Abstract
Mitochondria are semi-autonomous organelles that supply energy for cellular biochemistry through oxidative phosphorylation. Within a cell, hundreds of mobile mitochondria undergo fusion and fission events to form a dynamic network. These morphological and mobility dynamics are essential for maintaining mitochondrial functional homeostasis, and alterations both impact and reflect cellular stress states. Mitochondrial homeostasis is further dependent on production (biogenesis) and the removal of damaged mitochondria by selective autophagy (mitophagy). While mitochondrial function, dynamics, biogenesis and mitophagy are highly-integrated processes, it is not fully understood how systemic control in the cell is established to maintain homeostasis, or respond to bioenergetic demands. Here we used agent-based modeling (ABM) to integrate molecular and imaging knowledge sets, and simulate population dynamics of mitochondria and their response to environmental energy demand. Using high-dimensional parameter searches we integrated experimentally-measured rates of mitochondrial biogenesis and mitophagy, and using sensitivity analysis we identified parameter influences on population homeostasis. By studying the dynamics of cellular subpopulations with distinct mitochondrial masses, our approach uncovered system properties of mitochondrial populations: (1) mitochondrial fusion and fission activities rapidly establish mitochondrial sub-population homeostasis, and total cellular levels of mitochondria alter fusion and fission activities and subpopulation distributions; (2) restricting the directionality of mitochondrial mobility does not alter morphology subpopulation distributions, but increases network transmission dynamics; and (3) maintaining mitochondrial mass homeostasis and responding to bioenergetic stress requires the integration of mitochondrial dynamics with the cellular bioenergetic state. Finally, (4) our model suggests sources of, and stress conditions amplifying, cell-to-cell variability of mitochondrial morphology and energetic stress states. Overall, our modeling approach integrates biochemical and imaging knowledge, and presents a novel open-modeling approach to investigate how spatial and temporal mitochondrial dynamics contribute to functional homeostasis, and how subcellular organelle heterogeneity contributes to the emergence of cell heterogeneity.
Highlights
Mitochondria are essential sources of ATP, and their morphology is dynamic; mitochondria are highly mobile within a cell [1, 2] and undergo fusion and fission events, resulting in a continuum of morphologies among populations of mitochondria, from tubular to small puncta [3]
As morphologies of individual mitochondria are heterogeneous within a cell and among cell types [3], we introduced a continuous range of mitochondrial masses, from a minimum value (Mmin) of 0.5 μm2 [31] to a maximum value (Mmax) of 3 μm2 [32, 33] (Fig 1A)
Each constrained to the following respective range: mitophagy receptor (MR) threshold (0–30), fission probability (0–100), initial mitochondrial mass (50–500), fusion frequency (0–30), fusion probability (0–100), damage probability (0–100), damage threshold (0– 30), degradation frequency (0–30), ratio low/high damage (0–100), fission frequency (0–30) and biogenesis frequency (0–30)
Summary
Mitochondria are essential sources of ATP, and their morphology is dynamic; mitochondria are highly mobile within a cell [1, 2] and undergo fusion and fission events, resulting in a continuum of morphologies among populations of mitochondria, from tubular to small puncta [3]. Frequency of fusion and fission cycles determines efficiency of mitophagy [9], and suggests that altered cycles in aging organisms may contribute to maintaining mitochondrial mass [10]. Mitochondrial mobility has been predicted to have a role in maintaining a healthy mitochondrial population [12]. Of note, these studies did not address how morphological states and mass homeostasis coordinate bioenergetic supply and demand. In this study, we sought to analyze how reactions of individual mitochondria form a collective population response, to organize morphological states and maintain mass homeostasis, under basal conditions and in response to bioenergetic stress
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