Mitochondrial Morphologies Driven by Energy-Consuming Cell Sites in a Spatially and Time-Resolved Quality Model.

Mitochondria are the energy plants of eukaryotic cells. Mitochondrial network morphologies are essential for the energy supply of eukaryotic cells. However, the associated dynamics are not yet fully understood. They behave as a dynamic network that adapts to the cell's environment and its energetic needs. Various processes such as mitochondrial fission and fusion, mitochondrial recycling, repair mechanisms, and oxidative stress influence the state of the mitochondrial network. Here, we introduce a novel time-dependent and spatially resolved quality model on mitochondrial morphology. The interplay between the mitochondrial network and energy-consuming cell sites is modeled by biophysical interactions of quality-dependent mitochondrial clusters in the presence of adenosine triphosphate (ATP) consumers represented by Mie potentials. Mitochondria are modeled as simplified ballistic particles that move within the cytoplasm of a virtual cell, and connect and divide by inelastic collisions. With this model, we investigate the coupling of mitochondrial dynamics with oscillating cell functions, representing diverse global states of the energetic architecture in the cell. Our simulations based on a generalized cell reveal a perinuclear condensation of mitochondria during phases of high-energy demand. Furthermore, quality-increasing mechanisms disclose the benefits of high mitochondrial masses. Simulations reveal that varying energy demands modeled by oscillations of ATP consumers alter the morphology of the network. Phases of high-energy consumption lead to interconnected network structures and perinuclear condensation of mitochondria. The model explains quality-increasing benefits of high mitochondrial masses.

Fragmentation of the mitochondrial network in skin in vivo.

Mitochondria form dynamic networks which adapt to the environmental requirements of the cell. We investigated the aging process of these networks in human skin cells in vivo by multiphoton microscopy. A study on the age-dependency of the mitochondrial network in young and old volunteers revealed that keratinocytes in old skin establish a significantly more fragmented network with smaller and more compact mitochondrial clusters than keratinocytes in young skin. Furthermore, we investigated the mitochondrial network during differentiation processes of keratinocytes within the epidermis of volunteers. We observe a fragmentation similar to the age-dependent study in almost all parameters. These parallels raise questions about the dynamics of biophysical network structures during aging processes.

Quality Saving Mechanisms of Mitochondria during Aging in a Fully Time-Dependent Computational Biophysical Model.

Mitochondria are essential for the energy production of eukaryotic cells. During aging mitochondria run through various processes which change their quality in terms of activity, health and metabolic supply. In recent years, many of these processes such as fission and fusion of mitochondria, mitophagy, mitochondrial biogenesis and energy consumption have been subject of research. Based on numerous experimental insights, it was possible to qualify mitochondrial behaviour in computational simulations. Here, we present a new biophysical model based on the approach of Figge et al. in 2012. We introduce exponential decay and growth laws for each mitochondrial process to derive its time-dependent probability during the aging of cells. All mitochondrial processes of the original model are mathematically and biophysically redefined and additional processes are implemented: Mitochondrial fission and fusion is separated into a metabolic outer-membrane part and a protein-related inner-membrane part, a quality-dependent threshold for mitophagy and mitochondrial biogenesis is introduced and processes for activity-dependent internal oxidative stress as well as mitochondrial repair mechanisms are newly included. Our findings reveal a decrease of mitochondrial quality and a fragmentation of the mitochondrial network during aging. Additionally, the model discloses a quality increasing mechanism due to the interplay of the mitophagy and biogenesis cycle and the fission and fusion cycle of mitochondria. It is revealed that decreased mitochondrial repair can be a quality saving process in aged cells. Furthermore, the model finds strategies to sustain the quality of the mitochondrial network in cells with high production rates of reactive oxygen species due to large energy demands. Hence, the model adds new insights to biophysical mechanisms of mitochondrial aging and provides novel understandings of the interdependency of mitochondrial processes.