Molecular MedicineComplex metabolic diseases and mitochondria

Complex metabolic diseases and mitochondria

Age-related metabolic diseases have increased to epidemic proportions in all industrialized countries. Aging is the most universal contributor to the aetiologies of metabolic decline and related diseases, including type 2 diabetes mellitus, cardiovascular disease, non-alcoholic steatohepatitis (NASH), stroke, neurodegenerative diseases, and cancer. According to observational studies, obesity is a major determinant of premature mortality and a risk factor for leading causes of death. Diabetes has increased dramatically over the past century, registering of 371 million cases worldwide in 2012. The prevalence of diabetes mellitus and glucose intolerance increases significantly with age.

Mitochondrial dysfunction has been reported in complex age-related diseases, as well as in aging itself. These observations thus support the notion that mitochondrial dysfunction and the accumulation of oxidative damage contribute to the pathogenesis of these diseases. Aging is characterised by the accumulation of mutations in mitochondrial DNA, which may be responsible for the alterations detected in this condition. In addition, the deregulation of various signalling pathways can induce mitochondrial dysfunction. The regulatory network that governs mitochondrial homeostasis may therefore be involved in the development of age-related conditions.

We have shown that mitochondrial morphology determines the function of these organelles. Mitochondrial architecture is determined by motility, fusion, and fission events. Mitochondrial fusion is mediated by mitofusins (Mfn1 and Mfn2, located in the outer mitochondrial membrane) and optic atrophy gene 1 (Opa1, located in the inner membrane), while mitochondrial fission is mediated by dynamin-related protein 1 (Drp1), mitochondrial fission factor (Mff, located in the outer mitochondrial membrane), and fission 1 protein (Fis1, located in the outer mitochondrial membrane), among others.

Some of the proteins involved in mitochondrial dynamics are subject to exquisite control. In this regard, we have reported that the expression of Mfn2 is highly regulated in response to enhanced energy expenditure and exercise. Mfn2 is repressed in the muscle of obese or type 2 diabetic patients. The nuclear co-activators PGC-1alpha, and PGC-1beta activate Mfn2 gene transcription through ERRalpha and may participate in the changes in the expression of this gene. OPA1 and mitochondrial elongation are enhanced by insulin in cardiomyocytes.

In addition, we have reported that some proteins involved in mitochondrial fusion modulate metabolism in vivo. Mnf2 deficiency enhances proton leakage and reduces respiration, independently of changes in mitochondrial mass. Mfn2 ablation also alters glucose metabolism and energy expenditure. Liver-specific ablation of Mfn2 in mice leads to glucose intolerance and enhanced hepatic gluconeogenesis, whereas ablation in muscle causes higher susceptibility to glucose intolerance and insulin resistance in response to a high fat diet. Hypothalamic POMC neuron-specific ablation of Mfn2 results in hyperphagia, reduced energy expenditure, and obesity. OMA1 (an Opa1 protease) knockout mice are also obese as a result of deficient brown adipose tissue metabolism.

As to the mechanisms controlled by Mfn2, this protein regulates endoplasmic reticulum (ER) morphology, and the transfer of calcium from the ER to the mitochondria. We have also demonstrated that Mfn2 deficiency causes a chronic Unfolded Protein Response (UPR), which is crucial in the metabolic alterations associated with this condition.

Mitochondrial dynamics also plays a key regulatory role in determining the fate of mitochondria, namely whether they undergo degradation via selective autophagy.

We aim to identify the mechanisms by which mitochondrial dysfunction participates in the development of complex metabolic disorders such as obesity, insulin resistance, and type 2 diabetes. More specifically, we focus on the implications of mitochondrial fusion or mitochondrial fission proteins in age-related diseases, and the role of interplay between autophagy, mitochondrial function, and energy metabolism.

Our group is organised around 3 research lines:

1. Analysis of the implications of proteins involved in mitochondrial dynamics on the development of age-related diseases.

We have demonstrated that proteins participating in mitochondrial fusion, such as Mfn2 and the protease OMA1, are relevant regulators of metabolism and that their deficiency causes alterations such as insulin resistance or obesity. Thus, we have reported that Mfn2 in liver, muscle, and the hypothalamus plays a key role in metabolic homeostasis. Mfn2 deficiency represses mitochondrial respiration and triggers ROS production and endoplasmic reticulum stress in various cell contexts. These effects lead to deficient insulin signalling in skeletal muscle and liver, and to glucose intolerance.

We are currently using cell-based models and knockout mice to study the metabolic role of other relevant proteins in mitochondrial dynamics. In addition, we are analysing the mechanisms by which mitochondrial dynamics proteins alter mitochondrial function, paying special attention to the function of the protein on the mitochondrial-endoplasmic reticulum connections.

2. Role of interplay between autophagy, mitochondrial function, and energy metabolism.

We have identified a new regulator of autophagy named DOR (also TP53INP2), which operates in mammalian cells, flies, and mouse skeletal muscle. Found in autophagosomes under conditions of activated autophagy, DOR binds to Atg8 proteins, LC3, and GATE16. In addition, it activates autophagy in mammalian cells and in mouse skeletal muscle. Data from our laboratory also indicate that DOR regulates muscle mass in mice via the modulation of autophagy.

At present, we are addressing whether DOR participates in energy metabolism and in normal mitochondrial function. IN this regard, we plan to perform a specific analysis of the molecular mechanisms of DOR functions.

3. Identification of novel targets and development of new compounds for the treatment of metabolic disorders.

We aim to explore the innovation capacities of our mechanistic findings. At present, our therapeutic hypothesis is that the activation of Mfn2 will produce effects in tissues, which will be of therapeutic benefit to diabetic or obese patients and those affected by Charcot-Marie-Tooth type 2A neuropathy (caused by mutations in the MFN2 gene).

We have developed and validated a screening strategy to search for activators of Mfn2 in human cells. This screening protocol with a small chemical library has allowed the identification of a compound that induces Mfn2 expression. Studies in human and in mouse cell cultures have demonstrated that this compound increases the elongation of mitochondria, enhances the expression of Mfn2, and boostsmitochondrial membrane potential. These observations provide a proof of concept for the future identification of Mfn2 activators through our screening method.

Hernández-Alvarez MI, Díaz-Ramos A, Berdasco M, Cobb J, Planet E, Cooper D, Pazderska A, Wanic K, O'Hanlon D, Gomez A, de la Ballina LR, Esteller M, Palacin M, O'Gorman DJ, Nolan JJ and Zorzano A.
Sci Rep, 7 (1), 13850 (2017)
Trempolec N, Muñoz JP, Slobodnyuk K, Marin S, Cascante M, Zorzano A and Nebreda AR.
Sci Rep, 7 (1), 11367 (2017)
Kulkarni SS, Joffraud M, Boutant M, Ratajczak J, Gao AW, Maclachlan C, Hernandez-Alvarez MI, Raymond F, Metairon S, Descombes P, Houtkooper RH, Zorzano A and Cantó C.
Diabetes, (2016)
Zamudio-Vázquez R, Ivanova S, Moreno M, Hernandez-Alvarez MI, Giralt E, Bidon-Chanal A, Zorzano A, Albericio F and Tulla-Puche J
Chem Sci, 6 (8), 4537-4549 (2015)
Sala D, Ivanova S, Plana N, Ribas V, Duran J, Bach D, Turkseven S, Laville M, Vidal H, Karczewska-Kupczewska M, Kowalska I, Straczkowski M, Testar X, Palacín M, Sandri M, Serrano AL and Zorzano A.
J Clin Invest, 124 (5), 1914-27 (2014)
Muñoz JP, Ivanova S, Sánchez-Wandelmer J, Martínez-Cristóbal P, Noguera E, Sancho A, Díaz-Ramos A, Hernández-Alvarez MI, Sebastián D, Mauvezin C, Palacín M and Zorzano A.
Embo J, 32 (17), 2348-61 (2013)
Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Castaño C, Garcia A, Esteban Y, Gonzalez-Franquesa A, Rodríguez IC, Bortolozzi A, Garcia-Roves PM, Gomis R, Nogueiras R, Horvath TL, Zorzano A and Claret M.
Cell, 155 (1), 172-87 (2013)
Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Orešič M, Pich S, Burcelin R, Palacín M and Zorzano A.
P Natl Acad Sci Usa, 109 (14), 5523-8 (2012)
Francis VA, Zorzano A* and Teleman AA*
Curr Biol, 20 (20), 1799-808 (2010)
Mauvezin C, Orpinell M, Francis VA, Mansilla F, Duran J, Ribas V, Palacín M, Boya P, Teleman AA and Zorzano A.
Embo Rep, 11 (1), 37-44 (2010)

* shared senior authorship

The group receives financial support from the following:

  • Generalitat de Catalunya (Government of Catalonia)
  • Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad (Spanish National Institute of Health)
  • European Foundation for the Study of Diabetes (EFSD)
  • Ministerio de Economía y Competitividad (MINECO)
  • European Commission (EC), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa"

     

Highlighted Projects
  • Mechanisms of prevention of type 2 diabetes by lifestyle intervention in subjects with pre-diabetes or at high-risk for progression (DEXLIFE). Grant agreement no: 279228; http://dexlife.eu

People

Group news & mentions

17 Oct 2017

More than seven hundred experts from around the world are taking part in the first edition of the 1st Joint Meeting of the French-Portuguese Spanish Biochemical and Molecular and Biology Societies 

17 Oct 2017

Several media, including Canal Diabetes, has dedicated an article to the first joint meeting of the French, Portuguese and Spanish Biochemistry and Molecular Biology Societies (FEBS3+), which will

<p>Fluorescence microscopy image of the hypothalamus arcuate nucleus with POMC neurons in green (Image: Alicia G Gómez-Valadés).</p>
27 Jun 2017

Radio 5 (RNE) interviews Marc Claret, head of the Neuronal Metabolism Control Group at the August Pi i Sunyer Biomedical Research Institute – IDIBAPS, on the occasion of his recent study on the con

<p>Image: Diabetes UK.</p>
8 Jun 2017

The Global Diabetes Community, Diabetes UK, echoes on the study performed by IRB Barcelona and IDIBAPS scientists.

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