Alessandra Boletta

The tumor suppressor KDM6A / UTX , a histone demethylase and a 2-oxoglutarate-dependent dioxygenase, is frequently lost in many cancer types. We show that KDM6A loss pervasively activates oxidative phosphorylation in several solid tumors, generating a pseudo-hyperoxic environment, opposite from the pseudo-hypoxia observed in VHL-mutated renal carcinomas. Mechanistically, KDM6A sustains the expression of the coil-coil domain gene CCDC3 , which inhibits CREB1-driven transcription of the mitochondrial regulator PPARGC1A. In the hematological cancer multiple myeloma where KDM6A is frequently deleted, its loss similarly promotes oxidative phosphorylation, but via an alternative mechanism: the increased transfer of mitochondria from stromal to myeloma cells via tunneling nanotubes, triggered by the loss of the mTORC1 inhibitor TRAF3IP3 . Beyond cancer, KDM6A regulates oxidative phosphorylation also during development and in adult tissues, engaging either the CCDC3-CREB1 or the TRAF3IP3-mTORC1 pathways. These mutually exclusive associations suggest a tissue-level convergent evolution, positioning KDM6A as a central modulator of mitochondrial activity through context-specific partners.

Polycystic kidney disease (PKD) encompasses a class of disorders presenting with bilateral cyst formation in the kidney. PKD can be inherited as a dominant (ADPKD) or a recessive (ARPKD) trait, due to mutations into multiple genes, the most frequent being PKD1, PKD2, and PKHD1. The protein products of these genes (polycystin-1, polycystin-2, and fibrocystin, respectively) have been shown to reside within the primary cilium or to be important for the maturation and trafficking of proteins to the primary cilium. The primary cilium is an organelle protruding from the apical surfaces of renal epithelial cells that functions to sense extracellular signals and translate them into intracellular biochemical information. PKD represents the most common monogenic disorder affecting the kidney and the most common manifestation of human ciliopathies. The precise functions of the polycystin and fibrocystin proteins have not yet been fully elucidated nor have the molecular basis underlying the renal tubule cyst formation that occurs in the absence of sufficient functional expression of these proteins. The genes that are muted in PKD were cloned three decades ago, and since their identification, a wealth of information regarding their structure, cell biology, and physiological properties has been developed. Here, we provide a broad review of the relevant literature and summarize a large body of experimental evidence, while focusing particularly on more recent findings that are poised to change our understanding of the field.

Primary cilia are solitary organelles formed by a microtubule-based skeleton protruding in a single copy on the surface of most cells. Alterations in their function cause a plethora of human conditions collectively called the ciliopathies. The kidney is frequently and severely affected in the ciliopathies, presenting with a spectrum of phenotypes. Cyst formation is a common trait of all renal ciliopathies. Besides this common manifestation, however, the renal ciliopathies present with profoundly different phenotypes, resulting in either polycystic kidney disease (PKD) or nephronophthisis (NPH) phenotypes. The past decade has seen a surge of studies highlighting metabolic reprogramming as a major feature of PKD, with a distinct involvement of mitochondrial dysfunction. This discovery has brought forward the development of novel therapeutic approaches. More recent evidence suggests that primary cilia modulate the mitochondrial production of energy in response to environmental cues. Here, we summarize the evidence available to date and propose a more general involvement of metabolic and mitochondrial alterations in the renal ciliopathies that might in principle help defining the profoundly different, and potentially opposite, manifestations observed.

In this issue of EMBO Molecular Medicine, Sun and colleagues report the development of a novel therapeutic approach, and preclinical proof-of-concept evidence of its efficacy, for Autosomal Dominant Polycystic Kidney Disease (ADPKD) (Sun et al, 2024).

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Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns -ASO or Scr -ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns -ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns -ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD₁₅, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1^V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD₁₅ enhances renal cystogenesis without inducing pancreatic cysts in Pkd1^V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD₁₅ cleavage, crucial for cystogenesis mechanisms.

Polycystic Kidney Disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4-ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns -ASO or Scr -ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo . Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns -ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns -ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.