Interesting things are emerging recently about an axis between p53 (which turns out to be much more than a tumor suppressing pathway and very involved in metabolism as well) and various disorders like Parkinsons and diabetes:
http://www.ncbi.nlm....pubmed/23917356
http://www.pnas.org/...8/3116.full.pdf
... and most interestingly http://www.mdpi.com/...67/17/1/122/pdf
Although p53 has a well-documented role as a tumor suppressor, recent detailed studies have identified broader functions for p53 that are independent of its effects in tumorigenesis. p53 had been shown to regulate the transcription of several genes involved in redox and glucose metabolism and autophagy (5, 6). It also possesses an extranuclear function in which cytosolic p53 inhibits the process of autophagy by a poorly known mechanism (7). We have previously demonstrated the contribution of p53 to mitochondrial integrity. p53 is required for mitochondrial aerobic respiration through the expression of SCO2 (8). Conversely, cytosolic p53 has been shown to disturb the clearance of damaged mitochondria by an inhibitory interaction with Parkin (9). Other recent studies have also revealed that p53 has a distinct cellular function according to its cellular concentration and distribution (10).
Thus, p53-mediated inhibition of mitophagy modulates cardiac dysfunction, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and symptoms of cardiac ageing.
And some insight about yet another way Metformin might work by decreasing p53 expression, inducing mitophagy:
Cytosolic p53 inhibited mitophagy by disturbing the mitochondrial translocation of Parkin, as demonstrated by immunoprecipitation.
However, metformin decreased ER stress and p53 expression, resulting in induction of Parkin-mediated mitophagy. Furthermore, pifithrin-α, a specific inhibitor of p53, increased mitochondrial incorporation into autophagosomes. Taken together, these results indicate that metformin treatment facilitates Parkin-mediated mitophagy rather than mitochondrial spheroid formation by decreasing the inhibitory interaction with cytosolic p53 and increasing degradation of mitofusins.
Increased p53 is seen in senescent insulin resistant adipocytes (http://www.ncbi.nlm....pubmed/19718037)
Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).
So this may be either the way or another way Metformin works in reducing hyperglycemia.
Basically, what this might say is that p53 is (sometimes) inhibiting mitophagy, and bad mitochondria cannot be removed. p53 has put the cell into a senescent state, and it's not doing you any good, either. All the COQ10, buckyballs, and mitoQ won't beat the process of getting rid of the bad mitochondria to begin with.
It's interesting, that "p53 amyloids/aggregates" also exist, but this is possibly unrelated: http://www.ncbi.nlm....pubmed/22715097. "Other recent studies have also revealed that p53 has a distinct cellular function according to its cellular concentration and distribution (10)."
This probably does have implications for Parkinsons.
Edited by Logjam, 25 April 2016 - 03:04 PM.