title: G protein coupled receptor kinase 2 interacting protein 1 (GIT1) is a novel regulator of mitochondrial biogenesis in heart.
abstract: G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multi-function scaffold protein. However, little is known about its physiological role in the heart. Here we sought to identify the cardiac function of GIT1. Global GIT1 knockout (KO) mice were generated and exhibited significant cardiac hypertrophy that progressed to heart failure. Electron microscopy revealed that the hearts of GIT1 KO mice demonstrated significant morphological abnormities in mitochondria, including decreased mitochondrial volume density, cristae density and increased vacuoles. Moreover, mitochondrial biogenesis-related gene peroxisome proliferator-activated receptor γ (PPARγ) co-activator-1α (PGC-1α), PGC-1β, mitochondrial transcription factor A (Tfam) expression, and total mitochondrial DNA were remarkably decreased in hearts of GIT1 KO mice. These animals also had impaired mitochondrial function, as evidenced by reduced ATP production and dissipated mitochondrial membrane potential (Ψ(m)) in adult cardiomyocytes. Concordant with these mitochondrial observations, GIT1 KO mice showed enhanced cardiomyocyte apoptosis and cardiac dysfunction. In conclusion, our findings identify GIT1 as a new regulator of mitochondrial biogenesis and function, which is necessary for postnatal cardiac maturation.
authors.affiliation: Aab Cardiovascular Research Institute, Rochester, NY 14642, USA. Jinjiang_pang@URMC.rochester.edu
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Pang
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Getman
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Belmonte
authors.forename: Heidi
authors.initials: H
authors.lastname: Michaloski
authors.forename: Amy
authors.initials: A
authors.lastname: Mohan
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D000255:Adenosine Triphosphate