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Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
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Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
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Journal Article
Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
2023
Overview
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, ICD
15
, 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 ICD
15
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 ICD
15
cleavage, crucial for cystogenesis mechanisms.
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by
PKHD1
which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 147/143
/ 38
/ 49/109
/ 631/208
/ 631/337
/ 64/60
/ 692/308
/ 82/1
/ 82/29
/ 82/80
/ Animals
/ Cleavage
/ Coding
/ Cysts
/ Humanities and Social Sciences
/ Kidneys
/ Mice
/ Pancreas
/ Polycystic kidney disease 1 protein
/ Polycystic Kidney, Autosomal Recessive - metabolism
/ Receptors, Cell Surface - metabolism
/ Science
/ TRPP Cation Channels - genetics
/ TRPP Cation Channels - metabolism
/ Tubules
