mitophagy
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Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.
Fanconi anemia (FA) is a rare genetic disorder associated with bone-marrow failure, genome instability and cancer predisposition. Recently, we and others have demonstrated dysfunctional mitochondria with morphological alterations in FA cells accompanied by high reactive oxygen species (ROS) levels. Mitochondrial morphology is regulated by continuous fusion and fission events and the misbalance between these two is often accompanied by autophagy. Here, we provide evidence of impaired autophagy in FA. We demonstrate that FA cells have increased number of autophagic (presumably mitophagic) events and accumulate dysfunctional mitochondria due to an impaired ability to degrade them. Moreover, mitochondrial fission accompanied by oxidative stress (OS) is a prerequisite condition for mitophagy in FA and blocking this pathway may release autophagic machinery to clear dysfunctional mitochondria.
- MeSH
- autofagie MeSH
- buněčné linie MeSH
- Fanconiho anemie patofyziologie MeSH
- fluorescenční mikroskopie MeSH
- lidé MeSH
- mitochondriální dynamika * MeSH
- mitochondrie patologie ultrastruktura MeSH
- mitofagie * MeSH
- oxidační stres MeSH
- reaktivní formy kyslíku metabolismus MeSH
- transmisní elektronová mikroskopie MeSH
- vzácné nemoci patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.
- MeSH
- Alzheimerova nemoc * krev patologie mozkomíšní mok MeSH
- autofagie * fyziologie MeSH
- biologické markery * mozkomíšní mok krev MeSH
- frontotemporální lobární degenerace * patologie mozkomíšní mok krev MeSH
- homolog Atg1 metabolismus MeSH
- intracelulární signální peptidy a proteiny MeSH
- lidé středního věku MeSH
- lidé MeSH
- mitofagie * MeSH
- proteinkinasy metabolismus krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
AIM: The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood. METHODS: Male wild-type (WT) mice and mice with partial Hif1a deficiency (hif1a +/-) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy. RESULTS: We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a +/- mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection. CONCLUSION: These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.
- MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus genetika MeSH
- fyziologická adaptace fyziologie MeSH
- hypoxie * metabolismus MeSH
- infarkt myokardu * metabolismus patologie genetika MeSH
- kardiomyocyty metabolismus patologie MeSH
- mitofagie * fyziologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular 'garbage' clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.
- MeSH
- Alzheimerova nemoc * mozkomíšní mok krev diagnóza MeSH
- biologické markery * mozkomíšní mok krev metabolismus MeSH
- kognitivní dysfunkce mozkomíšní mok krev diagnóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové proteiny mozkomíšní mok metabolismus krev MeSH
- mitofagie * MeSH
- mozek metabolismus patologie MeSH
- nádorové supresorové proteiny MeSH
- proteinkinasy metabolismus MeSH
- proteiny tau mozkomíšní mok metabolismus MeSH
- protoonkogenní proteiny mozkomíšní mok krev metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transkripční faktory BHLH-Zip metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Dichloroacetate (DCA) is beneficial in cancer therapy because it induces apoptosis and decreases cancer growth in vitro and in vivo without affecting non-cancer cells. DCA stimulates the activity of the enzyme pyruvate dehydrogenase by inhibiting pyruvate dehydrogenase kinase. Consequently, DCA promotes oxidative phosphorylation after glycolysis. Therefore, DCA produces changes in energy metabolism that could affect the mitochondrial network and mitophagy. This investigation determined the effects of DCA treatment on mitophagy in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were cultured and distributed into 3 groups: control, NH4Cl and chloroquine. Each group was treated with DCA at 0, 5, 30 and 60 mM for 16 h. Samples were analyzed for cell viability, mtDNA copy number, mitochondrial network morphology and expression of key proteins involved in mitochondrial dynamics, such as LC3b, FIS1, OPA1, PARKIN and PINK1. In all groups, DCA caused a decrease in cell viability, an induction of autophagy in a dose-dependent manner and a decrease in Tim23, FIS1 and PARKIN protein expression, leading to profound morphological changes in the mitochondrial network resulting in shorter and more fragmented filaments. However, TFAM protein levels remained unchanged. Similarly, the mitochondrial copy number was not significantly different among the treatment groups. In conclusion, DCA induces mitophagy and remodeling of the mitochondrial network. In this remodeling, DCA induces a decrease in the expression of key proteins involved in protein degradation and mitochondrial dynamics but does not significantly affect the mtDNA density. Blocking late phase autophagy increases the effects of DCA, suggesting that autophagy protects the cell, at least partially, against DCA.
- MeSH
- autofagie účinky léků MeSH
- chlorochin farmakologie MeSH
- kyselina dichloroctová farmakologie MeSH
- lidé MeSH
- mitochondriální DNA účinky léků MeSH
- mitochondriální proteiny metabolismus MeSH
- mitofagie účinky léků MeSH
- nádorové buněčné linie MeSH
- neuroblastom genetika metabolismus patologie MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- variabilita počtu kopií segmentů DNA MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- biologické přípravky terapeutické užití MeSH
- Huntingtonova nemoc farmakoterapie genetika metabolismus patologie MeSH
- lidé MeSH
- mitochondrie genetika metabolismus patologie MeSH
- mitofagie fyziologie MeSH
- neurony metabolismus patologie MeSH
- neuroprotektivní látky terapeutické užití MeSH
- protein huntingtin genetika metabolismus MeSH
- proteinové agregáty fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor β (TGFβ) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGFβ-treatment and the loss of SMAD4, a downstream member of TGFβ signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGFβ-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGFβ signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGFβ signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.
- MeSH
- lidé MeSH
- mitofagie MeSH
- nádory slinivky břišní genetika metabolismus patologie MeSH
- protein Smad4 metabolismus MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Long non-coding RNAs (lncRNAs) are crucial in chronic liver diseases, but the specific molecular mechanism of lncRNAs in alcoholic fatty liver (AFL) remains unclear. In this study, we investigated the in-depth regulatory mechanism of mTOR affected by AIRN non-protein coding RNA (lncRNA-AIRN) in the development of AFL. LncRNA-AIRN was highly expressed in the liver tissues of AFL C57BL/6mice and oleic acid+alcohol (O+A)treated AML-12cells by using quantitative real-timePCR. RNA pull-down and RNA immunoprecipitation experiments demonstrated that there was an interaction between lncRNA-AIRN and mTOR, and that interference with lncRNA-AIRN could promote the mTOR protein level. Results ofcycloheximide-chase assay showed that the proteinlevel of mTOR was decreased with the treatment time after the knockdown of lncRNA-AIRN. Furthermore, the knockdown of lncRNA-AIRN reducedmTOR protein level by promoting the E3 ubiquitin ligase FBXW7-mediated ubiquitination.The lncRNA-AIRN/mTORaxis was involved in the regulation of the mitophagy of O+A treated hepatocytes, which was confirmed by the cell transfection and the MTT assay.SPSS 16.0 was used for analyzing data. The difference between the two groups was analyzed by performing Student's t-test, and ANOVA was used to analyze the difference when more than two groups. P values < 0.05 were considered to be significantly different.Our findings demonstrated that the knockdown of lncRNA-AIRN influencedmitophagy in AFL by promoting mTOR ubiquitination.
- MeSH
- alkoholická steatóza jater enzymologie genetika patologie MeSH
- buněčné linie MeSH
- down regulace MeSH
- F-Box a WD repetice obsahující protein 7 metabolismus MeSH
- hepatocyty enzymologie patologie MeSH
- jaterní mitochondrie enzymologie genetika patologie MeSH
- játra enzymologie patologie MeSH
- mitofagie * MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- RNA dlouhá nekódující genetika metabolismus MeSH
- signální transdukce MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- ubikvitinace MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
