CAP1 deficiency protects podocytes in diabetic kidney disease by reducing mitochondria-associated endoplasmic reticulum membrane formation and mitochondrial fission

The mitochondria-associated endoplasmic reticulum membrane (MAM) is crucial for mitochondrial homeostasis. Excessive mitochondrial fission has been recognized as an early pathological event in podocyte injury in diabetic kidney disease (DKD). Cyclase-associated protein 1 (CAP1), an actin-binding protein, has been implicated as a potential regulator of mitochondrial dynamics; however, its role in DKD remains unclear. This study revealed that increased MAM formation is associated with excessive mitochondrial fission in podocytes from DKD patients. Podocyte-specific CAP1 knockdown significantly ameliorated podocyte injury and albuminuria in diabetic mice, with the protective effect attributed to the inhibition of MAM formation and mitochondrial fission. Mechanistically, high glucose triggered the CAP1-induced actin depolymerization, which promoted the enrichment of inverted formin 2 (INF2) from the endoplasmic reticulum (ER) to the MAM. At the MAM interface, the protein interaction between CAP1 and the enriched INF2 was enhanced, thereby exacerbating mitochondrial fission and dysfunction, which ultimately led to podocyte injury. Our findings not only provide the first evidence for the pathogenic role of CAP1 in podocytes during DKD progression, but also elucidate a novel mechanism by which CAP1 modulates mitochondrial fission via the MAM.

Actin; Cyclase-associated protein 1; Diabetic kidney disease; Mitochondria-associated endoplasmic reticulum membrane; Mitochondrial fission.