title: Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting.
abstract: Alterations in muscle mitochondrial bioenergetics during cancer cachexia were previously suggested; however, the underlying mechanisms are not known. So, the goal of this study was to evaluate mitochondrial phospholipid remodeling in cancer-related muscle wasting and its repercussions to respiratory chain activity and fiber susceptibility to apoptosis. An animal model of urothelial carcinoma induced by exposition to N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and characterized by significant body weight loss due to skeletal muscle mass decrease was used. Morphological evidences of muscle atrophy were associated to decreased respiratory chain activity and increased expression of mitochondrial UCP3, which altogether highlight the lower ability of wasted muscle to produce ATP. Lipidomic analysis of isolated mitochondria revealed a significant decrease of phosphatidic acid, phosphatidylglycerol and cardiolipin in BBN mitochondria, counteracted by increased phosphatidylcholine levels. Besides the impact on membrane fluidity, this phospholipid remodeling seems to justify, at least in part, the lower oxidative phosphorylation activity observed in mitochondria from wasted muscle and their increased susceptibility to apoptosis. Curiously, no evidences of lipid peroxidation were observed but proteins from BBN mitochondria, particularly the metabolic ones, seem more prone to carbonylation with the consequent implications in mitochondria functionality. Overall, data suggest that bladder cancer negatively impacts skeletal muscle activity specifically by affecting mitochondrial phospholipid dynamics and its interaction with proteins, ultimately leading to the dysfunction of this organelle. The regulation of phospholipid biosynthetic pathways might be seen as potential therapeutic targets for the management of cancer-related muscle wasting.
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Antunes
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Padrão
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Maciel
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Deolinda
authors.initials: D
authors.lastname: Santinha
authors.affiliation: School of Agrarian Sciences, Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro, Vila Real, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Oliveira
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Vitorino
authors.affiliation: Faculty of Sports, University of Porto, Porto, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Moreira-Gonçalves
authors.affiliation: School of Agrarian Sciences, Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro, Vila Real, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Colaço
authors.affiliation: School of Agrarian Sciences, Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro, Vila Real, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Pires
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Nunes
authors.affiliation: Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.
authors.forename: Lúcio L
authors.initials: LL
authors.lastname: Santos
authors.affiliation: Health School of Sciences, University of Aveiro, Aveiro, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Amado
authors.affiliation: Faculty of Sports, University of Porto, Porto, Portugal.
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Duarte
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal.
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: Domingues
authors.affiliation: Department of Chemistry, University of Aveiro, Aveiro, Portugal. Electronic address: ritaferreira@ua.pt.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity; D004734:Energy Metabolism / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D000071247:Uncoupling Protein 3; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D002085:Butylhydroxybutylnitrosamine; D000255:Adenosine Triphosphate
keywords: Apoptosis; Bladder cancer; Gastrocnemius atrophy; OXPHOS impairment