PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization

doi:10.1083/jcb.202508040

PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization

2026-04-01

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DOI：10.1083/jcb.202508040

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Mitochondria form highly complex and dynamic networks to maintain their homeostasis. However, the underlying mechanisms remain elusive. Here we report a PI(3)P-dependent mechanism that regulates the mitochondrial dynamics required for formation of mitochondrial networks. Using genetic screening, we reveal that mutations of Caenorhabditis elegans EXC-5/FGD lead to formation of spherical and unconnected mitochondria. EXC-5 binds to endosomal PI(3)P generated by the PI 3-kinase VPS-34 and is recruited to endosome-mitochondrion contacts, where it acts as the guanine nucleotide exchange factor to activate the CDC-42 GTPase. Loss of exc-5 or vps-34 similarly disrupts mitochondrial and actin networks as well as mitochondrial recruitment of DRP-1, leading to failure of mitochondrial fission, branching, and elongation. In contrast, expression of constitutively activated CDC-42 ameliorates the defective mitochondrial networks in an actin-dependent manner. Together, these findings suggest a PI(3)P-EXC-5-CDC-42 axis that acts at endosome-mitochondrion contacts to regulate actin organization for maintenance of mitochondrial dynamics and networks.

Keywords:

FACIOGENITAL DYSPLASIA

ARP2/3 COMPLEX

FISSION

HOMEOSTASIS

DIVISION

CDC42

DRP1

PI(3)P regulates mitochondrial dynamics through FGD-dependent actin organization

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