Agent-Based Modeling of Mitochondria Links Sub-Cellular Dynamics to Cellular Homeostasis and Heterogeneity

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.

Mitochondrial fusion, fission, and mitochondrial toxicity

“…Mitochondrial dynamics may be altered in some cell types by circadian rhythms (Manella and Asher 2016) and as a function of age (Seo et al 2010). Finally, recent modeling efforts suggest that low mitochondrial mass impedes production of a more-networked morphology, again illustrating the interdependence of mitochondrial parameters (Dalmasso et al 2017). …”

“…In cell culture, fusion and fission can occur within minutes or even seconds, particularly in the case of rapid stress-induced fission or transient, partial fusion events described as “kiss-and-run” (Dalmasso et al 2017; Duarte et al 2012; Liu et al 2009). At the cellular level, mixing of contents between mitochondria can occur within an hour (Youle and van der Bliek 2012); however, there is also evidence that heterogeneous mitochondrial sub-populations persist within cells in some cases (Wikstrom et al 2009).…”

“…The relative rates of these two processes at any given time in specific tissues are not well understood (Mishra and Chan 2016), but presumably act in an integrated fashion to regulate both morphology and the potential rate at which morphology can be altered. This may also relate to the rate of movement of mitochondria in the cells, estimated to be ~0.1–0.2 μm/second in the perinuclear region and up to ~0.7 μm/second in the cytosol and in axons (Dalmasso et al 2017). …”

“…In most cases, initiation of mitophagy is somewhat slower than fusion and fission, occurring over minutes to hours, although some forms of mitophagy are faster than others (Lemasters 2014). Mitobiogenesis is slower yet, requiring hours or more (Dalmasso et al 2017). Finally, as was the case for fusion and fission genes, many proteins involved in these processes also participate in other biological functions.…”

“…Loss of membrane potential, which contributes to mitophagy via PINK1-mediated Parkin activation, can also inhibit mitochondrial fusion and mobility because Parkin can also ubiquinate mitofusins and Miro1 (involved in mitochondrial transport), leading to their degradation (Narendra et al 2012), and loss of membrane potential leads to OPA1 degradation (Head et al 2009). Additional mitochondrial parameters can also be altered, including energetics and calcium homeostasis (Archer 2013; Benard et al 2007; Dalmasso et al 2017; Mishra and Chan 2016). Thus, experimental manipulation of one parameter may cause other deleterious or compensatory responses.…”