title: Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis.
abstract: Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.
authors: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors: F
authors: F
authors: Rossin
authors: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors: M
authors: M
authors: D'Eletto
authors: National Institute for Infectious Diseases I.R.C.C.S. 'L. Spallanzani', Rome, Italy.
authors: L
authors: L
authors: Falasca
authors: Department of Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: S
authors: S
authors: Sepe
authors: European Brain Research Institute (EBRI), Rita Levi-Montalcini Foundation, Rome, Italy.
authors: S
authors: S
authors: Cocco
authors: 1] National Institute for Infectious Diseases I.R.C.C.S. 'L. Spallanzani', Rome, Italy [2] Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy.
authors: G M
authors: GM
authors: Fimia
authors: 1] European Brain Research Institute (EBRI), Rita Levi-Montalcini Foundation, Rome, Italy [2] Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London and UCL Consortium for Mitochondrial Research (CfMR), London, UK.
authors: M
authors: M
authors: Campanella
authors: Department of Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: P G
authors: PG
authors: Mastroberardino
authors: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors: M G
authors: MG
authors: Farrace
authors: 1] Department of Biology, University of Rome 'Tor Vergata', Rome, Italy [2] National Institute for Infectious Diseases I.R.C.C.S. 'L. Spallanzani', Rome, Italy.
authors: M
authors: M
authors: Piacentini
mesh_terms: D000332:Aerobiosis; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004734:Energy Metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins