Yesterday afternoon my interest was caught by a study that was submitted for a “young investigator award” from the Asian Pacific Congress of Nephrology. It is published in abstract form in the supplement of Nephrology, September 2016. The study is entitled “Mitochondrial dysfunction contributes to cyst proliferation of autosomal dominant polycystic kidney disease” and I believe it was undertaken at the University of Tokyo, though the author details include Harvard, US and Cambridge, UK.
Mitochondria are fascinating little things, they look like miniature sea-puddings inside the cell. However while sea-puddings are sluggish sedentary creatures, mitochondria are the energy power plants of the cell, involved in signalling, cell growth and eventually cell death.
The name “mitochondrium” comes from “mito” meaning thread and “chondrium” meaning granule-like, and they were first seen in 1894.
Almost all of our cells have mitochondria and amazingly, they are all inherited from our Mother alone – which makes sense when you realise that the sperm just delivers the nucleus alone into the egg.
I have drawn a diagram of the structure above. You can see there is a double membrane and it is this fact that led biologists to believe that originally way back in time the mitochondria were perhaps bacteria-like organisms that came to live symbiotically inside animal cells. The outer membrane has integral proteins embedded in it that act as little pores ( ‘porins’) allowing ions and small molecules to pass through. The inner membrane is highly convoluted by cristae to increase its surface area and this is where the energy production takes place.
Relevant to the study is the fact that mitochondria contain their own DNA (mitDNA) a circular chromosome that encodes for proteins essential for the energy production. This DNA can be measured as ‘mitDNA copy number’, a figure that reflects the stability of the mitochondria. Reduced mitDNA copy number is associated with mitochondrial dysfunction.
Cysts in ADPKD behave in some ways like solid tumours. It has been found that the mitochondria in tumour cells differ from those in healthy cells. Tumour cells generally have a lower mitDNA copy number. So the study authors decided to look at the mitochondria found in cyst epithelial cells. They used both rat models of ADPKD and human ADPKD epithelial cells grown in culture.
In both rat and human ADPKD cells the mitochondria were found to be swollen and fragmented and to contain fewer mitDNA copy number.
They hypothesise that deranged mitochondrial biogenesis leads to an increase in reactive oxygen species inside the mitochondria (stress oxidation) which in turn leads to cellular proliferation.
They confirmed this hypothesis by treating the cells with a substance called MitoQ. This is an anti-oxidant, a bit like the Co-enzyme Q (frequently sold as an anti-aging supplement) but aimed specifically at mitochondria. Adding MitoQ to the cell cultures suppressed cell proliferation.
They also found that where the intracellular calcium levels were low, another substance called PGC-1alpha was also reduced and this chemical is a regulator of mitochondrial formation. We already know that calcium inside the cell is important in ADPKD and that polycystins are involved in calcium movements into the cell so it begins to link up theoretically.
The bottom line of this piece of research is that mitochondria could be a new therapeutic target for ADPKD.
Mitochondrial dysfunction contributes to cyst proliferation of ADPKD. Ishimoto Y, Nangaku M, Nagao S et al. (2016) APSN young investigator award – basic science. NEphrology, 21;40-42.