G protein coupled receptor kinase 2 interacting protein 1 (GIT1) is a novel regulator of mitochondrial biogenesis in heart

J Mol Cell Cardiol. 2011 Nov;51(5):769-76. doi: 10.1016/j.yjmcc.2011.06.020. Epub 2011 Jul 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis*
  • Animals
  • Animals, Newborn
  • Apoptosis / genetics
  • Cell Cycle Proteins* / deficiency
  • Cell Cycle Proteins* / genetics
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • GTPase-Activating Proteins* / deficiency
  • GTPase-Activating Proteins* / genetics
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Membrane Potential, Mitochondrial / genetics*
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Mitochondria, Heart / genetics
  • Mitochondria, Heart / metabolism*
  • Mitochondria, Heart / ultrastructure
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / ultrastructure
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Cell Cycle Proteins
  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • GTPase-Activating Proteins
  • Git1 protein, mouse
  • Mitochondrial Proteins
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • mitochondrial transcription factor A
  • Adenosine Triphosphate