle-specific mechanisms of drug-induced autophagy-dependent cell death.

Laura Zein, Simone Fulda, Donat Kögel, Sjoerd J L van Wijk.

  The conserved catabolic process of autophagy is an important control mechanism that degrades cellular organelles, debris and pathogens in autolysosomes. Although autophagy primarily protects against cellular insults, nutrient starvation or oxidative stress, hyper-activation of autophagy is also believed to cause autophagy-dependent cell death (ADCD). ADCD is a caspase-independent form of programmed cell death (PCD), characterized by an over-activation of autophagy, leading to prominent self-digestion of cellular material in autolysosomes beyond the point of cell survival. ADCD plays important roles in the development of lower organisms, but also in the response of cancer cells upon exposure of specific drugs or natural compounds. Importantly, the induction of ADCD as an alternative cell death pathway is of special interest in apoptosis-resistant cancer types and serves as an attractive and potential therapeutic option. Although the mechanisms of ADCD are diverse and not yet fully understood, both non-selective (bulk) autophagy and organelle-specific types of autophagy are believed to be involved in this type of cell death. Accordingly, several ADCD-inducing drugs are known to trigger severe mitochondrial damage and endoplasmic reticulum (ER) stress, whereas the contribution of other cell organelles, like ribosomes or peroxisomes, to the control of ADCD is not well understood. In this review, we highlight the general mechanisms of ADCD and discuss the current evidence for mitochondria- and ER-specific killing mechanisms of ADCD-inducing drugs.

Keywords:  Autophagy-dependent cell death; ER, ER stress; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.matbio.2020.12.003
Autophagy. 2020 Dec 19. 1-16

Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy.

Qisheng Lin, Shu Li, Na Jiang, Haijiao Jin, Xinghua Shao, Xuying Zhu, Jingkui Wu, Minfang Zhang, Zhen Zhang, Jianxiao Shen, Wenyan Zhou, Leyi Gu, Renhua Lu, Zhaohui Ni.

  The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment. Abbreviations: BNIP3: BCL2/adenovirus E1B interacting protein 3; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EGLN2/PHD1: egl-9 family hypoxia-inducible factor 2; HIF1A: hypoxia inducible factor 1, alpha subunit; H-E: hematoxylin and eosin; IL18: interleukin 18; IL1B: interleukin 1 beta; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mRNA: messenger RNA; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family, pyrin domain containing 3; NS: normal saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RNA: ribonucleic acid; SEM: standard error of the mean; siRNA: small interfering RNA; TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin, alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VDAC: voltage-dependent anion channel; WT: wild-type.

Keywords:  Acute kidney injury; NLRP3 inflammasome; contrast media; hypoxia inducible factor; mitophagy

DOI:  https://doi.org/10.1080/15548627.2020.1848971
Mitochondrion. 2020 Dec 16. pii: S1567-7249(20)30227-0. [Epub ahead of print]

Altered mitochondrial calcium handling and cell death by necroptosis: An emerging paradigm.

Imam Faizan, Tanveer Ahmad.

  The classical necroptosis signaling is mediated by death receptors (DRs) that work in synergy with traditional caspase inhibitory signals. Currently, potential therapeutic molecules are in various phases of clinical trials for a spectrum of pathological conditions associated with necroptosis. However, a non-classical model of necroptosis has also emerged over the last decade with a relatively unexplored molecular mechanism. Although in vitro studies and preclinical models have shown its close association with mitochondrial dysfunction (mito-dysfunction), contradictory reports have emerged which complicate its definitiveness. Though impaired mitochondrial calcium [Ca2+]m handling is established in necrotic cell death, how this interplay regulates necroptosis is yet to be elucidated. Taking these questions into consideration, we have discussed various molecular aspects of necroptosis with the emerging role of mito-dysfunction. Based on the central role of altered [Ca2+]m handling in mito-dysfunction mediated necroptosis, we have provided a comprehensive molecular insight into this emerging paradigm. Potential reasons for the contradictory findings regarding the role of mito-dysfunction in necroptosis in general and mitochondrial-dependent necroptosis in specific are discussed. We also provide insights into the current understanding of how [Ca2+]m can be a critical determinant in deciding the cell fate under certain pathological conditions, while under others it may be dispensable. Lastly, we have highlighted the key molecular targets which have a direct implication for therapeutic intervention in conditions that are associated with impaired [Ca2+]m handling and cell death by necroptosis.

Keywords:  MCU; MICU1/2; Mitochondrial calcium; apoptosis; death receptors; necroptosis

DOI:  https://doi.org/10.1016/j.mito.2020.12.004
Oxid Med Cell Longev. 2020 ;2020 4132785

The Calcilytic Drug Calhex-231 Ameliorates Vascular Hyporesponsiveness in Traumatic Hemorrhagic Shock by Inhibiting Oxidative Stress and miR-208a-Mediated Mitochondrial Fission.

Yan Lei, Xiaoyong Peng, Yi Hu, Mingying Xue, Tao Li, Liangming Liu, Guangming Yang.

Background: The calcium-sensing receptor (CaSR) plays a fundamental role in extracellular calcium homeostasis in humans. Surprisingly, CaSR is also expressed in nonhomeostatic tissues and is involved in regulating diverse cellular functions. The objective of this study was to determine if Calhex-231 (Cal), a negative modulator of CaSR, may be beneficial in the treatment of traumatic hemorrhagic shock (THS) by improving cardiovascular function and investigated the mechanisms.
Methods: Rats that had been subjected to THS and hypoxia-treated vascular smooth muscle cells (VSMCs) were used in this study. The effects of Cal on cardiovascular function, animal survival, hemodynamics, and vital organ function in THS rats and the relationship to oxidative stress, mitochondrial fusion-fission, and microRNA (miR-208a) were investigated.
Results: Cal significantly improved hemodynamics, elevated blood pressure, increased vital organ blood perfusion and local oxygen supply, and markedly improved the survival outcomes of THS rats. Furthermore, Cal significantly improved vascular reactivity after THS in vivo and in vitro. Cal also restored the THS-induced decrease in myosin light chain (MLC) phosphorylation (the key element for VSMC contraction). Inhibition of MLC phosphorylation antagonized the Cal-induced restoration of vascular reactivity following THS. Cal suppressed oxidative stress in THS rats and hypoxic-VSMCs. Meanwhile, THS induced expression of mitochondrial fission proteins Drp1 and Fis1 and decreased expression of mitochondrial fusion protein Mfn1 in vascular tissues. Cal reduced expression of Drp1 and Fis1. In hypoxic-VSMCs, Cal inhibited mitochondrial fragmentation and preserved mitochondrial morphology. In addition, miR-208a mimic decreased Fis1 expression, and miR-208a inhibitor prevented Cal-induced Fis1 downregulation in hypoxic-VSMCs.
Conclusion: Calhex-231 exhibits outstanding potential for effective therapy of traumatic hemorrhagic shock, and the beneficial effects result from its protection of vascular function via inhibition of oxidative stress and miR-208a-mediated mitochondrial fission.

DOI: https://doi.org/10.1155/2020/4132785
Neurobiol Stress. 2020 Nov;13 100251

Proteomic and mitochondrial adaptations to early-life stress are distinct in juveniles and adults.

Kathie L Eagleson, Miranda Villaneuva, Rebecca M Southern, Pat Levitt.

  Exposure to early-life stress (ELS) increases risk for poor mental and physical health outcomes that emerge at different stages across the lifespan. Yet, how age interacts with ELS to impact the expression of specific phenotypes remains largely unknown. An established limited-bedding paradigm was used to induce ELS in mouse pups over the early postnatal period. Initial analyses focused on the hippocampus, based on documented sensitivity to ELS in humans and various animal models, and the large body of data reporting anatomical and physiological outcomes in this structure using this ELS paradigm. An unbiased discovery proteomics approach revealed distinct adaptations in the non-nuclear hippocampal proteome in male versus female offspring at two distinct developmental stages: juvenile and adult. Gene ontology and KEGG pathway analyses revealed significant enrichment in proteins associated with mitochondria and the oxidative phosphorylation (OXPHOS) pathway in response to ELS in female hippocampus only. To determine whether the protein adaptations to ELS reflected altered function, mitochondrial respiration (driven through complexes II-IV) and complex I activity were measured in isolated hippocampal mitochondria using a Seahorse X96 Flux analyzer and immunocapture ELISA, respectively. ELS had no effect on basal respiration in either sex at either age. In contrast, ELS increased OXPHOS capacity in juvenile males and females, and reduced OXPHOS capacity in adult females but not adult males. A similar pattern of ELS-induced changes was observed for complex I activity. These data suggest that initial adaptations in juvenile hippocampus due to ELS were not sustained in adults. Mitochondrial adaptations to ELS were also exhibited peripherally by liver. Overall, the temporal distinctions in mitochondrial responses to ELS show that ELS-generated adaptations and outcomes are complex over the lifespan. This may contribute to differences in the timing of appearance of mental and physical disturbances, as well as potential sex differences that influence only select outcomes.

Keywords:  AA, antimycin A; ADP, adenosine diphosphate; CI, confidence interval; Complex I activity; ELS, early-life stress; Early-life stress; FCCP, carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GO, gene ontology; HCD, high energy C-trap dissociation; Hippocampus; Liver; MS/MS, tandem mass spectrometry; Mitochondrial respiration; OCR, oxygen consumption rate; OXPHOS, oxidative phosphorylation; P, postnatal day; Proteomics; SCX, strong cation exchange; iTRAQ, isobaric tag for relative and absolute quantitation; oligo, oligomycin

DOI:  https://doi.org/10.1016/j.ynstr.2020.100251
Neurobiol Dis. 2020 Dec 18. pii: S0969-9961(20)30500-3. [Epub ahead of print] 105225

Systematic review and meta-analysis of human Transcriptomics reveals Neuroinflammation, deficient energy metabolism, and Proteostasis failure across Neurodegeneration.

Ayush Noori, Aziz M Mezlini, Bradley T Hyman, Alberto Serrano-Pozo, Sudeshna Das.

  Neurodegenerative disorders such as Alzheimer's disease (AD), Lewy body diseases (LBD), and the amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) spectrum are defined by the accumulation of specific misfolded protein aggregates. However, the mechanisms by which each proteinopathy leads to neurodegeneration remain elusive. We hypothesized that there is a common "pan-neurodegenerative" gene expression signature driving pathophysiology across these clinically and pathologically diverse proteinopathies. To test this hypothesis, we performed a meta-analysis of publicly available human brain transcriptomic datasets. We conducted a systematic review of human gene expression datasets of relevant CNS regions from AD, LBD, and ALS-FTD patients and age-matched controls in the Gene Expression Omnibus (GEO) and ArrayExpress databases, followed by consistent processing of each dataset, meta-analysis, pathway enrichment and overlap analyses. After applying pre-specified eligibility criteria and stringent data pre-processing, a total of 2600 samples from 26 CE, 21 LBD, and 13 ALS-FTD datasets were included in the meta-analysis. The pan-neurodegenerative gene signature is characterized by an upregulation of innate immunity, cytoskeleton, transcription and RNA processing genes, and a downregulation of mitochondrial electron chain transport. Pathway enrichment analyses also revealed the upregulation of neuroinflammation (including Toll-like receptor, TNF, and NFκB signaling) and phagocytosis, and downregulation of mitochondrial oxidative phosphorylation, lysosomal acidification, and ubiquitin-proteasome pathways. Our findings suggest that neuroinflammation and a failure in both neuronal energy metabolism and protein degradation systems are consistent features of underlying neurodegenerative diseases, despite differences in the extent of neuronal loss and brain regions involved.

Keywords:  ALZHEIMER'S DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; FRONTOTEMPORAL DEMENTIA; LEWY BODY DISEASES; META-ANALYSIS; MITOCHONDRIAL ENERGY METABOLISM; NEURODEGENERATION; NEUROINFLAMMATION; PROTEOSTASIS; TRANSCRIPTOMICS

DOI:  https://doi.org/10.1016/j.nbd.2020.105225