Mitochondrial <scp>E3</scp> ubiquitin ligase 1 (<scp>MUL1</scp>) as a novel therapeutic target for diseases associated with mitochondrial dysfunction

Calle, Ximena; Garrido-Moreno, Valeria; Lopez-Gallardo, Erik; Norambuena-Soto, Ignacio; Martínez, Daniela; Peñaloza-Otárola, Allan; Troncossi, Angelo; Guerrero-Moncayo, Alejandra; Ortega, Angélica; Maracaja-Coutinho, Vinícius; Parra, Valentina; Chiong, Mario; Lavandero, Sergio

doi:10.1002/iub.2657

Cited by 14 publications

(7 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The IMD of MUL1 is also the target of mitochondrial Omi/HtrA2 protease which is involved in protein quality control and can regulate MUL1 protein levels during mitochondrial stress ( Faccio et al, 2000 ; Cilenti et al, 2014 ). Our previous studies as well as work by other investigators have established the main function of MUL1 as a regulator of mitochondrial dynamics and mitophagy ( Cilenti et al, 2014 ; Puri et al, 2020 ; Calle et al, 2022 ). In the absence of Omi/HtrA2 protease, there is an accumulation of MUL1 protein and enhanced mitophagy ( Ambivero et al, 2014 ; Cilenti et al, 2014 ).…”

Section: Discussionmentioning

confidence: 75%

“…MUL1 (also known as Mulan, MAPL, GIDE, and HADES) is one of the three mitochondrial E3 ubiquitin ligases, alongside March5 and RNF185 ( Li et al, 2008 ; Zhang et al, 2008 ; Braschi et al, 2009 ; Jung et al, 2011 ; Tang et al, 2011 ). MUL1 is located on the outer mitochondrial membrane (OMM) and its function has been implicated in various cellular processes such as mitophagy, cell death, mitochondrial dynamics, and innate immune response ( Jenkins et al, 2013 ; Ambivero et al, 2014 ; Cilenti et al, 2014 ; Prudent et al, 2015 ; Ni et al, 2017 ; Puri et al, 2020 ; Calle et al, 2022 ). MUL1 can perform K48- and K63-ubiquitination, as well as SUMOylation, targeting specific substrates located in the OMM or the vicinity of the mitochondria ( Scorrano and Liu, 2009 ; Prudent et al, 2015 ; Doiron et al, 2017 ; Ni et al, 2017 ; Barry et al, 2018 ; Cilenti et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice

Cilenti,

Di Gregorio,

Mahar

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

Obesity is a growing epidemic affecting millions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(−/−) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice

Cilenti,

Di Gregorio,

Mahar

et al. 2024

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…In contrast, we detected, with the exposure to myristate 500 μM, an increase in the nuclear localization, therefore increased transcriptional activity, of FOXO1 in NRVM, which was persistent upon insulin action ( Figure 2B ). One protein that has been associated with FOXO1/O3 transcriptional activity is the mitochondrial E3 ubiquitin ligase MUL1, a novel regulator of mitochondrial dynamics and several other cellular functions ( Calle et al, 2022 ). We analyzed the promoter region of the Mul1 gene (from human, rat and mouse) and found several binding sites for FOXO1, using FOXOs consensus binding sequence 5′-TTGTTTAC-3’ ( Eijkelenboom and Burgering, 2013 ) ( Figure 2C ).…”

Section: Resultsmentioning

confidence: 99%

Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1

Vásquez‐Trincado

Navarro-Márquez

Morales

et al. 2023

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Introduction: Cardiovascular diseases, especially metabolic-related disorders, are progressively growing worldwide due to high-fat-containing foods, which promote a deleterious response at the cellular level, termed lipotoxicity, or lipotoxic stress. At the cardiac level, saturated fatty acids have been directly associated with cardiomyocyte lipotoxicity through various pathological mechanisms involving mitochondrial dysfunction, oxidative stress, and ceramide production, among others. However, integrative regulators connecting saturated fatty acid-derived lipotoxic stress to mitochondrial and cardiomyocyte dysfunction remain elusive.Methods: Here, we worked with a cardiomyocyte lipotoxicity model, which uses the saturated fatty acid myristate, which promotes cardiomyocyte hypertrophy and insulin desensitization.Results: Using this model, we detected an increase in the mitochondrial E3 ubiquitin ligase, MUL1, a mitochondrial protein involved in the regulation of growth factor signaling, cell death, and, notably, mitochondrial dynamics. In this context, myristate increased MUL1 levels and induced mitochondrial fragmentation, associated with the decrease of the mitochondrial fusion protein MFN2, and with the increase of the mitochondrial fission protein DRP1, two targets of MUL1. Silencing of MUL1 prevented myristate-induced mitochondrial fragmentation and cardiomyocyte hypertrophy.Discussion: These data establish a novel connection between cardiomyocytes and lipotoxic stress, characterized by hypertrophy and fragmentation of the mitochondrial network, and an increase of the mitochondrial E3 ubiquitin ligase MUL1.

show abstract

“…Multiple SNVs nearby the M188 were predicted to be detrimental by polymorphism phenotyping (PolyPhen), suggesting the importance of this portion in MUL1. MUL1 has been reported to play a role in mitochondrial dynamics including mitophagy ( 10 ), and dysfunction of the mitochondrial quality control system is one of the molecular underpinnings of NASH ( 2 ). Therefore, we isolated peripheral neutrophils and stained them with MitoTracker Red to evaluate the mitochondrial morphology as well as the membrane potential ( Fig.…”

Section: Discussionmentioning

confidence: 99%

A case of NASH with genetic predisposition successfully treated with an SGLT2 inhibitor: a possible involvement of mitochondrial dysfunction

Nakajima

Sekiya

Furuta

et al. 2022

Endocrinology, Diabetes &Amp; Metabolism Case Reports

View full text Add to dashboard Cite

Summary In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium–glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications. Learning points While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH). NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes. SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation. A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.

show abstract

Mitochondrial E3 ubiquitin ligase 1 (MUL1) as a novel therapeutic target for diseases associated with mitochondrial dysfunction

Cited by 14 publications

References 68 publications

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice

Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice

Myristate induces mitochondrial fragmentation and cardiomyocyte hypertrophy through mitochondrial E3 ubiquitin ligase MUL1

A case of NASH with genetic predisposition successfully treated with an SGLT2 inhibitor: a possible involvement of mitochondrial dysfunction

Contact Info

Product

Resources

About