Tuesday, 4 February 2014

Mitochondria supply membranes for autophagosome biogenesis during starvation


During starvation, autophagy is increased so that the cell can degrade its own components to retrieve nutrients. But where do the membranes that form the autophagosomes come from?

In this paper, they show that lipids for forming autophagosomes come from the outer membrane of mitochondria. The forming of autophagosomes is inhibited if cells lack MFN2, a protein necessary for mitochondrial fusion and also for tethering mitochondria to the ER. They think that the ER can resupply lipids to the mitochondrion (to make up for the lipids it lost to form the autophagosomal membrane (AM)).  But doesn't the mitochondrion lose its outer membrane proteins by using part of his membrane to form AMs? Apparently it does not. Most outer membrane proteins of mitochondria are not seen in the AM, which is hypothesized to be the result of a diffusion barrier for proteins. Only proteins associated with the outer leaflet of the outer mitochondrial membrane can traverse the barrier.

Interestingly, lipids from mitochondria only play a role in forming AMs if forming of autophagosomes is induced by starvation. Other mechanisms that induce autophagy (e.g. ER stress and calcium perturbations) do not show mitochondrial outer membrane components colocalized with EM.

Stimulus-triggered fate conversion of somatic cells into pluripotency

Stimulus-triggered fate conversion of somatic cells into pluripotency

A surprising new way to generate stem cells has been presented by Obokata et al. The authors found that low-pH stress applied to cells from various tissues, when grown in a medium supplemented with leukaemia inhibtory factor (LIF) and B27, causes the formation of pluripotent cells which are named "stimulus-triggered acquisition of pluripotency" (STAP) cells. Other stress stimuli, such as physical damage, also induced the formation of STAP cells, but low-pH was the most efficient. They worked with Oct4-gfp transgene mouse lymphocytes, which allowed the monitoring of the expression levels of the pluripotency marker Oct4, according to the amount of observed fluorescence in the cells. They found extensive demethylation in Oct4 and another pluripotency gene Nanog, in STAP cells, suggesting substantial epigenetic modification during physical stress.

When STAP cells were grafted into mice they formed teratomas, which are non-malignant encapsulated tumors with tissue or organ components resembling normal derivatives of more than one germ layer. Once parental STAP cells were formed, if they were grown in a medium used to grow embryonic stem (ES) cells, STAP stem cells were formed. These have unlimited proliferative potential and behave very much like ES cells. After blastocyst injection, STAP stem cells efficiently contributed to chimeric mice, and in differentiation culture generated: ectodermal, mesodermal and endodermal derivatives in vitro, including beating cardiac tissue. The precise mechanism of how these somatic cells gained pluripotency after physical stress is still a mystery, but raises many questions such as: how is this reprogramming mechanism normally repressed? and what epigenetic mechanism unites such disparate physical stresses to cause this response?

This article was retracted on 03 July 2014

Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging

Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging

Mitochondrial reactive oxygen species (ROS) accumulation is thought to participate in a vicious cycle of oxidative damage in aging. Damaged mtDNA results in a faulty respiratory chain, causing ROS generation, which may further damage the mtDNA, and so on. In this review, the authors discuss some of the mechanisms of mitochondrial dysfunction in aging, and potential ways this may be regulated. In particular, calorie restriction has been observed to reduce age-related phenotypes. The authors present evidence supporting the claim that a family of deacetylases called sirtuins, which commonly modify mitochondrial proteins, are responsible for this. The authors also discuss how low-levels of ROS are important for autophagic signalling, a pro-cell survival response which recycles damaged organelles. Loss of this quality control has been shown in aging and aging-related disorders such as neurodegenerative diseases.