Effect of p53 on mitochondrial morphology, import, and assembly in skeletal muscle

Am J Physiol Cell Physiol. 2015 Feb 15;308(4):C319-29. doi: 10.1152/ajpcell.00253.2014. Epub 2014 Dec 3.

Abstract

The purpose of this study was to investigate whether p53 regulates mitochondrial function via changes in mitochondrial protein import, complex IV (COX) assembly, or the expression of key proteins involved in mitochondrial dynamics and degradation. Mitochondria from p53 KO mice displayed ultra-structural alterations and were more punctate in appearance. This was accompanied by protein-specific alterations in fission, fusion, and mitophagy-related proteins. However, matrix-destined protein import into subsarcolemmal or intermyofibrillar mitochondria was unaffected in the absence of p53, despite mitochondrial subfraction-specific reductions in Tom20, Tim23, mtHsp70, and mtHsp60 in the knockout (KO) mitochondria. Complex IV activity in isolated mitochondria was also unchanged in KO mice, but two-dimensional blue native-PAGE revealed a reduction in the assembly of complex IV within the IMF fractions from KO mice in tandem with lower levels of the assembly protein Surf1. This observed defect in complex IV assembly may facilitate the previously documented impairment in mitochondrial function in p53 KO mice. We suspect that these morphological and functional impairments in mitochondria drive a decreased reliance on mitochondrial respiration as a means of energy production in skeletal muscle in the absence of p53.

Keywords: cytochrome c oxidase assembly; fission/fusion; mitophagy; protein import machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cell Respiration
  • Chaperonin 60 / metabolism
  • Electron Transport Complex IV / metabolism
  • Energy Metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice, Knockout
  • Mitochondria, Muscle / metabolism*
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Dynamics*
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins / metabolism
  • Mitophagy
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / ultrastructure
  • Protein Transport
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Chaperonin 60
  • HSP70 Heat-Shock Proteins
  • Hspd1 protein, mouse
  • Membrane Proteins
  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Mitochondrial Proteins
  • Receptors, Cell Surface
  • Surf-1 protein
  • Timm23 protein, mouse
  • Tomm20 protein, mouse
  • Tumor Suppressor Protein p53
  • Electron Transport Complex IV