Rhythms in Energy Storage Control the Ability of the Cyanobacterial Circadian Clock to Reset

Circadian clocks are oscillatory systems that schedule daily
rhythms of organismal behavior. The ability of the clock
to reset its phase in response to external signals is critical
for proper synchronization with the environment. In the
model clock from cyanobacteria, the KaiABC proteins that
comprise the core oscillator [1, 2] are directly sensitive to
metabolites. Reduced ATP/ADP ratio and oxidized quinones
cause clock phase shifts in vitro [3, 4]. However, it is unclear
what determines the metabolic response of the cell to darkness
and thus the magnitude of clock resetting. We show
that the cyanobacterial circadian clock generates a rhythm
in metabolism that causes cells to accumulate glycogen in
anticipation of nightfall. Mutation of the histidine kinase
CikA creates an insensitive clock-input phenotype by misregulating
clock output genome wide, leading to overaccumulation
of glycogen and subsequently high ATP in the dark.
Conversely, we show that disruption of glycogen metabolism
results in low ATP in the dark and makes the clock
hypersensitive to dark pulses. The observed changes in
cellular energy are sufficient to recapitulate phase-shifting
phenotypes in an in vitro model of the clock. Our results
show that clock-input phenotypes can arise from metabolic
dysregulation and illustrate a framework for circadian
biology where clock outputs feed back through metabolism
to control input mechanisms.