Amyloid β binds procaspase-9 to inhibit assembly of Apaf-1 apoptosome and intrinsic apoptosis pathway
Amyloid-β (Aβ) is a family of 36-43 amino-acids which form aggregates in the brains of Alzheimer's patients. The expression of Aβ has been linked to apoptosis in other studies, although the precise mechanism is poorly understood. For the first time, however, the authors of this study report that Aβ42 can actually inhibit apoptosis. Their experiments found that caspase activation and cell death induced by stauroporine (which activates the intrinsic pathway) was inhibited by Aβ42 somewhere between cytochrome c release and procaspase-9 activation. The authors suggest the mechanism is Aβ42 competing with Apaf-1 for procaspase-9 binding, which causes inhibition of the apoptosome. The effect was time-dependent (longer incubation times resulting in apoptosis), which suggests an initial transient period where the cell attempts to resist cell death in the presence of Aβ42. The effect was most prevalent in HeLa cells, but was also observed to a lesser extent in MG63 and SHSY5Y cell lines.
Monday 27 January 2014
Tuesday 14 January 2014
The Mitochondrial Proteome and Human Disease
The Mitochondrial Proteome and Human Disease
Defining the mitochondrial proteome is not a straightforward task: not all mitochondrial proteins possess a targeting sequence to direct their import into the organelle; abundance spans 6 orders of magnitude; and almost half of mitochondrial proteins are distributed in a tissue-specific manner. Surprisingly, it appears that complexes I, II, III and V are found in high abundance across many tissues but complex IV has a fair number of subunits which are expressed in a tissue-dependent manner, as well as many of the mitochondrial ribosome subunits. The most successful way of determining the mitochondrial proteome to date, has been with mass spectrometry by purifying mitochondrial extracts. It is believed that 1100-1400 distinct gene loci encode mitochondrial proteins, but these may also have splice isoforms. The authors also provide a list of useful online databases for mitochondrial proteins.
The authors discuss how the definition of mitochondrial disease has expanded from disorders of oxidative ATP production, to include diseases such as soft tissue tumours and diabetes mellitus. They suggest that a promising avenue to elucidate mitochondrial disorders is to combine disease genes, clinical features and biological pathways.
Defining the mitochondrial proteome is not a straightforward task: not all mitochondrial proteins possess a targeting sequence to direct their import into the organelle; abundance spans 6 orders of magnitude; and almost half of mitochondrial proteins are distributed in a tissue-specific manner. Surprisingly, it appears that complexes I, II, III and V are found in high abundance across many tissues but complex IV has a fair number of subunits which are expressed in a tissue-dependent manner, as well as many of the mitochondrial ribosome subunits. The most successful way of determining the mitochondrial proteome to date, has been with mass spectrometry by purifying mitochondrial extracts. It is believed that 1100-1400 distinct gene loci encode mitochondrial proteins, but these may also have splice isoforms. The authors also provide a list of useful online databases for mitochondrial proteins.
The authors discuss how the definition of mitochondrial disease has expanded from disorders of oxidative ATP production, to include diseases such as soft tissue tumours and diabetes mellitus. They suggest that a promising avenue to elucidate mitochondrial disorders is to combine disease genes, clinical features and biological pathways.
Homogeneous longitudinal profiles and synchronous fluctuations of mitochondrial transmembrane potential
http://www.sciencedirect.com/science/article/pii/S0014579300016835
What they did in this paper is measure the membrane potential along a mitochondrion, so along its longitudinal axis. They did this for about 80 mitochondria.
What they find is that within a mitochondrion, the membrane potential is more or less the same, the variations are around 5 mV. Interestingly, the points at the ends of the mitochondria were usually (in 78% of the cases) extrema. So it often occurred that the potential at the ends was either the minimum potential along the whole mitochondria, or the maximum. This maybe could have something to do with the ends being involved in fusion/fission processes.
They also find that the fluctuations in potential in mitochondria that are connected in the network occur simultaneously.
Another interesting thing is that they find that the potential does not depend on where in the cytosol the mitochondria are. This sort of contradicts other findings that the membrane potential depends on the localization of the mitochondrion in the cell (see e.g. http://www.pnas.org/content/88/9/3671.abstract)
Another thing that they mention (they don't measure this themselves) is that even if mitochondria don't have DNA, they still keep their membrane potential intact by using their ATP synthase in reverse. The ATP that is needed for this comes from glycolysis. But now the mitochondria are just things in the cell using up ATP and not generating anything at all, so I was wondering why they maintain their membrane potential at all. I guess the cell doesn't want to kill all its mitochondria if they don't work for a while..
What they did in this paper is measure the membrane potential along a mitochondrion, so along its longitudinal axis. They did this for about 80 mitochondria.
What they find is that within a mitochondrion, the membrane potential is more or less the same, the variations are around 5 mV. Interestingly, the points at the ends of the mitochondria were usually (in 78% of the cases) extrema. So it often occurred that the potential at the ends was either the minimum potential along the whole mitochondria, or the maximum. This maybe could have something to do with the ends being involved in fusion/fission processes.
They also find that the fluctuations in potential in mitochondria that are connected in the network occur simultaneously.
Another interesting thing is that they find that the potential does not depend on where in the cytosol the mitochondria are. This sort of contradicts other findings that the membrane potential depends on the localization of the mitochondrion in the cell (see e.g. http://www.pnas.org/content/88/9/3671.abstract)
Another thing that they mention (they don't measure this themselves) is that even if mitochondria don't have DNA, they still keep their membrane potential intact by using their ATP synthase in reverse. The ATP that is needed for this comes from glycolysis. But now the mitochondria are just things in the cell using up ATP and not generating anything at all, so I was wondering why they maintain their membrane potential at all. I guess the cell doesn't want to kill all its mitochondria if they don't work for a while..
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