Andras Kapus | St. Michael's Hospital

Altered mitochondrial dynamics and the underlying molecular mechanisms in Polycystic Kidney Disease

Lay Abstract

How do the power plants of the cells break up in polycystic kidney disease?

Background: Chronic kidney disease (CKD), characterized by the gradual loss of kidney function, is a common and devastating condition, affecting 12% of Canadians. Currently, there is no effective therapy to halt or reverse this process. The final stage of CKD necessitates transplantation or dialysis. The limited availability of transplantable kidneys, the significant complications of both interventions, the extremely high cost (e.g. for dialysis ˜ $100,000/year/patient), the loss of active years and, most importantly, the unsurmountable human suffering signify a major need for finding new therapies that stop disease progression. The most common causes of CKD are diabetes and high blood pressure, which induce kidney injury and chronic scarring or fibrosis. Importantly, CKD often develops on the basis of hereditary (genetic) conditions as well. The most common of these is polycystic kidney disease (PKD), which affects 1 in ˜500 people (˜66,000 Canadians), and over time leads to kidney failure. PKD is due to the loss or mutation of one of two proteins (PC1 or PC2), which are essential for the normal function of tubules. PKD has two mains features: the formation of large fluid-filled sacs or cysts (hence the name of the disease) and fibrosis (excessive scarring), which destroys the remaining kidney architecture. At the cellular level, one of the major abnormalities in PKD is the breaking up (fragmentation) of mitochondria, the energy producing power plants of the cells. Their damage alters metabolism and contributes to both cyst formation and scarring. However, the mechanism whereby PKD causes the break-up of mitochondria is not known.

Purpose: Our research program aims at understanding the fundamental question of how mitochondria, the power plants of the cells break into small pieces during PKD.

This knowledge is essential 1) to explain how specific disease-causing mutations lead to the reorganization of cellular structure and metabolism; 2) to develop therapies that protect mitochondria and thereby slow or stop the dire consequences of PKD, including cyst formation and fibrosis.

Approaches and Methods: Our previous studies have characterized key cellular mechanisms underlying kidney fibrosis. We have shown that changes in the cell’s skeleton (cytoskeleton) play a major role in turning healthy kidney cells to scar-inducing cells. We found that injury activates a central cell skeleton-reorganizing molecule, called RhoA. Interestingly, the loss of PC1/2 also activates RhoA. Moreover, our recent findings suggest that RhoA activation and the consequent cascade of events may be central to fragmentation of mitochondria as well. Thus, we wish to find out how RhoA is activated in PKD and how that leads to reshaping of mitochondria. To achieve these goals, we will use a host of modern biochemical and cell biological techniques. We will not only genetically eliminate PC1 or PC2 from normal kidney cells, but will also culture kidney cells from PKD patients, isolated by our collaborators (Drs. Wandinger-Ness and Bacallao). Using these and extending our long-term collaboration with Dr. Szaszi, we will identify molecules that connect PC1/2 to the regulation of the cell’s skeleton and the latter to mitochondria. These unique, state-of-the art tools will enable us to uncover a new pathway that may be critically important in PKD. We will also test whether and how various drugs that prevent the reorganization of the cell’s skeleton can recuse mitochondria and restore their normal shape and function.

Outcomes and Conclusions: Our studies will unravel a hitherto unrecognized mechanism that may have a fundamental role in PKD. They will unravel how a major metabolic organelle is disrupted in the most common genetic disorder of the kidney and how this phenomenon contributes to the central features of PKD. Our studies will also pave the road to novel, mitochondrion-protective drug therapies, ameliorating PKD.

Patient engagement: In addition to publishing our data in scientific journals, we will organize reach-out sessions to highlight our goals and results for the community of PKD patients. We can get excellent help for this endeavor from the Kidney Foundation of Canada and the PKD Consortium in the USA. We wish to communicate how basic science strives to improve the conditions and prognosis of people living with PKD.