Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder where clusters of cysts
develop in the kidneys. Still, despite being most often caused by mutations in PKD1 or PKD2 (encoding the
polycystin 1, PC1, and polycystin 2, PC2, proteins, respectively), disease presentation is phenotypically
heterogeneous. Most ADPKD patients have reduced quality and length of life, and while tolvaptan was
approved as the first and only ADPKD therapy, it does not cure ADPKD, shows no benefit for other PKD
manifestations, is associated with liver toxicity, and is expensive. Novel approaches to identifying and
prioritizing ADPKD biomarkers and therapeutic candidates are desperately needed. Mitochondrial dysfunction
and preference for aerobic glycolysis (i.e., the Warburg effect) over oxidative phosphorylation (oxphos) are
suggested hallmarks of ADPKD based on both animal models and ADPKD patient tissue studies.
Mitochondrial differences have been shown broadly to account for much of the observed variation in gene
expression, alternative splicing (also known to promote the Warburg effect), translation, and, ultimately, protein
levels. Intriguingly, in PKD kidney tissues and single-cell profiles, thousands of genes are differentially
expressed, the PC1-PC2 complex can regulate oxphos directly by mediating mitochondrial calcium uptake and
indirectly through multiple mechanisms (e.g., maintaining mitochondrial DNA copy number, mtCN), and
mitochondrial abnormalities have been shown to promote cyst formation and act as a modifier of disease
progression. We anticipate that similar to other conditions where mitochondria have central disease
pathogenesis roles, cell-specific mitochondrial dysfunction, metabolic reprogramming, and transcriptional
diversity are critical for renal cystogenesis and progression and are suitable disease biomarkers and
therapeutic targets. With innovative genomics and data science approaches, we will profile ADPKD mouse
model kidney tissue and patient urinary cells with mitochondrial single-cell ATAC-Seq (mtscATAC-Seq) and
long-read single-cell RNA-Seq (lrscRNA-Seq). We will test the hypotheses that a greater number of cell types
and proportion of cells are impacted by mitochondria dysfunction in rapidly compared to slowly progressive
ADPKD (Aim 1) and that proximal tubular cell alternative gene splicing and glycolysis and oxphos molecular
signatures distinguish slow from rapidly progressive ADPKD (Aim 2). This proposal is responsive to the Katz
program, does not include unpublished data, and targets research different from the Lasseigne Lab’s previous
focus and training (i.e., mitochondrial and metabolic contributions to disease, kidney cyst pathophysiology). In
addition to depositing all data in GEO and hosting version-controlled code with a digital object identifier on
Zenodo, we will develop an interactive web application to make the ADPKD mtscATAC-Seq and lrscRNA-Seq
maps widely available. Collectively these studies have the potential to transform unmet clinical ADPKD needs
by prioritizing biomarkers for monitoring disease progression and prioritizing precision-targeted therapeutics.
