Abstract
Temporal organization of biological processes requires massively parallel processing on a synchronized time-base. We analyzed time-series data obtained from the bioenergetic oscillatory outputs of Saccharomyces cerevisiae and isolated cardiomyocytes utilizing Relative Dispersional (RDA) and Power Spectral (PSA) analyses. These analyses revealed broad frequency distributions and evidence for long-term memory in the observed dynamics. Moreover RDA and PSA showed that the bioenergetic dynamics in both systems show fractal scaling over at least 3 orders of magnitude, and that this scaling obeys an inverse power law. Therefore we conclude that in S. cerevisiae and cardiomyocytes the dynamics are scale-free in vivo. Applying RDA and PSA to data generated from an in silico model of mitochondrial function indicated that in yeast and cardiomyocytes the underlying mechanisms regulating the scale-free behavior are similar. We validated this finding in vivo using single cells, and attenuating the activity of the mitochondrial inner membrane anion channel with 4-chlorodiazepam to show that the oscillation of NAD(P)H and reactive oxygen species (ROS) can be abated in these two evolutionarily distant species. Taken together these data strongly support our hypothesis that the generation of ROS, coupled to redox cycling, driven by cytoplasmic and mitochondrial processes, are at the core of the observed rhythmicity and scale-free dynamics. We argue that the operation of scale-free bioenergetic dynamics plays a fundamental role to integrate cellular function, while providing a framework for robust, yet flexible, responses to the environment.
Highlights
In their long evolutionary history, unicellular and multicellular organisms have pursued the two divergent, complementary, goals of matching the time dependencies of their internal environments with the periodicities of the external world, and optimizing for tolerance to external perturbation [1,2,3,4,5]
Multi-oscillatory behavior and fractal dynamics in yeast cultures It has previously been observed that yeast can produce multiple frequencies when grown continuously under precisely controlled conditions
By Relative Dispersional (RDA) and Power Spectral (PSA) (Fig. 4 A–C, and F–H) we show that mitochondrial dynamics in cardiomyocytes exhibit, as in the evolutionarily distant yeast, a fractal behavior of their temporal organization
Summary
In their long evolutionary history, unicellular and multicellular organisms have pursued the two divergent, complementary, goals of matching the time dependencies of their internal environments with the periodicities of the external world (i.e. the elaboration of annual, seasonal, daily and tidal rhythms), and optimizing for tolerance to external perturbation [1,2,3,4,5]. The provision of energy, biosynthetic pathways, assembly of multimeric proteins, membranes and organelles, stress responses, cell differentiation, migration and cell division require temporal organization on many time scales simultaneously [10,11,12,13] This complex biological timing requires more than circadian organization; coordination on the ultradian domain (i.e. faster time scales where clocks cycle many times in a day) is essential. It is evident that additional clocks are required, for instance, a circahoralian clock provides a time base on a scale of hours [14] while faster rhythms or oscillations measured in minutes [15,16], seconds [17] or milliseconds [18] abound in biological systems. This leads to the central but enigmatic questions in biological timekeeping of whether synchrony occurs between these disparate oscillators, and how function correlates across different time domains
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