Maternally-inherited Leigh syndrome-related mutations bolster mitochondrial-mediated apoptosis

Journal of Neurochemistry
Rosalba CarrozzoPaola Matarrese

Abstract

The key role of mitochondria in the apoptotic process is well understood, but not many data are available regarding the specific role of mitochondrial DNA mutations in determining cell fate. We investigated whether two mitochondrial DNA mutations (L217R and L156R) associated with maternally-inherited Leigh syndrome may play a specific role in triggering the apoptotic cascade. Considering that different nuclear genetic factors may influence the expression of mtDNA mutations, we used a 143BTK(-) osteosarcoma cell line deprived from its own mtDNA in order to insert mutated mtDNAs. Analysis of mitochondrial features in these cybrids indicated that both mitochondrial DNA mutations produced evidence of biochemical, functional and ultrastructural modifications of mitochondria, and that these modifications were associated with an increased apoptotic proneness. Cybrids were highly susceptible to two different apoptotic stimuli, tumour necrosis factor-alpha and Staurosporin. The mechanism involved was the mitochondrial 'intrinsic' pathway, i.e. the caspase 9-driven cascade. More importantly, our results also indicated that the polarization state of the mitochondrial membrane, i.e. a constitutive hyperpolarization detected in cybrid clone...Continue Reading

Citations

Jul 6, 2014·Human Molecular Genetics·Ester López-GallardoJulio Montoya
Nov 10, 2006·International Journal of Cardiology·Perundurai S DhandapanyKumarasamy Thangaraj
Jan 23, 2009·Journal of Cellular Biochemistry·Martha Elisa Vazquez-MemijeRosalba Carrozzo
Apr 17, 2016·Mitochondrion·Katarzyna NiedzwieckaRoza Kucharczyk
Nov 1, 2011·The International Journal of Biochemistry & Cell Biology·Guillaume RommelaerePatricia Renard
Apr 1, 2009·Biochemical and Biophysical Research Communications·Teresa RizzaRosalba Carrozzo
May 18, 2016·Mitochondrion·Josef Finsterer, Marlies Frank
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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis