title: SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress.
abstract: Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. There is significant evidence suggesting a stringent association between morphology and bioenergetics of mitochondria. Morphological alterations in mitochondria are linked to several pathological disorders, including cardiovascular diseases. The consequences of stress-induced acetylation of mitochondrial proteins on the organelle morphology remain largely unexplored. Here we report that OPA1, a mitochondrial fusion protein, was hyperacetylated in hearts under pathological stress and this posttranslational modification reduced the GTPase activity of the protein. The mitochondrial deacetylase SIRT3 was capable of deacetylating OPA1 and elevating its GTPase activity. Mass spectrometry and mutagenesis analyses indicated that in SIRT3-deficient cells OPA1 was acetylated at lysine 926 and 931 residues. Overexpression of a deacetylation-mimetic version of OPA1 recovered the mitochondrial functions of OPA1-null cells, thus demonstrating the functional significance of K926/931 acetylation in regulating OPA1 activity. Moreover, SIRT3-dependent activation of OPA1 contributed to the preservation of mitochondrial networking and protection of cardiomyocytes from doxorubicin-mediated cell death. In summary, these data indicated that SIRT3 promotes mitochondrial function not only by regulating activity of metabolic enzymes, as previously reported, but also by regulating mitochondrial dynamics by targeting OPA1.
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, USA.
authors.forename: Sadhana A
authors.initials: SA
authors.lastname: Samant
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Zhang
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.forename: Donald
authors.initials: D
authors.lastname: Wolfgeher
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D000107:Acetylation; D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006321:Heart / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D056566:Sirtuin 3; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse