Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease.

نویسندگان

  • Rosa Pello
  • Miguel A Martín
  • Valerio Carelli
  • Leo G Nijtmans
  • Alessandro Achilli
  • Maria Pala
  • Antonio Torroni
  • Aurora Gómez-Durán
  • Eduardo Ruiz-Pesini
  • Andrea Martinuzzi
  • Jan A Smeitink
  • Joaquín Arenas
  • Cristina Ugalde
چکیده

Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disorder, is mostly due to three mitochondrial DNA (mtDNA) mutations in respiratory chain complex I subunit genes: 3460/ND1, 11778/ND4 and 14484/ND6. Despite considerable clinical evidences, a genetic modifying role of the mtDNA haplogroup background in the clinical expression of LHON remains experimentally unproven. We investigated the effect of mtDNA haplogroups on the assembly of oxidative phosphorylation (OXPHOS) complexes in transmitochondrial hybrids (cybrids) harboring the three common LHON mutations. The steady-state levels of respiratory chain complexes appeared normal in mutant cybrids. However, an accumulation of low molecular weight subcomplexes suggested a complex I assembly/stability defect, which was further demonstrated by reversibly inhibiting mitochondrial protein translation with doxycycline. Our results showed differentially delayed assembly rates of respiratory chain complexes I, III and IV amongst mutants belonging to different mtDNA haplogroups, revealing that specific mtDNA polymorphisms may modify the pathogenic potential of LHON mutations by affecting the overall assembly kinetics of OXPHOS complexes.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Novel Missense Mitochondrial ND4L Gene Mutations in Friedreich's Ataxia

Objective(s) The mitochondrial defects in Friedreich's ataxia have been reported in many researches. Mitochondrial DNA is one of the candidates for defects in mitochondrion, and complex I is the first and one of the largest catalytic complexes of oxidative phosphorylation (OXPHOS) system. Materials and Methods We searched the mitochondrial ND4L gene for mutations by TTGE and sequencing on 30...

متن کامل

O-9: The Central Role of Mitochondrial Function in Quality of Human Oocyte

Background: Mitochondria are the most aboudent and small essential organelles found in eukaryotic cells. These are semiautonomous organelles for the production of cellular ATP that through its various biochemical pathways. The primary pathway for ATP production is OXPHOS via the electron transfer chain (ETC) which is encoded by nuclear DNA and mtdna genomes. Mitochondria consist of double stran...

متن کامل

OXPHOS mutations and neurodegeneration.

Mitochondrial oxidative phosphorylation (OXPHOS) sustains organelle function and plays a central role in cellular energy metabolism. The OXPHOS system consists of 5 multisubunit complexes (CI-CV) that are built up of 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encod...

متن کامل

The Effect of Fibroblast Growth Factor 21 on a Cellular Model of Alzheimer's Disease with Emphasis on Cell Viability and Mitochondrial Membrane Potential

Background and Objective: Alzheimer’s disease (AD) is a neurodegenerative disorder which is associated with extracellular accumulation of amyloid beta (Aβ) plaques. AD is accompanied by mitochondrial dysfunction and energy metabolism reduction. Fibroblast growth factor 21 (FGF21) is an endogenous polypeptide which its beneficial effects have been demonstrated on mitochondrial function, energy m...

متن کامل

Oxidative phosphorylation: synthesis of mitochondrially encoded proteins and assembly of individual structural subunits into functional holoenzyme complexes.

The bulk of ATP consumed by various cellular processes in higher eukaryotes is normally produced by five multimeric protein complexes (I-V) embedded within the inner mitochondrial membrane, in a process known as oxidative phosphorylation (OXPHOS). Maintenance of energy homeostasis under most physiological conditions is therefore contingent upon the ability of OXPHOS to meet cellular changes in ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Human molecular genetics

دوره 17 24  شماره 

صفحات  -

تاریخ انتشار 2008