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1.
Annu Rev Cell Dev Biol ; 36: 141-164, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-32886535

RESUMEN

Mitochondrial function depends on the efficient import of proteins synthesized in the cytosol. When cells experience stress, the efficiency and faithfulness of the mitochondrial protein import machinery are compromised, leading to homeostatic imbalances and damage to the organelle. Yeast Msp1 (mitochondrial sorting of proteins 1) and mammalian ATAD1 (ATPase family AAA domain-containing 1) are orthologous AAA proteins that, fueled by ATP hydrolysis, recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. Msp1 also extracts proteins that have become stuck in the import channel. The extracted proteins are targeted for proteasome-dependent degradation or, in the case of mistargeted tail-anchored proteins, are given another chance to be routed correctly. In addition, ATAD1 is implicated in the regulation of synaptic plasticity, mediating the release of neurotransmitter receptors from postsynaptic scaffolds to allow their trafficking. Here we discuss how structural and functional specialization imparts the unique properties that allow Msp1/ATAD1 ATPases to fulfill these diverse functions and also highlight outstanding questions in the field.


Asunto(s)
Adenosina Trifosfatasas/metabolismo , Sinapsis/metabolismo , Animales , Humanos , Mitocondrias/metabolismo , Proteínas Mitocondriales/química , Proteínas Mitocondriales/metabolismo , Modelos Moleculares
2.
Mol Cell ; 82(15): 2815-2831.e5, 2022 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-35752171

RESUMEN

Protein import into mitochondria is a highly regulated process, yet how cells clear mitochondria undergoing dysfunctional protein import remains poorly characterized. Here we showed that mitochondrial protein import stress (MPIS) triggers localized LC3 lipidation. This arm of the mitophagy pathway occurs through the Nod-like receptor (NLR) protein NLRX1 while, surprisingly, without the engagement of the canonical mitophagy protein PINK1. Mitochondrial depolarization, which itself induces MPIS, also required NLRX1 for LC3 lipidation. While normally targeted to the mitochondrial matrix, cytosol-retained NLRX1 recruited RRBP1, a ribosome-binding transmembrane protein of the endoplasmic reticulum, which relocated to the mitochondrial vicinity during MPIS, and the NLRX1/RRBP1 complex in turn controlled the recruitment and lipidation of LC3. Furthermore, NLRX1 controlled skeletal muscle mitophagy in vivo and regulated endurance capacity during exercise. Thus, localization and lipidation of LC3 at the site of mitophagosome formation is a regulated step of mitophagy controlled by NLRX1/RRBP1 in response to MPIS.


Asunto(s)
Proteínas Mitocondriales , Mitofagia , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Transporte de Proteínas
3.
Mol Cell ; 77(1): 180-188.e9, 2020 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-31630969

RESUMEN

The mitochondrial proteome is built mainly by import of nuclear-encoded precursors, which are targeted mostly by cleavable presequences. Presequence processing upon import is essential for proteostasis and survival, but the consequences of dysfunctional protein maturation are unknown. We find that impaired presequence processing causes accumulation of precursors inside mitochondria that form aggregates, which escape degradation and unexpectedly do not cause cell death. Instead, cells survive via activation of a mitochondrial unfolded protein response (mtUPR)-like pathway that is triggered very early after precursor accumulation. In contrast to classical stress pathways, this immediate response maintains mitochondrial protein import, membrane potential, and translation through translocation of the nuclear HMG-box transcription factor Rox1 to mitochondria. Rox1 binds mtDNA and performs a TFAM-like function pivotal for transcription and translation. Induction of early mtUPR provides a reversible stress model to mechanistically dissect the initial steps in mtUPR pathways with the stressTFAM Rox1 as the first line of defense.


Asunto(s)
Mitocondrias/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada/fisiología , Muerte Celular/fisiología , Núcleo Celular/metabolismo , ADN Mitocondrial/metabolismo , Potenciales de la Membrana/fisiología , Biosíntesis de Proteínas/fisiología , Saccharomyces cerevisiae/metabolismo , Transcripción Genética/fisiología
4.
Mol Cell ; 79(4): 575-587.e7, 2020 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-32589965

RESUMEN

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/- mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.


Asunto(s)
Factor 3 de Iniciación Eucariótica/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Extensión de la Cadena Peptídica de Translación , Animales , Membrana Celular/genética , Membrana Celular/metabolismo , Factor 3 de Iniciación Eucariótica/genética , Células HeLa , Humanos , Ratones Noqueados , Mitocondrias/genética , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/patología , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Subunidades Ribosómicas/genética , Subunidades Ribosómicas/metabolismo
5.
J Cell Sci ; 137(14)2024 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-38940185

RESUMEN

Mitochondrial biogenesis relies on hundreds of proteins that are derived from genes encoded in the nucleus. According to the characteristic properties of N-terminal targeting peptides (TPs) and multi-step authentication by the protein translocase called the TOM complex, nascent polypeptides satisfying the requirements are imported into mitochondria. However, it is unknown whether eukaryotic cells with a single mitochondrion per cell have a similar complexity of presequence requirements for mitochondrial protein import compared to other eukaryotes with multiple mitochondria. Based on putative mitochondrial TP sequences in the unicellular red alga Cyanidioschyzon merolae, we designed synthetic TPs and showed that functional TPs must have at least one basic residue and a specific amino acid composition, although their physicochemical properties are not strictly determined. Combined with the simple composition of the TOM complex in C. merolae, our results suggest that a regional positive charge in TPs is verified solely by TOM22 for mitochondrial protein import in C. merolae. The simple authentication mechanism indicates that the monomitochondrial C. merolae does not need to increase the cryptographic complexity of the lock-and-key mechanism for mitochondrial protein import.


Asunto(s)
Mitocondrias , Proteínas Mitocondriales , Transporte de Proteínas , Rhodophyta , Rhodophyta/metabolismo , Rhodophyta/genética , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Mitocondrias/metabolismo , Secuencia de Aminoácidos
6.
Mol Microbiol ; 121(6): 1112-1126, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38622999

RESUMEN

All mitochondria import >95% of their proteins from the cytosol. This process is mediated by protein translocases in the mitochondrial membranes, whose subunits are generally highly conserved. Most eukaryotes have two inner membrane protein translocases (TIMs) that are specialized to import either presequence-containing or mitochondrial carrier proteins. In contrast, the parasitic protozoan Trypanosoma brucei has a single TIM complex consisting of one conserved and five unique subunits. Here, we identify candidates for new subunits of the TIM or the presequence translocase-associated motor (PAM) using a protein-protein interaction network of previously characterized TIM and PAM subunits. This analysis reveals that the trypanosomal TIM complex contains an additional trypanosomatid-specific subunit, designated TbTim15. TbTim15 is associated with the TIM complex, lacks transmembrane domains, and localizes to the intermembrane space. TbTim15 is essential for procyclic and bloodstream forms of trypanosomes. It contains two twin CX9C motifs and mediates import of both presequence-containing and mitochondrial carrier proteins. While the precise function of TbTim15 in mitochondrial protein import is unknown, our results are consistent with the notion that it may function as an import receptor for the non-canonical trypanosomal TIM complex.


Asunto(s)
Mitocondrias , Proteínas de Transporte de Membrana Mitocondrial , Membranas Mitocondriales , Transporte de Proteínas , Proteínas Protozoarias , Trypanosoma brucei brucei , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/enzimología , Proteínas Protozoarias/metabolismo , Proteínas Protozoarias/genética , Membranas Mitocondriales/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Subunidades de Proteína/metabolismo
7.
J Cell Sci ; 136(2)2023 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-36601773

RESUMEN

TIM22 pathway cargos are essential for sustaining mitochondrial homeostasis as an excess of these proteins leads to proteostatic stress and cell death. Yme1 is an inner membrane metalloprotease that regulates protein quality control with chaperone-like and proteolytic activities. Although the mitochondrial translocase and protease machinery are critical for organelle health, their functional association remains unexplored. The present study unravels a novel genetic connection between the TIM22 complex and YME1 machinery in Saccharomyces cerevisiae that is required for maintaining mitochondrial health. Our genetic analyses indicate that impairment in the TIM22 complex rescues the respiratory growth defects of cells without Yme1. Furthermore, Yme1 is essential for the stability of the TIM22 complex and regulates the proteostasis of TIM22 pathway substrates. Moreover, impairment in the TIM22 complex suppressed the mitochondrial structural and functional defects of Yme1-devoid cells. In summary, excessive levels of TIM22 pathway substrates could be one of the reasons for respiratory growth defects of cells lacking Yme1, and compromising the TIM22 complex can compensate for the imbalance in mitochondrial proteostasis caused by the loss of Yme1.


Asunto(s)
Proteínas de Transporte de Membrana Mitocondrial , Proteínas de Saccharomyces cerevisiae , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteostasis , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas de Saccharomyces cerevisiae/metabolismo , Mitocondrias/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Proteasas ATP-Dependientes
8.
Mol Cell ; 67(3): 471-483.e7, 2017 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-28712724

RESUMEN

Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome.


Asunto(s)
Cardiomiopatías/enzimología , Catarata/enzimología , Mitocondrias/enzimología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Translocador 1 del Nucleótido Adenina/metabolismo , Antiportadores/metabolismo , Apoptosis , Proteínas de Unión al Calcio/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/patología , Catarata/genética , Catarata/patología , Predisposición Genética a la Enfermedad , Células HEK293 , Células HeLa , Humanos , Mitocondrias/patología , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos , Mutación , Fenotipo , Fosfolípidos/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Transporte de Proteínas , Factores de Tiempo , Transfección
9.
Bioessays ; 45(3): e2200160, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36709422

RESUMEN

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import.


Asunto(s)
Mitocondrias , Proteínas Mitocondriales , Citosol/metabolismo , Proteínas Mitocondriales/metabolismo , Mitocondrias/metabolismo , Transporte de Proteínas
10.
Trends Biochem Sci ; 45(8): 650-667, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32409196

RESUMEN

While targeting of proteins synthesized in the cytosol to any organelle is complex, mitochondria present the most challenging of destinations. First, import of nuclear-encoded proteins needs to be balanced with production of mitochondrial-encoded ones. Moreover, as mitochondria are divided into distinct subdomains, their proteins harbor a number of different targeting signals and biophysical properties. While translocation into the mitochondrial membranes has been well studied, the cytosolic steps of protein import remain poorly understood. Here, we review current knowledge on mRNA and protein targeting to mitochondria, as well as recent advances in our understanding of the cellular programs that respond to accumulation of mitochondrial precursor proteins in the cytosol, thus linking defects in targeting-capacity to signaling.


Asunto(s)
Citosol/metabolismo , Proteínas Mitocondriales/biosíntesis , Proteínas de Choque Térmico/metabolismo , Homeostasis , Proteínas Mitocondriales/metabolismo , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Partícula de Reconocimiento de Señal/metabolismo , Transducción de Señal
11.
EMBO J ; 39(19): e103889, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32815200

RESUMEN

Plasticity of the proteome is critical to adapt to varying conditions. Control of mitochondrial protein import contributes to this plasticity. Here, we identified a pathway that regulates mitochondrial protein import by regulated N-terminal processing. We demonstrate that dipeptidyl peptidases 8/9 (DPP8/9) mediate the N-terminal processing of adenylate kinase 2 (AK2) en route to mitochondria. We show that AK2 is a substrate of the mitochondrial disulfide relay, thus lacking an N-terminal mitochondrial targeting sequence and undergoing comparatively slow import. DPP9-mediated processing of AK2 induces its rapid proteasomal degradation and prevents cytosolic accumulation of enzymatically active AK2. Besides AK2, we identify more than 100 mitochondrial proteins with putative DPP8/9 recognition sites and demonstrate that DPP8/9 influence the cellular levels of a number of these proteins. Collectively, we provide in this study a conceptual framework on how regulated cytosolic processing controls levels of mitochondrial proteins as well as their dual localization to mitochondria and other compartments.


Asunto(s)
Adenilato Quinasa/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Proteínas Mitocondriales/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Células HEK293 , Células HeLa , Humanos , Transporte de Proteínas
12.
J Cell Sci ; 135(16)2022 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-35833493

RESUMEN

Nuclear-encoded mitochondrial protein mRNAs have been found to be localized and locally translated within neuronal processes. However, the mechanism of transport for those mRNAs to distal locations is not fully understood. Here, we describe axonal co-transport of Cox7c with mitochondria. Fractionation analysis and single-molecule fluorescence in situ hybridization (smFISH) assay revealed that endogenous mRNA encoding Cox7c was preferentially associated with mitochondria in a mouse neuronal cell line and within mouse primary motor neuron axons, whereas other mRNAs that do not encode mitochondrial protein were much less associated. Live-cell imaging of MS2-tagged Cox7c mRNA further confirmed the preferential colocalization and co-transport of Cox7c mRNA with mitochondria in motor neuron axons. Intriguingly, the coding region, rather than the 3' untranslated region (UTR), was the key domain for the co-transport. Our results reveal that Cox7c mRNA can be transported with mitochondria along significant distances and that its coding region is a major recognition feature. This is consistent with the idea that mitochondria can play a vital role in spatial regulation of the axonal transcriptome at distant neuronal sites.


Asunto(s)
Axones , Complejo IV de Transporte de Electrones/metabolismo , Mitocondrias , Regiones no Traducidas 3'/genética , Animales , Axones/metabolismo , Hibridación Fluorescente in Situ , Ratones , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo
13.
Biochem Soc Trans ; 52(3): 1539-1548, 2024 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-38864432

RESUMEN

Mitochondria are essential organelles of eukaryotic cells and thus mitochondrial proteome is under constant quality control and remodelling. Yme1 is a multi-functional protein and subunit of the homo-hexametric complex i-AAA proteinase. Yme1 plays vital roles in the regulation of mitochondrial protein homeostasis and mitochondrial plasticity, ranging from substrate degradation to the regulation of protein functions involved in mitochondrial protein biosynthesis, energy production, mitochondrial dynamics, and lipid biosynthesis and signalling. In this mini review, we focus on discussing the current understanding of the roles of Yme1 in mitochondrial protein import via TIM22 and TIM23 pathways, oxidative phosphorylation complex function, as well as mitochondrial lipid biosynthesis and signalling, as well as a brief discussion of the role of Yme1 in modulating mitochondrial dynamics.


Asunto(s)
Mitocondrias , Dinámicas Mitocondriales , Proteínas Mitocondriales , Fosforilación Oxidativa , Transporte de Proteínas , Proteostasis , Humanos , Proteínas Mitocondriales/metabolismo , Mitocondrias/metabolismo , Animales , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Lípidos/biosíntesis , Lípidos/química , Metabolismo de los Lípidos , Homeostasis , Transducción de Señal , Proteasas ATP-Dependientes/metabolismo
14.
Acta Pharmacol Sin ; 45(9): 1898-1911, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38760545

RESUMEN

Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.


Asunto(s)
Hidroximetilglutaril-CoA Sintasa , Hígado , Ratones Endogámicos C57BL , Tacrolimus , Animales , Tacrolimus/farmacología , Ratones , Masculino , Hidroximetilglutaril-CoA Sintasa/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Humanos , Hígado/metabolismo , Hígado/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Proteína Forkhead Box O1/metabolismo , Inmunosupresores/farmacología , Trastornos del Metabolismo de los Lípidos/metabolismo , Trastornos del Metabolismo de los Lípidos/inducido químicamente , Trastornos del Metabolismo de los Lípidos/tratamiento farmacológico , Línea Celular
15.
J Appl Toxicol ; 44(8): 1257-1268, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38700028

RESUMEN

This study demonstrated that both copper oxide nanoparticles (CuO-NPs) and copper nanoparticles (Cu-NPs) can cause swelling, inflammation, and cause damage to the mitochondria of alveolar type II epithelial cells in mice. Cellular examinations indicated that both CuO-NPs and Cu-NPs can reduce cell viability and harm the mitochondria of human bronchial epithelial cells, particularly Beas-2B cells. However, it is clear that CuO-NPs exhibit a more pronounced detrimental effect compared with Cu-NPs. Using bafilomycin A1 (Bafi A1), an inhibitor of lysosomal acidification, was found to enhance cell viability and alleviate mitochondrial damage caused by CuO-NPs. Additionally, Bafi A1 also reduces the accumulation of dihydrolipoamide S-acetyltransferase (DLAT), a marker for mitochondrial protein toxicity, induced by CuO-NPs. This observation suggests that the toxicity of CuO-NPs depends on the distribution of copper particles within cells, a process facilitated by the acidic environment of lysosomes. The release of copper ions is thought to be triggered by the acidic conditions within lysosomes, which aligns with the lysosomal Trojan horse mechanism. However, this association does not seem to be evident with Cu-NPs.


Asunto(s)
Supervivencia Celular , Cobre , Lisosomas , Macrólidos , Nanopartículas del Metal , Mitocondrias , Cobre/toxicidad , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Animales , Humanos , Nanopartículas del Metal/toxicidad , Macrólidos/toxicidad , Ratones , Supervivencia Celular/efectos de los fármacos , Línea Celular , Masculino
16.
Int J Mol Sci ; 25(14)2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39063070

RESUMEN

Plastid retrograde signaling plays a key role in coordinating the expression of plastid genes and photosynthesis-associated nuclear genes (PhANGs). Although plastid retrograde signaling can be substantially compromised by mitochondrial dysfunction, it is not yet clear whether specific mitochondrial factors are required to regulate plastid retrograde signaling. Here, we show that mitochondrial ATP synthase beta-subunit mutants with decreased ATP synthase activity are impaired in plastid retrograde signaling in Arabidopsis thaliana. Transcriptome analysis revealed that the expression levels of PhANGs were significantly higher in the mutants affected in the AT5G08670 gene encoding the mitochondrial ATP synthase beta-subunit, compared to wild-type (WT) seedlings when treated with lincomycin (LIN) or norflurazon (NF). Further studies indicated that the expression of nuclear genes involved in chloroplast and mitochondrial retrograde signaling was affected in the AT5G08670 mutant seedlings treated with LIN. These changes might be linked to the modulation of some transcription factors (TFs), such as LHY (Late Elongated Hypocotyl), PIF (Phytochrome-Interacting Factors), MYB, WRKY, and AP2/ERF (Ethylene Responsive Factors). These findings suggest that the activity of mitochondrial ATP synthase significantly influences plastid retrograde signaling.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Regulación de la Expresión Génica de las Plantas , ATPasas de Translocación de Protón Mitocondriales , Plastidios , Transducción de Señal , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , ATPasas de Translocación de Protón Mitocondriales/genética , Plastidios/metabolismo , Plastidios/genética , Mitocondrias/metabolismo , Plantones/genética , Plantones/metabolismo , Mutación , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Lincomicina/farmacología , Perfilación de la Expresión Génica
17.
Am J Physiol Cell Physiol ; 325(4): C807-C816, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37642234

RESUMEN

Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria [translocase of the outer mitochondrial membrane (TOMM) complex, translocase of the inner mitochondrial membrane (TIMM) complex, OXPHOS complexes, mitoribosomes]. These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines but also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress, and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.


Asunto(s)
Mitocondrias , Membranas Mitocondriales , Fosforilación Oxidativa , Apoptosis , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Micropéptidos
18.
J Biol Chem ; 298(7): 102107, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35671825

RESUMEN

An ever-increasing number of proteins have been shown to translocate across various membranes of bacterial as well as eukaryotic cells in their folded states as a part of physiological and/or pathophysiological processes. Herein, we provide an overview of the systems/processes that are established or likely to involve the membrane translocation of folded proteins, such as protein export by the twin-arginine translocation system in bacteria and chloroplasts, unconventional protein secretion and protein import into the peroxisome in eukaryotes, and the cytosolic entry of proteins (e.g., bacterial toxins) and viruses into eukaryotes. We also discuss the various mechanistic models that have previously been proposed for the membrane translocation of folded proteins including pore/channel formation, local membrane disruption, membrane thinning, and transport by membrane vesicles. Finally, we introduce a newly discovered vesicular transport mechanism, vesicle budding and collapse, and present evidence that vesicle budding and collapse may represent a unifying mechanism that drives some (and potentially all) of folded protein translocation processes.


Asunto(s)
Pliegue de Proteína , Transporte de Proteínas , Bacterias/metabolismo , Proteínas Bacterianas/metabolismo , Eucariontes/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Peroxisomas/metabolismo , Señales de Clasificación de Proteína , Sistema de Translocación de Arginina Gemela/metabolismo
19.
J Transl Med ; 21(1): 441, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37407961

RESUMEN

Endothelial cells (ECs) angiogenesis is the process of sprouting new vessels from the existing ones, playing critical roles in physiological and pathological processes such as wound healing, placentation, ischemia/reperfusion, cardiovascular diseases and cancer metastasis. Although mitochondria are not the major sites of energy source in ECs, they function as important biosynthetic and signaling hubs to regulate ECs metabolism and adaptations to local environment, thus affecting ECs migration, proliferation and angiogenic process. The understanding of the importance and potential mechanisms of mitochondria in regulating ECs metabolism, function and the process of angiogenesis has developed in the past decades. Thus, in this review, we discuss the current understanding of mitochondrial proteins and signaling molecules in ECs metabolism, function and angiogeneic signaling, to provide new and therapeutic targets for treatment of diverse cardiovascular and angiogenesis-dependent diseases.


Asunto(s)
Células Endoteliales , Transducción de Señal , Células Endoteliales/metabolismo , Transducción de Señal/fisiología , Neovascularización Fisiológica , Mitocondrias
20.
J Transl Med ; 21(1): 189, 2023 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-36899366

RESUMEN

BACKGROUND: The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. METHODS: Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. RESULTS: High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. CONCLUSION: This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Multiómica , Recurrencia Local de Neoplasia , Medicina de Precisión , Proteínas Mitocondriales/genética , Microambiente Tumoral , Proteínas Musculares/metabolismo
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