title: Overexpression of TNF-α in mitochondrial diseases caused by mutations in mtDNA: evidence for signaling through its receptors on mitochondria.
abstract: Mitochondrial diseases (MDs) are heterogeneous disorders due to impaired respiratory chain function causing defective ATP production. Although the disruption of oxidative phosphorylation is central to the MD pathophysiology, other factors may contribute to these disorders. We investigated the expression and the cellular localization of TNF-α and its receptors, TNFR1 and TNFR2, in muscle biopsies from 15 patients with mitochondrial respiratory chain dysfunction. Our data unambiguously demonstrate that TNF-α is expressed in muscle fibers with abnormal focal accumulations of mitochondria, so-called ragged red fibers, and is delivered to mitochondria where both receptors are localized. Moreover TNF receptors are differentially regulated in patients' muscle in which the expression levels of TNFR1 mRNA are decreased and those of TNFR2 mRNA are increased compared with controls. These findings suggest for the first time that TNF-α could exert a direct effect on mitochondria via its receptors.
authors.affiliation: Section of Clinical Neurology, Department of Neurological, Neuropsychological, Morphological, and Movement Sciences, University of Verona, 37134 Verona, Italy. gaetano.vattemi@univr.it
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vattemi
authors.forename: Matteo
authors.initials: M
authors.lastname: Marini
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Ferreri
authors.forename: Shoujin
authors.initials: S
authors.lastname: Hao
authors.forename: Manuela
authors.initials: M
authors.lastname: Malatesta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Meneguzzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Guglielmi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Fava
authors.forename: Pietro
authors.initials: P
authors.lastname: Minuz
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
mesh_terms: D001706:Biopsy; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010085:Oxidative Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha
keywords: COX; CPEO; Chronic progressive external ophthalmoplegia; Cytochrome c oxidase; Free radicals; MD; MELAS; MERRF; Mitochondria; Mitochondrial disease; Mitochondrial diseases; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; Myoclonic epilepsy with ragged red fibers; OXPHOS; Oxidative phosphorylation; Quantitative real-time PCR; ROS; Reactive oxygen species; SDH; Succinate dehydrogenase; TNF receptor type 1; TNF receptor type 2; TNF-α; TNFR1; TNFR2; Tumor necrosis factor-α; qRT-PCR