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1.
J Biochem ; 173(1): 1-11, 2022 Dec 27.
Artículo en Inglés | MEDLINE | ID: mdl-36346121

RESUMEN

Mitochondria are involved in various cellular processes, such as energy production, inflammatory responses and cell death. Mitochondrial dysfunction is associated with many age-related diseases, including neurological disorders and heart failure. Mitochondrial quality is strictly maintained by mitochondrial dynamics linked to an adequate supply of phospholipids and other substances from the endoplasmic reticulum (ER). The outer mitochondrial membrane-localized E3 ubiquitin ligase MITOL/MARCHF5 is responsible for mitochondrial quality control through the regulation of mitochondrial dynamics, formation of mitochondria-ER contacts and mitophagy. MITOL deficiency has been shown to impair mitochondrial function, cause an excessive inflammatory response and increase vulnerability to stress, resulting in the exacerbation of the disease. In this study, we overview the ubiquitin-mediated regulation of mitochondrial function by MITOL and the relationship between MITOL and diseases.


Asunto(s)
Ubiquitina-Proteína Ligasas , Ubiquitina , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Retículo Endoplásmico/metabolismo , Muerte Celular , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo
2.
iScience ; 25(7): 104582, 2022 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-35789860

RESUMEN

Abnormal mitochondrial fragmentation by dynamin-related protein1 (Drp1) is associated with the progression of aging-associated heart diseases, including heart failure and myocardial infarction (MI). Here, we report a protective role of outer mitochondrial membrane (OMM)-localized E3 ubiquitin ligase MITOL/MARCH5 against cardiac senescence and MI, partly through Drp1 clearance by OMM-associated degradation (OMMAD). Persistent Drp1 accumulation in cardiomyocyte-specific MITOL conditional-knockout mice induced mitochondrial fragmentation and dysfunction, including reduced ATP production and increased ROS generation, ultimately leading to myocardial senescence and chronic heart failure. Furthermore, ischemic stress-induced acute downregulation of MITOL, which permitted mitochondrial accumulation of Drp1, resulted in mitochondrial fragmentation. Adeno-associated virus-mediated delivery of the MITOL gene to cardiomyocytes ameliorated cardiac dysfunction induced by MI. Our findings suggest that OMMAD activation by MITOL can be a therapeutic target for aging-associated heart diseases, including heart failure and MI.

3.
J Biochem ; 171(5): 529-541, 2022 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-34964862

RESUMEN

The transfer of phospholipids from the endoplasmic reticulum (ER) to mitochondria via the mitochondria-ER contact site (MERCS) is essential for maintaining mitochondrial function and integrity. Here, we identified RMDN3/PTPIP51, possessing phosphatidic acid (PA)-transfer activity, as a neighbouring protein of the mitochondrial E3 ubiquitin ligase MITOL/MARCH5 by proximity-dependent biotin labelling using APEX2. We found that MITOL interacts with and ubiquitinates RMDN3. Mutational analysis identified lysine residue 89 in RMDN3 as a site of ubiquitination by MITOL. Loss of MITOL or the substitution of lysine 89 to arginine in RMDN3 significantly reduced the PA-binding activity of RMDN3, suggesting that MITOL regulates the transport of PA to mitochondria by activating RMDN3. Our findings imply that ubiquitin signalling regulates phospholipid transport at the MERCS.


Asunto(s)
Lisina , Proteínas Mitocondriales , Retículo Endoplásmico/metabolismo , Lisina/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Ácidos Fosfatidicos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
4.
J Biol Chem ; 296: 100620, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33811862

RESUMEN

Mouse models of various neuropsychiatric disorders, such as schizophrenia, often display an immature dentate gyrus, characterized by increased numbers of immature neurons and neuronal progenitors and a dearth of mature neurons. We previously demonstrated that the CRMP5-associated GTPase (CRAG), a short splice variant of Centaurin-γ3/AGAP3, is highly expressed in the dentate gyrus. CRAG promotes cell survival and antioxidant defense by inducing the activation of serum response factors at promyelocytic leukemia protein bodies, which are nuclear stress-responsive domains, during neuronal development. However, the physiological role of CRAG in neuronal development remains unknown. Here, we analyzed the role of CRAG using dorsal forebrain-specific CRAG/Centaurin-γ3 knockout mice. The mice revealed maturational abnormality of the hippocampal granule cells, including increased doublecortin-positive immature neurons and decreased calbindin-positive mature neurons, a typical phenotype of immature dentate gyri. Furthermore, the mice displayed hyperactivity in the open-field test, a common measure of exploratory behavior, suggesting that these mice may serve as a novel model for neuropsychiatric disorder associated with hyperactivity. Thus, we conclude that CRAG is required for the maturation of neurons in the dentate gyrus, raising the possibility that its deficiency might promote the development of psychiatric disorders in humans.


Asunto(s)
Giro Dentado/patología , GTP Fosfohidrolasas/fisiología , Células-Madre Neurales/patología , Neurogénesis , Neuronas/patología , Prosencéfalo/patología , Agitación Psicomotora/patología , Animales , Giro Dentado/metabolismo , Conducta Exploratoria , Femenino , Masculino , Ratones , Ratones Noqueados , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Prosencéfalo/metabolismo , Agitación Psicomotora/etiología , Agitación Psicomotora/metabolismo
5.
EMBO Rep ; 22(3): e49097, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33565245

RESUMEN

Parkin promotes cell survival by removing damaged mitochondria via mitophagy. However, although some studies have suggested that Parkin induces cell death, the regulatory mechanism underlying the dual role of Parkin remains unknown. Herein, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) regulates Parkin-mediated cell death through the FKBP38-dependent dynamic translocation from the mitochondria to the ER during mitophagy. Mechanistically, MITOL mediates ubiquitination of Parkin at lysine 220 residue, which promotes its proteasomal degradation, and thereby fine-tunes mitophagy by controlling the quantity of Parkin. Deletion of MITOL leads to accumulation of the phosphorylated active form of Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. Thus, we have shown that MITOL blocks Parkin-induced cell death, at least partially, by protecting FKBP38 from Parkin. Our findings unveil the regulation of the dual function of Parkin and provide a novel perspective on the pathogenesis of PD.


Asunto(s)
Mitofagia , Ubiquitina-Proteína Ligasas , Supervivencia Celular , Células HeLa , Humanos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
6.
Commun Biol ; 4(1): 192, 2021 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-33580194

RESUMEN

Mitochondrial pathophysiology is implicated in the development of Alzheimer's disease (AD). An integrative database of gene dysregulation suggests that the mitochondrial ubiquitin ligase MITOL/MARCH5, a fine-tuner of mitochondrial dynamics and functions, is downregulated in patients with AD. Here, we report that the perturbation of mitochondrial dynamics by MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in a mouse model with AD-related Aß pathology. Notably, MITOL deletion in the brain enhanced the seeding effect of Aß fibrils, but not the spontaneous formation of Aß fibrils and plaques, leading to excessive secondary generation of toxic and dispersible Aß oligomers. Consistent with this, MITOL-deficient mice with Aß etiology exhibited worsening cognitive decline depending on Aß oligomers rather than Aß plaques themselves. Our findings suggest that alteration in mitochondrial morphology might be a key factor in AD due to directing the production of Aß form, oligomers or plaques, responsible for disease development.


Asunto(s)
Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/metabolismo , Encéfalo/enzimología , Mitocondrias/enzimología , Proteínas Mitocondriales/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Conducta Animal , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Cognición , Modelos Animales de Enfermedad , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/patología , Proteínas Mitocondriales/genética , Placa Amiloide , Proteínas de Unión a Poli(A)/genética , Proteínas de Unión a Poli(A)/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Agregado de Proteínas , Agregación Patológica de Proteínas , Ubiquitina-Proteína Ligasas/genética
7.
Int J Mol Sci ; 21(11)2020 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-32471110

RESUMEN

The molecular pathology of diseases seen from the mitochondrial axis has become more complex with the progression of research. A variety of factors, including the failure of mitochondrial dynamics and quality control, have made it extremely difficult to narrow down drug discovery targets. We have identified MITOL (mitochondrial ubiquitin ligase: also known as MARCH5) localized on the mitochondrial outer membrane and previously reported that it is an important regulator of mitochondrial dynamics and mitochondrial quality control. In this review, we describe the pathological aspects of MITOL revealed through functional analysis and its potential as a drug discovery target.


Asunto(s)
Mitocondrias/metabolismo , Enfermedades Mitocondriales/enzimología , Proteínas Mitocondriales/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Retículo Endoplásmico/metabolismo , Humanos , Dinámicas Mitocondriales
8.
J Biochem ; 168(3): 305-312, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32302394

RESUMEN

In mitochondrial disorders, short stature and growth failure are common symptoms, but their underlying mechanism remains unknown. In this study, we examined the cause of growth failure of mice induced by nestin promoter-driven knockout of the mitochondrial ubiquitin ligase MITOL (MARCH5), a key regulator of mitochondrial function. MITOL-knockout mice have congenital hypoplasia of the anterior pituitary caused by decreased expression of pituitary transcript factor 1 (Pit1). Consistently, both mRNA levels of growth hormone (GH) and prolactin levels were markedly decreased in the anterior pituitary of mutant mice. Growth failure of mutant mice was partly rescued by hypodermic injection of recombinant GH. To clarify whether this abnormality was induced by the primary effect of MITOL knockdown in the anterior pituitary or a secondary effect of other lesions, we performed lentiviral-mediated knockdown of MITOL on cultured rat pituitary GH3 cells, which secrete GH. GH production was severely compromised in MITOL-knockdown GH3 cells. In conclusion, MITOL plays a critical role in the development of the anterior pituitary; therefore, mice with MITOL dysfunction exhibited pituitary dwarfism caused by anterior pituitary hypoplasia. Our findings suggest that mitochondrial dysfunction is commonly involved in the unknown pathogenesis of pituitary dwarfism.


Asunto(s)
Enanismo/genética , Enanismo/metabolismo , Proteínas Mitocondriales/genética , Adenohipófisis/metabolismo , Ubiquitina-Proteína Ligasas/genética , Animales , Línea Celular Tumoral , Enanismo/tratamiento farmacológico , Técnicas de Silenciamiento del Gen , Hormona del Crecimiento/administración & dosificación , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Prolactina/genética , Prolactina/metabolismo , ARN Mensajero/genética , Ratas , Transducción de Señal/genética , Transfección
9.
Biomolecules ; 10(3)2020 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-32183225

RESUMEN

Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.


Asunto(s)
Dinaminas/metabolismo , Fibroblastos/metabolismo , Enfermedad de Leigh/metabolismo , Síndrome MELAS/metabolismo , Mitocondrias/metabolismo , Piel/metabolismo , Muerte Celular , Células Cultivadas , Fibroblastos/patología , Humanos , Enfermedad de Leigh/patología , Síndrome MELAS/patología , Mitocondrias/patología , Piel/patología
10.
Sci Rep ; 9(1): 20107, 2019 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-31882856

RESUMEN

CRMP-5-associated GTPase (CRAG), a short splicing variant of centaurin-γ3/AGAP3, is predominantly expressed in the developing brain. We previously demonstrated that CRAG, but not centaurin-γ3, translocates to the nucleus and activates the serum response factor (SRF)-c-Fos pathway in cultured neuronal cells. However, the physiological relevance of CRAG in vivo is unknown. Here, we found that CRAG/centaurin-γ3-knockout mice showed intensively suppressed kainic acid-induced c-fos expression in the hippocampus. Analyses of molecular mechanisms underlying CRAG-mediated SRF activation revealed that CRAG has an essential role in GTPase activity, interacts with ELK1 (a co-activator of SRF), and activates SRF in an ELK1-dependent manner. Furthermore, CRAG and ELK1 interact with promyelocytic leukaemia bodies through SUMO-interacting motifs, which is required for SRF activation. These results suggest that CRAG plays a critical role in ELK1-dependent SRF-c-fos activation at promyelocytic leukaemia bodies in the developing brain.


Asunto(s)
Empalme Alternativo , Proteínas de Unión al GTP/genética , Proteínas Activadoras de GTPasa/genética , Factor de Respuesta Sérica/metabolismo , Proteína Elk-1 con Dominio ets/genética , Animales , Hipocampo/metabolismo , Ácido Kaínico/farmacología , Ratones , Ratones Noqueados , Neuronas/metabolismo , Proteína de la Leucemia Promielocítica/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Sumoilación
11.
EMBO J ; 38(15): e100999, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31368599

RESUMEN

Unresolved endoplasmic reticulum (ER) stress shifts the unfolded protein response signaling from cell survival to cell death, although the switching mechanism remains unclear. Here, we report that mitochondrial ubiquitin ligase (MITOL/MARCH5) inhibits ER stress-induced apoptosis through ubiquitylation of IRE1α at the mitochondria-associated ER membrane (MAM). MITOL promotes K63-linked chain ubiquitination of IRE1α at lysine 481 (K481), thereby preventing hyper-oligomerization of IRE1α and regulated IRE1α-dependent decay (RIDD). Therefore, under ER stress, MITOL depletion or the IRE1α mutant (K481R) allows for IRE1α hyper-oligomerization and enhances RIDD activity, resulting in apoptosis. Similarly, in the spinal cord of MITOL-deficient mice, ER stress enhances RIDD activity and subsequent apoptosis. Notably, unresolved ER stress attenuates IRE1α ubiquitylation, suggesting that this directs the apoptotic switch of IRE1α signaling. Our findings suggest that mitochondria regulate cell fate under ER stress through IRE1α ubiquitylation by MITOL at the MAM.


Asunto(s)
Retículo Endoplásmico/metabolismo , Endorribonucleasas/química , Endorribonucleasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Apoptosis , Células COS , Línea Celular , Chlorocebus aethiops , Estrés del Retículo Endoplásmico , Endorribonucleasas/genética , Células HEK293 , Células HeLa , Humanos , Lisina/metabolismo , Proteínas de la Membrana/genética , Ratones , Mitocondrias/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
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