title: Extracellular regulated kinase phosphorylates mitofusin 1 to control mitochondrial morphology and apoptosis.
abstract: Controlled changes in mitochondrial morphology participate in cellular signaling cascades. However, the molecular mechanisms modifying mitochondrial shape are largely unknown. Here we show that the mitogen-activated protein (MAP) kinase cascade member extracellular-signal-regulated kinase (ERK) phosphorylates the pro-fusion protein mitofusin (MFN) 1, modulating its participation in apoptosis and mitochondrial fusion. Phosphoproteomic and biochemical analyses revealed that MFN1 is phosphorylated at an atypical ERK site in its heptad repeat (HR) 1 domain. This site proved essential to mediate MFN1-dependent mitochondrial elongation and apoptosis regulation by the MEK/ERK cascade. A mutant mimicking constitutive MFN1 phosphorylation was less efficient in oligomerizing and mitochondria tethering but bound more avidly to the proapoptotic BCL-2 family member BAK, facilitating its activation and cell death. Moreover, neuronal apoptosis following oxygen glucose deprivation and MEK/ERK activation required an intact MFN1(T562). Our data identify MFN1 as an ERK target to modulate mitochondrial shape and apoptosis.
authors: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.
authors: Aswin
authors: A
authors: Pyakurel
authors: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy.
authors: Claudia
authors: C
authors: Savoia
authors: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors: Daniel
authors: D
authors: Hess
authors: Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy. Electronic address: luca.scorrano@unipd.it.
authors: Luca
authors: L
authors: Scorrano
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008565:Membrane Proteins; C489709:Mfn1 protein, rat; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse