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Theranostics 2023Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular... (Review)
Review
Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis. In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on. It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases. In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development. Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.
Topics: Humans; Mitophagy; Autophagy; Mitochondria; Neurodegenerative Diseases; Neoplasms
PubMed: 36632220
DOI: 10.7150/thno.79876 -
Trends in Neurosciences Mar 2017Neurons affected in Alzheimer's disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid... (Review)
Review
Neurons affected in Alzheimer's disease (AD) experience mitochondrial dysfunction and a bioenergetic deficit that occurs early and promotes the disease-defining amyloid beta peptide (Aβ) and Tau pathologies. Emerging findings suggest that the autophagy/lysosome pathway that removes damaged mitochondria (mitophagy) is also compromised in AD, resulting in the accumulation of dysfunctional mitochondria. Results in animal and cellular models of AD and in patients with sporadic late-onset AD suggest that impaired mitophagy contributes to synaptic dysfunction and cognitive deficits by triggering Aβ and Tau accumulation through increases in oxidative damage and cellular energy deficits; these, in turn, impair mitophagy. Interventions that bolster mitochondrial health and/or stimulate mitophagy may therefore forestall the neurodegenerative process in AD.
Topics: Alzheimer Disease; Animals; Autophagy; Humans; Mitochondria; Mitophagy
PubMed: 28190529
DOI: 10.1016/j.tins.2017.01.002 -
Cells Apr 2019Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by... (Review)
Review
Mitochondrion harbors its own DNA (mtDNA), which encodes many critical proteins for the assembly and activity of mitochondrial respiratory complexes. mtDNA is packed by many proteins to form a nucleoid that uniformly distributes within the mitochondrial matrix, which is essential for mitochondrial functions. Defects or mutations of mtDNA result in a range of diseases. Damaged mtDNA could be eliminated by mitophagy, and all paternal mtDNA are degraded by endonuclease G or mitophagy during fertilization. In this review, we describe the role and mechanism of mtDNA distribution and elimination. In particular, we focus on the regulation of paternal mtDNA elimination in the process of fertilization.
Topics: DNA, Mitochondrial; Humans; Mitochondria; Mitophagy; Mutation
PubMed: 31027297
DOI: 10.3390/cells8040379 -
Trends in Molecular Medicine Oct 2022With the growing prevalence of cardiovascular disease (CVD), there is an urgent need to explore non-conventional therapeutic measures to alleviate the burden of CVD on... (Review)
Review
With the growing prevalence of cardiovascular disease (CVD), there is an urgent need to explore non-conventional therapeutic measures to alleviate the burden of CVD on global healthcare. Mitochondrial injury plays a cardinal role in the pathogenesis of CVD. Mitochondrial dynamics and mitophagy are essential machineries that govern mitochondrial health in cardiomyocytes in physiological and pathophysiological settings. However, with the onset and progression of CVD, homeostasis of mitophagy is disturbed through largely unknown pathological mechanisms, causing mitochondrial damage and ultimately cardiomyocyte death. In this review we decipher the dual regulatory role of mitophagy in CVD pathogenesis, summarize controversies in mitophagy, and highlight recently identified compounds capable of modulating mitophagy. We share our perspectives on future mitophagy research directions in the context of CVD.
Topics: Cardiovascular Diseases; Humans; Mitochondria; Mitochondrial Dynamics; Mitophagy; Myocytes, Cardiac
PubMed: 35879138
DOI: 10.1016/j.molmed.2022.06.007 -
Seminars in Cell & Developmental Biology Feb 2020Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global... (Review)
Review
Metabolic reprogramming in tumours is now recognized as a hallmark of cancer, participating both in tumour growth and cancer progression. Cancer cells develop global metabolic adaptations allowing them to survive in the low oxygen and nutrient tumour microenvironment. Among these metabolic adaptations, cancer cells use glycolysis but also mitochondrial oxidations to produce ATP and building blocks needed for their high proliferation rate. Another particular adaptation of cancer cell metabolism is the use of autophagy and specific forms of autophagy like mitophagy to recycle intracellular components in condition of metabolic stress or during anticancer treatments. The plasticity of cancer cell metabolism is a major limitation of anticancer treatments and could participate to therapy resistances. The aim of this review is to report recent advances in the understanding of the relationship between tumour metabolism and autophagy/mitophagy in order to propose new therapeutic strategies.
Topics: Animals; Autophagy; Cellular Reprogramming; Humans; Mitophagy; Neoplasms
PubMed: 31154012
DOI: 10.1016/j.semcdb.2019.05.029 -
Current Biology : CB Feb 2018The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations... (Review)
Review
The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations and stress conditions. Owing to their role in energy production, mitochondria are exposed to high levels of reactive oxygen species, making them particularly vulnerable to mitochondrial DNA mutations and protein misfolding. Given that mitochondria are formed from proteins encoded by both nuclear and mitochondrial genomes, an additional layer of complexity is inherent in the coordination of protein synthesis and the mitochondrial import of nuclear-encoded proteins. For these reasons, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet the demands of the cell. These pathways work to eliminate damaged mitochondrial proteins or parts of the mitochondrial network by mitophagy and renew components by adding protein and lipids through biogenesis, collectively resulting in mitochondrial turnover. Mitochondrial quality control mechanisms are multi-tiered, operating at the protein, organelle and cell levels. Herein, we discuss mitophagy in different physiological contexts and then relate it to other quality control pathways, including the unfolded protein response, shedding of vesicles, proteolysis, and degradation by the ubiquitin-proteasome system. Understanding how these pathways contribute to the maintenance of mitochondrial homeostasis could provide insights into the development of targeted treatments when these systems fail in disease.
Topics: Animals; Cell-Derived Microparticles; Homeostasis; Humans; Mitochondria; Mitophagy; Proteasome Endopeptidase Complex; Proteolysis; Ubiquitin; Unfolded Protein Response
PubMed: 29462587
DOI: 10.1016/j.cub.2018.01.004 -
Nature Communications Jan 2021Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate....
Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.
Topics: Animals; Cell Death; Corticosterone; Glucocorticoids; Hydrocortisone; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Mitochondria; Mitochondrial Proteins; Mitophagy; Neuronal Plasticity; Neurons; Protective Agents; Protein Kinases; Synapses
PubMed: 33473105
DOI: 10.1038/s41467-020-20679-y -
Neurobiology of Disease Feb 2019Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting this pathway as a therapeutic strategy in neurodegenerative disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; Humans; Mitophagy; Neurons
PubMed: 29981842
DOI: 10.1016/j.nbd.2018.07.005 -
Autophagy Sep 2021Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the...
Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases. AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.
Topics: Autophagy; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membranes; Mitophagy
PubMed: 32967533
DOI: 10.1080/15548627.2020.1822097 -
Autophagy Jun 2022Owing to the dominant functions of mitochondria in multiple cellular metabolisms and distinct types of regulated cell death, maintaining a functional mitochondrial...
Owing to the dominant functions of mitochondria in multiple cellular metabolisms and distinct types of regulated cell death, maintaining a functional mitochondrial network is fundamental for the cellular homeostasis and body fitness in response to physiological adaptations and stressed conditions. The process of mitophagy, in which the dysfunctional or superfluous mitochondria are selectively engulfed by autophagosome and subsequently degraded in lysosome, has been well formulated as one of the major mechanisms for mitochondrial quality control. To date, the PINK1-PRKN-dependent and receptors (including proteins and lipids)-dependent pathways have been characterized to determine the mitophagy in mammalian cells. The mitophagy is highly responsive to the dynamics of endogenous metabolites, including iron-, calcium-, glycolysis-TCA-, NAD-, amino acids-, fatty acids-, and cAMP-associated metabolites. Herein, we summarize the recent advances toward the molecular details of mitophagy regulation in mammalian cells. We also highlight the key regulations of mammalian mitophagy by endogenous metabolites, shed new light on the bidirectional interplay between mitophagy and cellular metabolisms, with attempting to provide a perspective insight into the nutritional intervention of metabolic disorders with mitophagy deficit. acetyl-CoA: acetyl-coenzyme A; ACO1: aconitase 1; ADCYs: adenylate cyclases; AMPK: AMP-activated protein kinase; ATM: ATM serine/threonine kinase; BCL2L1: BCL2 like 1; BCL2L13: BCL2 like 13; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ca: calcium ion; CALCOCO2: calcium binding and coiled-coil domain 2; CANX: calnexin; CO: carbon monoxide; CYCS: cytochrome c, somatic; DFP: deferiprone; DNM1L: dynamin 1 like; ER: endoplasmic reticulum; FKBP8: FKBP prolyl isomerase 8; FOXO3: forkhead box O3; FTMT: ferritin mitochondrial; FUNDC1: FUN14 domain containing 1; GABA: γ-aminobutyric acid; GSH: glutathione; HIF1A: hypoxia inducible factor 1 subunit alpha; IMMT: inner membrane mitochondrial protein; IRP1: iron regulatory protein 1; ISC: iron-sulfur cluster; ITPR2: inositol 1,4,5-trisphosphate type 2 receptor; KMO: kynurenine 3-monooxygenase; LIR: LC3 interacting region; MAM: mitochondria-associated membrane; MAP1LC3: microtubule associated protein 1 light chain 3; MFNs: mitofusins; mitophagy: mitochondrial autophagy; mPTP: mitochondrial permeability transition pore; MTOR: mechanistic target of rapamycin kinase; NAD: nicotinamide adenine dinucleotide; NAM: nicotinamide; NMN: nicotinamide mononucleotide; NO: nitric oxide; NPA: Niemann-Pick type A; NR: nicotinamide riboside; NR4A1: nuclear receptor subfamily 4 group A member 1; NRF1: nuclear respiratory factor 1; OPA1: OPA1 mitochondrial dynamin like GTPase; OPTN: optineurin; PARL: presenilin associated rhomboid like; PARPs: poly(ADP-ribose) polymerases; PC: phosphatidylcholine; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; PPARG: peroxisome proliferator activated receptor gamma; PPARGC1A: PPARG coactivator 1 alpha; PRKA: protein kinase AMP-activated; PRKDC: protein kinase, DNA-activated, catalytic subunit; PRKN: parkin RBR E3 ubiquitin protein ligase; RHOT: ras homolog family member T; ROS: reactive oxygen species; SIRTs: sirtuins; STK11: serine/threonine kinase 11; TCA: tricarboxylic acid; TP53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VDAC1: voltage dependent anion channel 1.
Topics: Animals; Autophagy; Calcium; Iron; Mammals; Mitophagy; NAD; PPAR gamma; Protein Kinases; Protein Serine-Threonine Kinases; Serine; bcl-X Protein
PubMed: 34583624
DOI: 10.1080/15548627.2021.1975914