Fibrogenesis: Fibrogenic Cells, Their Origins, and a Site for Therapeutic Targeting

Cell Stress and Mitochondrial Dysfunction

Mitochondrial dysfunction has been implicated as an important, if not central, problem in chronic human diseases, including neurological diseases, cancer, and, more recently, chronic kidney disease. In normal tissue, mitochondria function as the metabolic powerhouses of the cell, producing energy in the form of ATP and regulating many aspects of metabolic homeostasis. The generation of energy through oxidative phosphorylation leads to the creation of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, which are normally regulated through a tightly controlled network of ROS scavenging proteins. However, when this controlled network is not functioning properly, there is an increase in cellular ROS and a propagation of free radicals, causing damage to the cell and precipitating disease.

Recently, our group identified microRNA-21 (miR-21) as an important miRNA that is upregulated in kidney diseases. MiR-21 acts to accelerate kidney disease by blocking mitochondrial biogenesis and, in so doing, exacerbates mitochondrial dysfunction. We have shown that highly specific oligonucleotides that inhibit miR-21 markedly retard the progression of kidney diseases, and this treatment is now in early clinical trials as a therapy for Alport syndrome.

We have also discovered that the normal recycling of defunct mitochondria by autophagy (mitophagy) is a critical homeostatic function that may be deficient in kidney diseases. When cellular autophagy is blocked in the kidney by genetic deletion of critical autophagy genes, animals develop spontaneous disease highly similar to human Focal and Segmental Glomerulosclerosis. This model is characterized by severe mitochondrial dysfunction with significant accumulation of ROS, which precedes the onset of disease.

Currently, we are actively investigating mitochondrial dysfunction and deficient mitophagy as proximal drivers of kidney disease, inflammation, and fibrosis.