title: Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes.
abstract: Human age-related diseases, including obesity and type 2 diabetes (T2DM), have long been associated to mitochondrial dysfunction; however, the role for adipose tissue mitochondria in these conditions remains unknown. We have tackled the impact of aging and T2DM on adipocyte mitochondria from obese patients by quantitating not only the corresponding abundance changes of proteins, but also the redox alterations undergone by Cys residues thereof. For that, we have resorted to a high-throughput proteomic approach based on isobaric labeling, liquid chromatography and mass spectrometry. The alterations undergone by the mitochondrial proteome revealed aging- and T2DM-specific hallmarks. Thus, while a global decrease of oxidative phosphorylation (OXPHOS) subunits was found in aging, the diabetic patients exhibited a reduction of specific OXPHOS complexes as well as an up-regulation of the anti-oxidant response. Under both conditions, evidence is shown for the first time of a link between increased thiol protein oxidation and decreased protein abundance in adipose tissue mitochondria. This association was stronger in T2DM, where OXPHOS mitochondrial- vs. nuclear-encoded protein modules were found altered, suggesting impaired mitochondrial protein translocation and complex assembly. The marked down-regulation of OXPHOS oxidized proteins and the alteration of oxidized Cys residues related to protein import through the redox-active MIA (Mitochondrial Intermembrane space Assembly) pathway support that defects in protein translocation to the mitochondria may be an important underlying mechanism for mitochondrial dysfunction in T2DM and physiological aging. The present draft of redox targets together with the quantification of protein and oxidative changes may help to better understand the role of oxidative stress in both a physiological process like aging and a pathological condition like T2DM.
authors.affiliation: Instituto de Investigaciones Biomédicas, Alberto Sols, (IIBM); Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28029, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Gómez-Serrano
authors.affiliation: Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Camafeita
authors.affiliation: Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: López
authors.affiliation: Department of Endocrinology, Hospital Clínico San Carlos (IDISSC), Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Rubio
authors.affiliation: Department of Endocrinology and Nutrition, Hospital General Universitario Gregorio Marañón (IISGM), Madrid 28007, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Bretón
authors.affiliation: Instituto de Investigación, Hospital Universitario 12 de Octubre (i+12), Madrid 28041, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723, Madrid 28029, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: García-Consuegra
authors.affiliation: Instituto de Investigaciones Biomédicas, Alberto Sols, (IIBM); Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28029, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: García-Santos
authors.affiliation: Department of Surgery, Hospital General Universitario Gregorio Marañón (IISGM), Madrid 28007, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Lago
authors.affiliation: Department of Surgery, Hospital Clínico San Carlos (IDISSC), Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Sánchez-Pernaute
authors.affiliation: Department of Surgery, Hospital Clínico San Carlos (IDISSC), Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.affiliation: Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Instituto de Investigaciones Biomédicas, Alberto Sols, (IIBM); Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid (CSIC-UAM), Madrid 28029, Spain. Electronic address: bperal@iib.uam.es.
authors.forename: Belén
authors.initials: B
authors.lastname: Peral
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D021381:Protein Transport / Q000235:genetics; D020543:Proteome / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D024101:Mitochondrial Proteins; D020543:Proteome; D013438:Sulfhydryl Compounds
keywords: Adipose tissue; Mitochondria; OXPHOS; Redox proteomics; Thiol oxidation; Type 2 diabetes