A hyperfused mitochondrial state achieved at G ₁ –S regulates cyclin E buildup and entry into S phase

Abstract

Mitochondria undergo fission-fusion events that render these organelles highly dynamic in cells. We report a relationship between mitochondrial form and cell cycle control at the G1-S boundary. Mitochondria convert from isolated, fragmented elements into a hyperfused, giant network at G1-S transition. The network is electrically continuous and has greater ATP output than mitochondria at any other cell cycle stage. Depolarizing mitochondria at early G1 to prevent these changes causes cell cycle progression into S phase to be blocked. Inducing mitochondrial hyperfusion by acute inhibition of dynamin-related protein-1 (DRP1) causes quiescent cells maintained without growth factors to begin replicating their DNA and coincides with buildup of cyclin E, the cyclin responsible for G1-to-S phase progression. Prolonged or untimely formation of hyperfused mitochondria, through chronic inhibition of DRP1, causes defects in mitotic chromosome alignment and S-phase entry characteristic of cyclin E overexpression. These findings suggest a hyperfused mitochondrial system with specialized properties at G1-S is linked to cyclin E buildup for regulation of G1-to-S progression.cell cycle ͉ mitochondrial morphology ͉ dynamin-related protein 1

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“…Progression from G1 to S phase during the cell cycle was shown to depend on hyperfusion of mitochondria. Also, mitochondrial fission was increased during mitosis [60][61][62]. These results further strengthen the general view that mitochondrial dynamics is strictly regulated at several levels (for a review see [63]).…”

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