Déborah Naón

Institute for Research in Biomedicine

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António Zorzano

Universitat de Barcelona

Luca Scorrano

Veneto Institute of Molecular Medicine

Geltrude Mingrone

Università Cattolica del Sacro Cuore

Manuel Palacı́n

Universitat de Barcelona

María Isabel Hernández‐Álvarez

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

Marta Zaninello

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Melania Manco

Bambino Gesù Children's Hospital

Marc Liesa

University of California, Los Angeles

José Manuel Fernández‐Real

Hospital Universitari de Girona Doctor Josep Trueta

Elías Delgado

Central University Hospital of Asturias

Cooperative Institutions

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Universitat de Barcelona

Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas

University of Padua

Veneto Institute of Molecular Medicine

Institute for Research in Biomedicine

Dulbecco Telethon Institute

Institut d'Investigació Biomèdica de Girona

Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition

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The promoter activity of human Mfn2 depends on Sp1 in vascular smooth muscle cells

Cardiovascular Research (2012)

Eleonora Sorianello Francesc X. Soriano Sergio Fernández‐Pascual Ana Sancho Déborah Naón

Mitofusin-2 (Mfn2) expression is dysregulated in vascular proliferative disorders and its overexpression attenuates the proliferation of vascular smooth muscle cells (VSMCs) and neointimal lesion development after balloon angioplasty. We sought to gain insight into the mechanisms that control Mfn2 expression in VSMCs. We cloned and characterized 2 kb of the 5′-flanking region of the human Mfn2 gene. Its TATA-less promoter contains a CpG island. In keeping with this, 5′-rapid amplification of cDNA ends revealed six transcriptional start sites (TSSs), of which TSS2 and TSS5 were the most frequently used. The strong CpG island was found to be non-methylated under conditions characterized by large differences in Mfn2 gene expression. The proximal Mfn2 promoter contains six putative Sp1 motifs. Sp1 binds to the Mfn2 promoter and its overexpression activates the Mfn2 promoter in VSMCs. Chemical inhibition of Sp1 reduced Mfn2 expression, and Sp1 silencing reduced transcriptional activity of the Mfn2 promoter. In keeping with this view, Sp1 and Mfn2 mRNA levels were down-regulated in the aorta early after an atherogenic diet in apolipoprotein E-knockout mice or in VSMCs cultured in the presence of low serum. Sp1 is a key factor in maintaining basal Mfn2 transcription in VSMCs. Given the anti-proliferative actions of Mfn2, Sp1-induced Mfn2 transcription may represent a mechanism for prevention of VSMC proliferation and neointimal lesion and development.

MFN2

10.1093/cvr/cvs006

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Citations (27)

At the right distance: ER-mitochondria juxtaposition in cell life and death

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2014)

Déborah Naón Luca Scorrano

Calcium Signaling

Cell function

10.1016/j.bbamcr.2014.05.011

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Citations (163)

Erratum to: Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes

Journal of Molecular Medicine (2013)

Francisco Ortega Josep M. Mercader José María Moreno‐Navarrete Mònica Sabater Neus Pueyo

S100A9

10.1007/s00109-013-1014-4

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Citations (1)

Targeting the association of calgranulin B (S100A9) with insulin resistance and type 2 diabetes

Journal of Molecular Medicine (2012)

Francisco Ortega Josep M. Mercader José María Moreno‐Navarrete Mònica Sabater Neus Pueyo

S100A9

Ex vivo

Glycated hemoglobin

10.1007/s00109-012-0979-8

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Citations (21)

Subjects With Early-Onset Type 2 Diabetes Show Defective Activation of the Skeletal Muscle PGC-1α/Mitofusin-2 Regulatory Pathway in Response to Physical Activity

Diabetes Care (2009)

María Isabel Hernández‐Álvarez Hood Thabit Nicole Burns Syed Muhammad Ismail Shah Imad Brema

OBJECTIVE Type 2 diabetes is associated with insulin resistance and skeletal muscle mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show incapacity to increase Vo2max in response to chronic exercise. This suggests a defect in muscle mitochondrial response to exercise. Here, we have explored the nature of the mechanisms involved. RESEARCH DESIGN AND METHODS Muscle biopsies were collected from young type 2 diabetic subjects and obese control subjects before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was measured. In particular, the regulatory pathway peroxisome proliferator–activated receptor γ coactivator (PGC)-1α/mitofusin-2 (Mfn2) was analyzed. RESULTS At baseline, subjects with diabetes showed reduced expression (by 26%) of the mitochondrial fusion protein Mfn2 and a 39% reduction of the α-subunit of ATP synthase. Porin expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the α-subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individuals with diabetes, whereas porin and α-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1α expression in muscle from control subjects but not in subjects with diabetes. CONCLUSIONS Our results demonstrate alterations in the regulatory pathway that controls PGC-1α expression and induction of Mfn2 in muscle from patients with early-onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise-dependent pathway that regulates the expression of PGC-1α and Mfn2.

MFN2

10.2337/dc09-1305

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Citations (177)

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

Diabetologia (2005)

Geltrude Mingrone Melania Manco Menotti Calvani M Castagneto Déborah Naón

MFN2

GLUT4

10.1007/s00125-005-1918-9

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Citations (67)

Reply to Filadi et al.: Does Mitofusin 2 tether or separate endoplasmic reticulum and mitochondria?

Proceedings of the National Academy of Sciences (2017)

Déborah Naón Marta Zaninello Marta Giacomello Tatiana Varanita Francesca Grespi

We thank Filadi et al. for their comments (1) on our paper (2), where we address whether the discrepancies between their paper (3) and our original discovery of Mitofusin (Mfn) 2 as an endoplasmic reticulum (ER)–mitochondria tether (4) resulted from: ( i ) clonal effects of chronic Mfn2 ablation, ( ii ) proximity measurement inappropriateness, or ( iii ) changes in mitochondrial Ca2+ uniporter (MCU) levels in WT and Mfn2 −/−cells. Filadi et al. (1) conclude that we fell short in solving the issue and that our data reinforce Mfn2 function as an ER–mitochondria spacer (3). First, Filadi et al. (1) reason that we did not measure contacts number upon Mfn2 ablation. However, contact surface (which depends on contact number and extent) can be extracted from the ER–mitochondria contact coefficient and data in our paper (2). The average mitochondrial surface contacting ER … [↵][1]1To whom correspondence should be addressed. Email: luca.scorrano{at}unipd.it. [1]: #xref-corresp-1-1

MFN2

Uniporter

10.1073/pnas.1618610114

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Citations (23)

A localized autophagic filter prevents entry of mitochondria carrying pathogenic Opa1 mutations in retinal ganglion cell axons

Biochimica et Biophysica Acta (BBA) - Bioenergetics (2016)

Marta Zaninello Kostas Palikaras Déborah Naón Fred N. Ross‐Cisneros Nektarios Tavernarakis

DNM1L

MFN1

Mitochondrial apoptosis-induced channel

MFN2

10.1016/j.bbabio.2016.04.343

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Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy

Nature Communications (2020)

Marta Zaninello Konstantinos Palikaras Déborah Naón Keiko Iwata Stéphanie Herkenne

In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5' AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.

PINK1

10.1038/s41467-020-17821-1

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Citations (72)

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

Diabetologia (2009)

María Isabel Hernández‐Álvarez Chiara Chiellini Melania Manco Déborah Naón Marc Liesa

PPARGC1A

10.1007/s00125-009-1403-y

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Citations (27)